Pulmonary Fibrosis, Emphysema, COPD Stem Cell Treatment

Stem Cell Therapy Pulmonary Fibrosis

 

Stem Cell Treatment for Pulmonary Fibrosis and COPD are now available at ASCI

Pulmonary fibrosis is the formation or development of excess fibrous connective tissue (fibrosis) in the lungs. It is also described as "scarring of the lung."

Pulmonary fibrosis is suggested by a history of progressive shortness of breath (dyspnea) with exertion. Sometimes fine inspiratory crackles can be heard at the lung bases on auscultation. A chest x-ray may or may not be abnormal, but high Resolution CT will frequently demonstrate abnormalities.

Symptoms

Symptoms of pulmonary fibrosis are mainly:

  • Shortness of breath, particularly with exertion
  • Chronic dry, hacking coughing
  • Fatigue and weakness
  • Chest discomfort
  • Loss of appetite and rapid weight loss

Stem Cell Therapy Pulmonary Fibrosis and COPD

Possible Causes

Pulmonary fibrosis may be a secondary effect of other diseases. Most of these are classified as interstitial lung diseases. Examples include autoimmune disorders, viral infections or other microscopic injuries to the lung. However, pulmonary fibrosis can also appear without any known cause. In this case, it is termed "idiopathic". Most idiopathic cases are diagnosed as idiopathic pulmonary fibrosis. This is a diagnosis of exclusion of a characteristic set of histologic/pathologic features known as usual interstitial pneumonia (UIP). In either case, there is a growing body of evidence which points to a genetic predisposition in a subset of patients. For example, a mutation in Surfactant protein C (SP-C) has been found to exist in some families with a history of pulmonary fibrosis.

Diseases and conditions that may cause pulmonary fibrosis as a secondary effect include:

  • Inhalation of environmental and occupational pollutants, such as in asbestosis, silicosis and exposure to certain gases. Coal miners, ship workers and sand blasters among others are at higher risk. Hypersensitivity pneumonitis, most often resulting from inhaling dust contaminated with bacterial, fungal, or animal products.
  • Cigarette smoking can increase the risk or make the illness worse.
  • Some typical connective tissue diseases such as rheumatoid arthritis and Scleroderma. Other diseases that involve connective tissue, such as sarcoidosis and Wegener's granulomatosis.
  • Infections
  • Certain medications, e.g. amiodarone, bleomycin, busulfan, methotrexate, and nitrofurantoin
  • Radiation therapy to the chest.

Stem Cell Treatments for Pulmonary Fibrosis and COPD. Pulmonary Fibrosis and COPD and Stem Cell studies and protocols from the NIH:

Related Articles GeneReviews(®) Book. 1993 Authors: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong CT, Smith RJH, Stephens K Abstract DISEASE CHARACTERISTICS: Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder of phagocytes (neutrophils, monocytes, macrophages, and eosinophils) resulting from impaired killing of bacteria and fungi. CGD is characterized by severe recurrent bacterial and fungal infections and dysregulated inflammatory response resulting in granuloma formation and other inflammatory disorders such as colitis. Infections typically involve the lung (pneumonia), lymph nodes (lymphadenitis), liver (abscess), bone (osteomyelitis), and skin (abscesses or cellulitis); granulomas typically involve the genitourinary system (bladder) and gastrointestinal track (often the pylorus initially, and later the esophagus, jejunum, ileum, cecum, rectum, and perirectal area). Some males with X-linked CGD have McLeod neuroacanthocytosis syndrome as the result of a contiguous gene deletion. CGD may present any time from infancy to late adulthood; however, the vast majority of affected individuals are diagnosed before age five years. Use of antimicrobial prophylaxis and therapy has greatly improved overall survival. DIAGNOSIS/TESTING: CGD is diagnosed by tests that measure neutrophil superoxide production via the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex: the dihydrorhodamine (DHR) test has largely replaced the nitroblue tetrazolium (NBT) test, the oldest and most recognized diagnostic test for CGD. CGD is caused by mutation of one of five genes that encode the subunits of phagocyte NADPH oxidase: biallelic mutations in CYBA, NCF1, NCF2, and NCF4 cause autosomal recessive CGD (AR-CGD); mutation of CYBB causes X-linked CGD. MANAGEMENT: Treatment of manifestations: A definitive microbiologic diagnosis is essential to proper treatment of infections. Newer azole drugs (voriconazole and posaconazole) have expanded therapeutic options for fungal infections. Long courses of antimicrobials are often needed for adequate treatment. Abscesses may require percutaneous drainage or excisional surgery. Simultaneous administration of antimicrobials and corticosteroids can help resolve the associated heightened inflammatory response, including colitis. Prevention of primary manifestations: Allogeneic hematopoietic stem cell transplantation (HSCT) is the only known cure for CGD; however, indications for HSCT are yet to be resolved. Antibacterial and antifungal prophylaxis is the cornerstone of prevention; immunomodulatory therapy with interferon gamma (IFN-gamma) is part of the prophylactic regimen in many centers. Surveillance: Regular follow-up visits can aid in early detection and treatment of asymptomatic or minimally symptomatic infections and non-infectious complications such as colitis, pulmonary granulomas, and pulmonary fibrosis. Agents/circumstances to avoid: (1) Decayed organic matter (e.g., mulching, gardening, leaf raking, house demolition) as inhalation of fungal spores can result in fulminant pneumonitis; (2) Persons with CGD and McLeod neuroacanthocytosis syndrome: blood transfusions that are Kell antigen positive. Evaluation of relatives at risk: Early diagnosis of relatives at risk allows prompt initiation of antimicrobial prophylaxis and other treatment. Pregnancy management: The major concern during the pregnancy of a woman known to have CGD is use of prophylactic antimicrobials: trimethoprim, a folic acid antagonist, is discontinued during pregnancy because of the high risk for birth defects. Although sulfamethoxazole is not known to increase the risk of birth defects in humans, it is typically administered in conjunction with trimethoprim; data regarding teratogenicity of itraconazole are limited. GENETIC COUNSELING: Granulomatous disease associated with mutation in CYBB is inherited in an X-linked manner. Chronic granulomatous disease associated with biallelic mutations in CYBA, NCF1, NCF2, or NCF4 is inherited in an autosomal recessive manner. X-linked CGD. If the mother of an affected male has a disease-causing mutation, the chance of transmitting it in each pregnancy is 50%. Males who inherit the mutation will be affected; females who inherit the mutation will be carriers and will usually not be affected. AR-CGD. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutation(s) in a family are known. PMID: 22876374
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Related Articles Fibrotic and sclerotic manifestations of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2012 Jan;18(1 Suppl):S46-52 Authors: Kitko CL, White ES, Baird K PMID: 22226112 [PubMed - indexed for MEDLINE]
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Related Articles Alveolar epithelial type II cells from embryonic stem cells: knights in shining armour? Eur Respir J. 2012 Feb;39(2):240-1 Authors: Fehrenbach H PMID: 22298611 [PubMed - indexed for MEDLINE]
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Related Articles Adult stem cells underlying lung regeneration. Cell Cycle. 2012 Mar 1;11(5):887-94 Authors: Xian W, McKeon F Abstract Despite the massive toll in human suffering imparted by degenerative lung disease, including COPD, idiopathic pulmonary fibrosis and ARDS, the scientific community has been surprisingly agnostic regarding the potential of lung tissue, and in particular the alveoli, to regenerate. However, there is circumstantial evidence in humans and direct evidence in mice that ARDS triggers robust regeneration of lung tissue rather than irreversible fibrosis. The stem cells responsible for this remarkable regenerative process has garnered tremendous attention, most recently yielding a defined set of cloned human airway stem cells marked by p63 expression but with distinct commitment to differentiated cell types typical of the upper or lower airways, the latter of which include alveoli-like structures in vitro and in vivo. These recent advances in lung regeneration and distal airway stem cells and the potential of associated soluble factors in regeneration must be harnessed for therapeutic options in chronic lung disease. PMID: 22333577 [PubMed - indexed for MEDLINE]
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Related Articles Role of bone marrow-derived mesenchymal stem cells in the prevention of hyperoxia-induced lung injury in newborn mice. Cell Biol Int. 2012 Jun 1;36(6):589-94 Authors: Zhang X, Wang H, Shi Y, Peng W, Zhang S, Zhang W, Xu J, Mei Y, Feng Z Abstract BPD (bronchopulmonary dysplasia) is predominantly characterized by persistent abnormalities in lung structure and arrested lung development, but therapy can be palliative. While promising, the use of BMSC (bone marrow-derived mesenchymal stem cell) in the treatment of lung diseases remains controversial. We have assessed the therapeutic effects of BMSC in vitro and in vivo. In vitro co-culturing with injured lung tissue increased the migration-potential of BMSC; and SP-C (surfactant protein-C), a specific marker of AEC2 (type II alveolar epithelial cells), was expressed. Following intraperitoneal injection of BMSC into experimental BPD mice on post-natal day 7, it was found that BMSC can home to the injured lung, express SP-C, improve pulmonary architecture, attenuate pulmonary fibrosis and increase the survival rate of BPD mice. This work supports the notion that BMSC are of therapeutic benefit through the production of soluble factors at bioactive levels that regulate the pathogenesis of inflammation and fibrosis following hyperoxia. PMID: 22339670 [PubMed - indexed for MEDLINE]
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Related Articles [The experimental study of suppressing silicosis fibrosis]. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi. 2011 Oct;29(10):740-5 Authors: Weng ZP, Zhang JJ, Liu WW, Chen J, Liu YM, Yu W, Tang LJ, Chen JY, Fang M, Zhang C, Ye GX, Chen LZ, Zhong XY Abstract OBJECTIVE: To compare the difference of effects on SiO(2)-induced alveolitis and early fibrosis between bone marrow-derived mesenchymal-like stem cells (BM-MSCs) and BM-MSCs transfected by pcDNA3.1-HGF and to explore the mechanism of this effects. METHODS: The Primary BM-MSCs from Wistar male young rats were cultured and labeled by 4, 6-diamidino-2-phenylindole (DAPI). Fifty Wistar rats were randomly divided into 3 groups:model group (10 rats),which was administered with SiO(2) by the trache, the next day,injected PBS via the tail vein; BM-MSCs group (20 rats),which was administered with SiO(2) by the trache, the next day,injected with 1 ml suspension of BM-MSCs via the tail vein; pcDNA3.1-HGF plus BM-MSC group (20 rats),which was administered with SiO(2) by the trache, the next day,injected with 1 ml suspension of BM-MSCs transfected by pcDNA3.1-HGF via the tail vein. On the 14th and 28th days after treatment, half of the animals were sacrificed, respectively, and the lungs were harvested for frozen section to observe the cell marked by DAPI. HE staining under a fluorescent microscope, and to observe the pulmonary alveolitis and fibrosis by HE and Masson staining under a light microscope. Western blot assay was used to detect the expression of HGF in rat lungs. The expression levels of tumor necrosis factor-α (TNF-α) in pulmonary tissues were analyzed quantitatively by ELISA. The contents of HYP in pulmonary tissues were analyzed quantitatively by sample hydrolysis method. RESULTS: On the 14th and 28th days after treatment, the scores of pulmonary alveolitis and early fibrosis in pcDNA3.1-HGF plus BM-MSCs group were 2.36 ± 0.17, 2.8 ± 0.14 and 0.1 ± 0.11, 1.16 ± 0.13, which were significantly lower than those (1.68 ± 0.17, 1.58 ± 0.31 and 0.54 ± 0.15, 1.36 ± 0.13) in BM-MSCs group, also which were significantly lower those (2.36 ± 0.17, 2.80 ± 0.14 and 0.64 ± 0.09, 1.84 ± 0.17) in model group (P < 0.05); On the 14th and 28th days after treatment, the TNF-α contents of pulmonary tissues in pcDNA3.1-HGF plus BM-MSCs group were 280.4 ± 23.11 and 249.78 ± 22.33 pg/mg, which were significantly lower than those (341.58 ± 35.34, 442.29 ± 36.76 pg/mg and 319.51 ± 17.84, 348.53 ± 33.95 pg/mg) in BM-MSCs and model groups (P < 0.05); On the 14th and 28th days after treatment, the HYP contents of pulmonary tissues in pcDNA3.1-HGF plus BM-MSCs group were 0.46 ± 0.04 and 0.65 ± 0.05 µg/mg, which were significantly lower than those (0.63 ± 0.04, 1.04 ± 0.07 µg/mg and 0.72 ± 0.60, 1.39 ± 0.60 µg/mg) in BM-MSCs and model groups (P < 0.05). CONCLUSION: The effects of BM-MSCs transfected by pcDNA3.1-HGF on suppressing pulmonary alveolitis and early fibrosis induced by SiO2 were better than those of BM-MSCs. The mechanism may be associated with the reduced pulmonary inflammation. PMID: 22357488 [PubMed - indexed for MEDLINE]
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Related Articles Neonatal periostin knockout mice are protected from hyperoxia-induced alveolar simplication. PLoS One. 2012;7(2):e31336 Authors: Bozyk PD, Bentley JK, Popova AP, Anyanwu AC, Linn MD, Goldsmith AM, Pryhuber GS, Moore BB, Hershenson MB Abstract In bronchopulmonary dysplasia (BPD), alveolar septae are thickened with collagen and α-smooth muscle actin, transforming growth factor (TGF)-β-positive myofibroblasts. Periostin, a secreted extracellular matrix protein, is involved in TGF-β-mediated fibrosis and myofibroblast differentiation. We hypothesized that periostin expression is required for hypoalveolarization and interstitial fibrosis in hyperoxia-exposed neonatal mice, an animal model for this disease. We also examined periostin expression in neonatal lung mesenchymal stromal cells and lung tissue of hyperoxia-exposed neonatal mice and human infants with BPD. Two-to-three day-old wild-type and periostin null mice were exposed to air or 75% oxygen for 14 days. Mesenchymal stromal cells were isolated from tracheal aspirates of premature infants. Hyperoxic exposure of neonatal mice increased alveolar wall periostin expression, particularly in areas of interstitial thickening. Periostin co-localized with α-smooth muscle actin, suggesting synthesis by myofibroblasts. A similar pattern was found in lung sections of infants dying of BPD. Unlike wild-type mice, hyperoxia-exposed periostin null mice did not show larger air spaces or α-smooth muscle-positive myofibroblasts. Compared to hyperoxia-exposed wild-type mice, hyperoxia-exposed periostin null mice also showed reduced lung mRNA expression of α-smooth muscle actin, elastin, CXCL1, CXCL2 and CCL4. TGF-β treatment increased mesenchymal stromal cell periostin expression, and periostin treatment increased TGF-β-mediated DNA synthesis and myofibroblast differentiation. We conclude that periostin expression is increased in the lungs of hyperoxia-exposed neonatal mice and infants with BPD, and is required for hyperoxia-induced hypoalveolarization and interstitial fibrosis. PMID: 22363622 [PubMed - indexed for MEDLINE]
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Related Articles Scleroderma - new aspects in pathogenesis and treatment. Best Pract Res Clin Rheumatol. 2012 Feb;26(1):13-24 Authors: Balbir-Gurman A, Braun-Moscovici Y Abstract Systemic sclerosis (SSc) is a multisystem disease with a variable clinical course and a poor prognosis corresponding to extent of microangiopathy and skin and internal organ fibrosis. Microvascular damage provokes immune cells to produce autoantibodies, pro-inflammatory and pro-fibrotic cytokines and chemokines. The hallmark of SSc is excessive collagen production by activated fibroblasts and myofibroblasts, and its accumulation in skin and internal organs. Better understanding of SSc pathogenesis resulted in the development of drugs, such as prostanoids, endothelin-1 and phosphodiesterase inhibitors, for treatment of pulmonary arterial hypertension and digital ulcers. The use of biological therapies and anti-fibrotic agents is under investigation. Stem cell transplantation seems to be promising in restarting the immune system to diminish fibrosis and restore microvasculature. Future research will be directed at genetic factors, diagnostic and prognostic markers for fibrosis and microangiopathy, and development of drugs directed to pathogenic key cells and mediators. PMID: 22424190 [PubMed - indexed for MEDLINE]
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Related Articles Human embryonic stem cells differentiated to lung lineage-specific cells ameliorate pulmonary fibrosis in a xenograft transplant mouse model. PLoS One. 2012;7(3):e33165 Authors: Banerjee ER, Laflamme MA, Papayannopoulou T, Kahn M, Murry CE, Henderson WR Abstract BACKGROUND: Our aim was to differentiate human (h) embryonic stem (ES) cells into lung epithelial lineage-specific cells [i.e., alveolar epithelial type I (AEI) and type II (AEII) cells and Clara cells] as the first step in the development of cell-based strategies to repair lung injury in the bleomycin mouse model of idiopathic pulmonary fibrosis (IPF). A heterogeneous population of non-ciliated lung lineage-specific cells was derived by a novel method of embryoid body (EB) differentiation. This differentiated human cell population was used to modulate the profibrotic phenotype in transplanted animals. METHODOLOGY AND PRINCIPAL FINDINGS: Omission or inclusion of one or more components in the differentiation medium skewed differentiation of H7 hES cells into varying proportions of AEI, AEII, and Clara cells. ICG-001, a small molecule inhibitor of Wnt/β-catenin/Creb-binding protein (CBP) transcription, changed marker expression of the differentiated ES cells from an AEII-like phenotype to a predominantly AEI-like phenotype. The differentiated cells were used in xenograft transplantation studies in bleomycin-treated Rag2γC(-/-) mice. Human cells were detected in lungs of the transplanted groups receiving differentiated ES cells treated with or without ICG-001. The increased lung collagen content found in bleomycin-treated mice receiving saline was significantly reduced by transplantation with the lung-lineage specific epithelial cells differentiated from ES cells. A significant increase in progenitor number was observed in the airways of bleomycin-treated mice after transplantation of differentiated hES cells. CONCLUSIONS: This study indicates that ES cell-based therapy may be a powerful novel approach to ameliorate lung fibrosis. PMID: 22470441 [PubMed - indexed for MEDLINE]
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Related Articles [Clinical outcomes of allogeneic hematopoietic stem cell transplantation for adult primary myelofibrosis: retrospective analysis by Fukuoka BMT group]. Rinsho Ketsueki. 2012 Mar;53(3):323-8 Authors: Kamimura T, Yong C, Ito Y, Henzan H, Miyamoto T, Ohno Y, Eto T, Takenaka K, Akashi K Abstract We retrospectively analyzed outcomes of eight evaluable patients with primary myelofibrosis (PMF) who received allogeneic hematopoietic stem cell transplantation (allo-HSCT), using different graft sources; four patients received peripheral blood stem cells, three bone marrow, and one umbilical cord blood. The median age was 48 years (range, 43~64 years). Seven patients had an intermediate or high Dupriez score. Three patients underwent myeloablative conditioning, whereas five underwent reduced-intensity conditioning regimens. Engraftment was obtained in all of these recipients. The median days to reach a neutrophil count above 0.5×10(9)/l and platelet count above 20×10(9)/l were 20 and 35 days, respectively. No treatment-related deaths were observed within 100 days after allo-HSCT. Two patients died of sepsis or late-onset non-infectious pulmonary complications. Four patients developed grade I to II acute GVHD, and six patients developed chronic GVHD. The estimated 3-year overall survival was 75% with a median follow up time of 43 months (range, 6~127). Four of 5 patients who were transfusion-dependent became free from transfusion after allo-HSCT. In six of seven patients, a regression of fibrosis was confirmed by bone marrow biopsy. Despite the small number of cases, our results suggested that allo-HSCT is an encouraging curative strategy for treating PMF. PMID: 22499049 [PubMed - indexed for MEDLINE]
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Related Articles Mechanisms of attenuation of abdominal sepsis induced acute lung injury by ascorbic acid. Am J Physiol Lung Cell Mol Physiol. 2012 Jul 1;303(1):L20-32 Authors: Fisher BJ, Kraskauskas D, Martin EJ, Farkas D, Wegelin JA, Brophy D, Ward KR, Voelkel NF, Fowler AA, Natarajan R Abstract Bacterial infections of the lungs and abdomen are among the most common causes of sepsis. Abdominal peritonitis often results in acute lung injury (ALI). Recent reports demonstrate a potential benefit of parenteral vitamin C [ascorbic acid (AscA)] in the pathogenesis of sepsis. Therefore we examined the mechanisms of vitamin C supplementation in the setting of abdominal peritonitis-mediated ALI. We hypothesized that vitamin C supplementation would protect lungs by restoring alveolar epithelial barrier integrity and preventing sepsis-associated coagulopathy. Male C57BL/6 mice were intraperitoneally injected with a fecal stem solution to induce abdominal peritonitis (FIP) 30 min prior to receiving either AscA (200 mg/kg) or dehydroascorbic acid (200 mg/kg). Variables examined included survival, extent of ALI, pulmonary inflammatory markers (myeloperoxidase, chemokines), bronchoalveolar epithelial permeability, alveolar fluid clearance, epithelial ion channel, and pump expression (aquaporin 5, cystic fibrosis transmembrane conductance regulator, epithelial sodium channel, and Na(+)-K(+)-ATPase), tight junction protein expression (claudins, occludins, zona occludens), cytoskeletal rearrangements (F-actin polymerization), and coagulation parameters (thromboelastography, pro- and anticoagulants, fibrinolysis mediators) of septic blood. FIP-mediated ALI was characterized by compromised lung epithelial permeability, reduced alveolar fluid clearance, pulmonary inflammation and neutrophil sequestration, coagulation abnormalities, and increased mortality. Parenteral vitamin C infusion protected mice from the deleterious consequences of sepsis by multiple mechanisms, including attenuation of the proinflammatory response, enhancement of epithelial barrier function, increasing alveolar fluid clearance, and prevention of sepsis-associated coagulation abnormalities. Parenteral vitamin C may potentially have a role in the management of sepsis and ALI associated with sepsis. PMID: 22523283 [PubMed - indexed for MEDLINE]
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Related Articles Comparison of epithelial differentiation and immune regulatory properties of mesenchymal stromal cells derived from human lung and bone marrow. PLoS One. 2012;7(5):e35639 Authors: Ricciardi M, Malpeli G, Bifari F, Bassi G, Pacelli L, Nwabo Kamdje AH, Chilosi M, Krampera M Abstract Mesenchymal stromal cells (MSCs) reside in many organs including lung, as shown by their isolation from fetal lung tissues, bronchial stromal compartment, bronchial-alveolar lavage and transplanted lung tissues. It is still controversial whether lung MSCs can undergo mesenchymal-to-epithelial-transition (MET) and possess immune regulatory properties. To this aim, we isolated, expanded and characterized MSCs from normal adult human lung (lung-hMSCs) and compared with human bone marrow-derived MSCs (BM-hMSCs). Our results show that lung-MSCs reside at the perivascular level and do not significantly differ from BM-hMSCs in terms of immunophenotype, stemness gene profile, mesodermal differentiation potential and modulation of T, B and NK cells. However, lung-hMSCs express higher basal level of the stemness-related marker nestin and show, following in vitro treatment with retinoic acid, higher epithelial cell polarization, which is anyway partial when compared to a control epithelial bronchial cell line. Although these results question the real capability of acquiring epithelial functions by MSCs and the feasibility of MSC-based therapeutic approaches to regenerate damaged lung tissues, the characterization of this lung-hMSC population may be useful to study the involvement of stromal cell compartment in lung diseases in which MET plays a role, such as in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. PMID: 22567106 [PubMed - indexed for MEDLINE]
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Related Articles Investigation of Telomerase/Telomeres system in Bone Marrow Mesenchymal Stem Cells derived from IPF and RA-UIP. J Inflamm (Lond). 2012;9(1):27 Authors: Antoniou KM, Margaritopoulos GA, Proklou A, Karagiannis K, Lasithiotaki I, Soufla G, Kastrinaki MC, Spandidos DA, Papadaki HA, Siafakas NM Abstract OBJECTIVE: Idiopathic Pulmonary Fibrosis and Rheumatoid Arthritis associated usual interstitial pneumonia seem to have the same poor outcome as there is not an effective treatment. The aim of the study is to explore the reparative ability of bone marrow mesenchymal stem cells by evaluating the system telomerase/telomeres and propose a novel therapeutic approach. METHODS: BM-MSCs were studied in 6 IPF patients, 7 patients with RA-UIP and 6 healthy controls. We evaluated the telomere length as well as the mRNA expression of both components of telomerase (human telomerase reverse transcriptase, h-TERT and RNA template complementary to the telomeric loss DNA, h-TERC). RESULTS: We found that BM-MSCs from IPF, RA-UIP cases do not present smaller telomere length than the controls (p = 0.170). There was no significant difference regarding the expression of both h-TERT and h-TERC genes between patients and healthy controls (p = 0.107 and p = 0.634 respectively). CONCLUSIONS: We demonstrated same telomere length and telomerase expression in BM-MSCs of both IPF and RA-UIP which could explain similarities in pathogenesis and prognosis. Maintenance of telomere length in these cells could have future implication in cell replacement treatment with stem cells of these devastating lung disorders. PMID: 22747954 [PubMed]
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Related Articles Modulating the alveolar milieu to enhance resolution of fibrotic lung injury. Proc Am Thorac Soc. 2012 Jul;9(3):117-9 Authors: Garcia O, Buckley S, Navarro S, Driscoll B, Warburton D Abstract Fibrotic lung injury is often attributed to a myriad of factors, including environmental exposure, age, genetic predisposition, epigenetics, coexisting conditions, acute lung injury, and viral infection. No effective therapies, other than lung transplantation, have proven effective against lung fibrosis. Loss of cellular homeostasis mechanisms in alveolar epithelial type I cells and any inability of type II progenitor cells to resist and repair epithelial injury are indicators that impaired response to injury and regeneration is a critical component of this disorder. The alveolar epithelium has a limited repertoire of responses to injury, which are dictated by the alveolar milieu, a repository of cytokines and growth factors that affect recruitment of other cells to the site of injury, or the proliferation of resident cells at the site of injury. The identification and characterization of the cytokines, growth factors, and other biomarkers that dictate the response to disease is key to understanding, diagnosing, treating, and determining the trajectory of various lung disorders. Corrective therapy of the alveolar milieu may therefore prove to be beneficial in many presently serious and incurable lung diseases that likely begin and progress with injury to the alveolar epithelium. PMID: 22802284 [PubMed - indexed for MEDLINE]
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Related Articles Stem cells and pulmonary fibrosis: cause or cure? Proc Am Thorac Soc. 2012 Jul;9(3):164-71 Authors: McNulty K, Janes SM Abstract Pulmonary fibrosis is a feature of a number of important lung diseases, and alveolar epithelial injury plays a key role in their pathogenesis. Traditionally, type II alveolar epithelial cells have been viewed as the progenitor cells of the alveolar epithelium; however, recent studies have identified a number of other progenitor and stem cell populations that may participate in alveolar epithelial repair. These studies suggest that the injury microenvironment plays a role in regulation of progenitor cell populations. In human idiopathic pulmonary fibrosis, epithelial abnormalities including altered cell cycling characteristics, hyperplasia, and metaplasia are observed, suggesting that dysregulation of epithelial progenitor cells contributes to the characteristic aberrant repair process. Reactivation of developmental signaling pathways such as the Wnt-β-catenin pathway is implicated in the dysregulation of these cells, and targeting these pathways may provide opportunities for therapeutic intervention. There has been a great deal of interest in the delivery of exogenous stem cells as a therapeutic strategy, and various stem and progenitor cell populations have improved outcomes in animal lung fibrosis models. The contributions of these cells to alveolar epithelial regeneration have been variable, and secretion of soluble mediators has been implicated in the beneficial effects. It remains to be seen whether the promising results seen in the preclinical studies will translate to human disease, and the first studies using mesenchymal stem cells in clinical trials for fibrotic lung disease are underway. Strategies using other stem cell populations hold promise, but currently these are a lot further from the bedside. PMID: 22802292 [PubMed - indexed for MEDLINE]
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Related Articles Effect of antiserotonin drug on the development of lung fibrosis and blood system reactions after intratracheal administration of bleomycin. Bull Exp Biol Med. 2012 Feb;152(4):519-23 Authors: Skurikhin EG, Andreeva TV, Khmelevskaya ES, Ermolaeva LA, Pershina OV, Krupin VA, Ermakova NN, Reztsova AM, Stepanova IE, Gol'dberg VE, Dygai AM Abstract The effects of antiserotonin preparation on the development of the connective tissue in the lungs, reaction of the blood system, and the content of hemopoietic stem cells, committed hemopoietic and stromal precursors in BM, spleen, and peripheral blood were studied on C57Bl/6 mice with experimental toxic lung fibrosis caused by intratracheal administration of bleomycin. It was demonstrated that the antiserotonin drug inhibits the growth of the connective tissue in the lungs and attenuates the course inflammatory process primarily due to inhibition of the granulocytic lineage, which was related to suppression of hemopoietic stem cells. Reduced content of the stromal precursor cells in BM and spleen was noted. PMID: 22803125 [PubMed - indexed for MEDLINE]
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Related Articles Antifibrotic and anti-inflammatory activity of a neuroleptic drug on the model of pulmonary fibrosis. Bull Exp Biol Med. 2012 Apr;152(6):679-83 Authors: Dygai AM, Skurikhin EG, Andreeva TV, Pershina OV, Ermolaeva LA, Khmelevskaya ES, Krupin VA, Reztsova AM, Stepanova IE Abstract The effect of course treatment with neuroleptic haloperidol on the inflammatory response and state of the connective tissue in the lungs of C57Bl/6 mice was studied on the model of toxic pulmonary fibrosis induced by intratracheal administration of bleomycin. This neuroleptic decreased the inflammatory response and reduced the growth of the connective tissue in the lungs. The anti-inflammatory effect of haloperidol is related to a decrease in activity of bone marrow hemopoietic stem cells and committed hemopoietic precursors. The antifibrotic effect of this drug is associated with inhibition of mesenchymal precursor cells. PMID: 22803163 [PubMed - indexed for MEDLINE]
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Related Articles Mesenchymal stem cell-mediated reversal of bronchopulmonary dysplasia and associated pulmonary hypertension. Pulm Circ. 2012 Apr-Jun;2(2):170-81 Authors: Hansmann G, Fernandez-Gonzalez A, Aslam M, Vitali SH, Martin T, Mitsialis SA, Kourembanas S Abstract Clinical trials have failed to demonstrate an effective preventative or therapeutic strategy for bronchopulmonary dysplasia (BPD), a multifactorial chronic lung disease in preterm infants frequently complicated by pulmonary hypertension (PH). Mesenchymal stem cells (MSCs) and their secreted components have been shown to prevent BPD and pulmonary fibrosis in rodent models. We hypothesized that treatment with conditioned media (CM) from cultured mouse bone marrow-derived MSCs could reverse hyperoxia-induced BPD and PH. Newborn mice were exposed to hyperoxia (FiO(2)=0.75) for two weeks, were then treated with one intravenous dose of CM from either MSCs or primary mouse lung fibroblasts (MLFs), and placed in room air for two to four weeks. Histological analysis of lungs harvested at four weeks of age was performed to determine the degree of alveolar injury, blood vessel number, and vascular remodeling. At age six weeks, pulmonary artery pressure (PA acceleration time) and right ventricular hypertrophy (RVH; RV wall thickness) were assessed by echocardiography, and pulmonary function tests were conducted. When compared to MLF-CM, a single dose of MSC-CM-treatment (1) reversed the hyperoxia-induced parenchymal fibrosis and peripheral PA devascularization (pruning), (2) partially reversed alveolar injury, (3) normalized lung function (airway resistance, dynamic lung compliance), (4) fully reversed the moderate PH and RVH, and (5) attenuated peripheral PA muscularization associated with hyperoxia-induced BPD. Reversal of key features of hyperoxia-induced BPD and its long-term adverse effects on lung function can be achieved by a single intravenous dose of MSC-CM, thereby pointing toward a new therapeutic intervention for chronic lung diseases. PMID: 22837858 [PubMed]
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Related Articles Autologous peripheral blood hematopoietic cell transplantation in dogs with B-cell lymphoma. J Vet Intern Med. 2012 Sep-Oct;26(5):1155-63 Authors: Willcox JL, Pruitt A, Suter SE Abstract BACKGROUND: Peripheral blood CD34+ hematopoietic cell transplantation (PBHCT) is commonly used to treat human patients with relapsed non-Hodgkin diffuse, large B-cell lymphoma with cure rates approaching 50%. OBJECTIVE: To determine the safety and feasibility of performing PBHCT to treat canine B-cell lymphoma (LSA) patients in a clinical academic setting. ANIMALS: Twenty-four client-owned dogs diagnosed with B-cell LSA. METHODS: After high-dose cyclophosphamide and rhG-colony-stimulating factor treatment, peripheral blood mononuclear cells were collected using cell separator machines. The harvested cells then were infused after a 10 Gy dose of total body irradiation (TBI). Post-irradiation adverse effects were managed symptomatically and dogs were discharged upon evidence of engraftment. RESULTS: More than 2 × 10(6) CD34+ cells/kg were harvested in 23/24 dogs. Preapheresis peripheral blood monocyte count was correlated with the number of CD34+ cells/kg harvested. Twenty-one of 24 (87.5%) dogs engrafted appropriately, whereas 2 dogs (8.3%) died in the hospital. One (5%) dog exhibited delayed engraftment and died 45 days after PBHCT. One dog developed presumed TBI-induced pulmonary fibrosis approximately 8 months after PBHCT. The median disease-free interval and overall survival (OS) of all dogs from the time of PBHCT was 271 and 463 days, respectively. Five of 15 (33%) dogs transplanted before they relapsed remain in clinical remission for their disease at a median OS of 524 days (range, 361-665 days). CONCLUSIONS AND CLINICAL IMPORTANCE: In most cases, PBHCT led to complete hematologic reconstitution. Therefore, PBHCT may be considered as a treatment option for dogs with B-cell lymphoma. PMID: 22882500 [PubMed - indexed for MEDLINE]
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Related Articles Increased tissue endothelial progenitor cells in end-stage lung diseases with pulmonary hypertension. J Heart Lung Transplant. 2012 Sep;31(9):1025-30 Authors: Schiavon M, Fadini GP, Lunardi F, Agostini C, Boscaro E, Calabrese F, Marulli G, Rea F Abstract BACKGROUND: Diffuse lung diseases promote the development of vascular changes and pulmonary hypertension (PH). Endothelial progenitor cells (EPCs) seem to be involved in pulmonary vascular remodeling. We evaluated circulating and intra-pulmonary EPCs in end-stage lung diseases in relation to pulmonary arterial pressure (PAP). METHODS: The study included 19 patients affected by different end-stage lung diseases, with or without PH. Six lung donors were considered as control group. EPCs were measured in blood samples taken at the time of transplant from pulmonary arteries and veins (by flow cytometry) as well as in lung specimen sections (by confocal microscopy) and expressed as percentage of total number of cells. RESULTS: The amount of EPC in lung specimens was significantly different according to type of disease (p = 0.001). Specifically, a higher number of EPCs was detected in idiopathic pulmonary hypertension and idiopathic pulmonary fibrosis with high (> 25 mm Hg) mean PAP (p = 0.03 for both) compared with chronic obstructive pulmonary disease and control group. There was a direct correlation between intrapulmonary EPCs and PAP. According to receiver operating characteristic curve analysis, the presence of > 3% EPCs had a 91% sensitivity and 93% specificity in identifying high mean PAP. There were no differences in circulating arterial or venous EPCs among groups. CONCLUSIONS: Intra-pulmonary EPCs are increased in lung diseases with high PAP, suggesting that EPCs may contribute to vascular remodeling in end-stage pulmonary disease. PMID: 22884387 [PubMed - indexed for MEDLINE]
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Related Articles Mesenchymal stem cells protect cigarette smoke-damaged lung and pulmonary function partly via VEGF-VEGF receptors. J Cell Biochem. 2013 Feb;114(2):323-35 Authors: Guan XJ, Song L, Han FF, Cui ZL, Chen X, Guo XJ, Xu WG Abstract Progressive pulmonary inflammation and emphysema have been implicated in the progression of chronic obstructive pulmonary disease (COPD), while current pharmacological treatments are not effective. Transplantation of bone marrow mesenchymal stem cells (MSCs) has been identified as one such possible strategy for treatment of lung diseases including acute lung injury (ALI) and pulmonary fibrosis. However, their role in COPD still requires further investigation. The aim of this study is to test the effect of administration of rat MSCs (rMSCs) on emphysema and pulmonary function. To accomplish this study, the rats were exposed to cigarette smoke (CS) for 11 weeks, followed by administration of rMSCs into the lungs. Here we show that rMSCs infusion mediates a down-regulation of pro-inflammatory mediators (TNF-α, IL-1β, MCP-1, and IL-6) and proteases (MMP9 and MMP12) in lung, an up-regulation of vascular endothelial growth factor (VEGF), VEGF receptor 2, and transforming growth factor (TGFβ-1), while reducing pulmonary cell apoptosis. More importantly, rMSCs administration improves emphysema and destructive pulmonary function induced by CS exposure. In vitro co-culture system study of human umbilical endothelial vein cells (EA.hy926) and human MSCs (hMSCs) provides the evidence that hMSCs mediates an anti-apoptosis effect, which partly depends on an up-regulation of VEGF. These findings suggest that MSCs have a therapeutic potential in emphysematous rats by suppressing the inflammatory response, excessive protease expression, and cell apoptosis, as well as up-regulating VEGF, VEGF receptor 2, and TGFβ-1. PMID: 22949406 [PubMed - indexed for MEDLINE]
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Related Articles Isolation of basal cells and submucosal gland duct cells from mouse trachea. J Vis Exp. 2012;(67):e3731 Authors: Hegab AE, Ha VL, Attiga YS, Nickerson DW, Gomperts BN Abstract The large airways are directly in contact with the environment and therefore susceptible to injury from toxins and infectious agents that we breath in. The large airways therefore require an efficient repair mechanism to protect our bodies. This repair process occurs from stem cells in the airways and isolating these stem cells from the airways is important for understanding the mechanisms of repair and regeneration. It is also important for understanding abnormal repair that can lead to airway diseases. The goal of this method is to isolate a novel stem cell population from the mouse tracheal submucosal gland ducts and to place these cells in in vitro and in vivo model systems to identify the mechanisms of repair and regeneration of the submucosal glands. This production shows methods that can be used to isolate and assay the duct and basal stem cells from the large airways.This will allow us to study diseases of the airway, such as cystic fibrosis, asthma and chronic obstructive pulmonary disease. Currently, there are no methods for isolation of submucosal gland duct cells and there are no in vivo models to study the regeneration of submucosal glands. PMID: 23007468 [PubMed - indexed for MEDLINE]
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Related Articles Experimental basis and new insights for cell therapy in Chronic Obstructive Pulmonary Disease. Stem Cell Rev. 2012 Dec;8(4):1236-44 Authors: de Faria CA, de las Heras Kozma R, Stessuk T, Ribeiro-Paes JT Abstract Chronic Obstructive Pulmonary Disease (COPD) can be briefly described as air flow limitation and chronic dyspnea associated to an inflammatory response of the respiratory tract to noxious particles and gases. Its main feature is the obstruction of airflow and consequent chronic dyspnea. Despite recent advances, and the development of new therapeutic, medical and clinical approaches, a curative therapy is yet to be achieved. Therapies involving the use of tissue-specific or donor derived cells present a promising alternative in the treatment of degenerative diseases and injuries. Recent studies demonstrate that mesenchymal stem cells have the capacity to modulate immune responses in acute lung injury and pulmonary fibrosis in animal models, as well as in human patients. Due to these aspects, different groups raised the possibility that the stem cells from different sources, such as those found in bone marrow or adipose tissue, could act preventing the emphysematous lesion progression. In this paper, it is proposed a review of the current state of the art and future perspectives on the use of cell therapy in obstructive lung diseases. PMID: 23054962 [PubMed - indexed for MEDLINE]
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Related Articles Mechanisms of the anti-inflammatory and antifibrotic activity of a sympatholytic agent during toxic pulmonary fibrosis. Bull Exp Biol Med. 2012 Sep;153(5):638-43 Authors: Skurikhin EG, Khmelevskaya ES, Pershina OV, Andreeva TV, Ermolaeva LA, Krupin VA, Ermakova NN, Reztsova AM, Stepanova IE, Dygai AM Abstract The effect of a course treatment with a sympatholytic reserpine on the inflammatory response and connective tissue proliferation in the lungs of C57Bl/6 mice was studied on the model of toxic pulmonary fibrosis induced by intratracheal administration of bleomycin. This sympatholytic reduced infiltration of the alveolar interstitium and alveolar ducts with inflammatory cells (lymphocytes, macrophages, neutrophils, and plasma cells) and prevented connective tissue proliferation in the lungs. The anti-inflammatory effect of reserpine was associated with a decrease in activity of bone marrow granulocyte-erythroid-macrophage-megakaryocyte and granulocyte precursors (proliferation and mobilization). The antifibrotic effect of reserpine was due to a decrease in the number of committed precursors for mesenchymopoiesis. PMID: 23113245 [PubMed - indexed for MEDLINE]
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Related Articles A novel surgical approach for intratracheal administration of bioactive agents in a fetal mouse model. J Vis Exp. 2012;(68) Authors: Carlon MS, Toelen J, da Cunha MM, Vidović D, Van der Perren A, Mayer S, Sbragia L, Nuyts J, Himmelreich U, Debyser Z, Deprest J Abstract Prenatal pulmonary delivery of cells, genes or pharmacologic agents could provide the basis for new therapeutic strategies for a variety of genetic and acquired diseases. Apart from congenital or inherited abnormalities with the requirement for long-term expression of the delivered gene, several non-inherited perinatal conditions, where short-term gene expression or pharmacological intervention is sufficient to achieve therapeutic effects, are considered as potential future indications for this kind of approach. Candidate diseases for the application of short-term prenatal therapy could be the transient neonatal deficiency of surfactant protein B causing neonatal respiratory distress syndrome(1,2) or hyperoxic injuries of the neonatal lung(3). Candidate diseases for permanent therapeutic correction are Cystic Fibrosis (CF)(4), genetic variants of surfactant deficiencies(5) and α1-antitrypsin deficiency(6). Generally, an important advantage of prenatal gene therapy is the ability to start therapeutic intervention early in development, at or even prior to clinical manifestations in the patient, thus preventing irreparable damage to the individual. In addition, fetal organs have an increased cell proliferation rate as compared to adult organs, which could allow a more efficient gene or stem cell transfer into the fetus. Furthermore, in utero gene delivery is performed when the individual's immune system is not completely mature. Therefore, transplantation of heterologous cells or supplementation of a non-functional or absent protein with a correct version should not cause immune sensitization to the cell, vector or transgene product, which has recently been proven to be the case with both cellular and genetic therapies(7). In the present study, we investigated the potential to directly target the fetal trachea in a mouse model. This procedure is in use in larger animal models such as rabbits and sheep(8), and even in a clinical setting(9), but has to date not been performed before in a mouse model. When studying the potential of fetal gene therapy for genetic diseases such as CF, the mouse model is very useful as a first proof-of-concept because of the wide availability of different transgenic mouse strains, the well documented embryogenesis and fetal development, less stringent ethical regulations, short gestation and the large litter size. Different access routes have been described to target the fetal rodent lung, including intra-amniotic injection(10-12), (ultrasound-guided) intrapulmonary injection(13,14) and intravenous administration into the yolk sac vessels(15,16) or umbilical vein(17). Our novel surgical procedure enables researchers to inject the agent of choice directly into the fetal mouse trachea which allows for a more efficient delivery to the airways than existing techniques(18). PMID: 23149801 [PubMed - indexed for MEDLINE]
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Related Articles [The effect of marrow mesenchymal stem cell transplantation on pulmonary fibrosis in rats]. Zhonghua Jie He He Hu Xi Za Zhi. 2012 Sep;35(9):659-64 Authors: Huang K, Wu XM, Wang XY, Kang XW, Xiao JL, Li ZG, Lu P Abstract OBJECTIVE: To study the possible mechanisms of marrow mesenchymal stem cells (MSC) in therapy of bleomycin (BLM)-induced pulmonary fibrosis in rats. METHODS: Fifty-four female Wistar rats were randomly divided into a control group, a BLM group and a MSC group. The control group received intratracheal normal saline, the BLM group received intratracheal instillation of bleomycin, and the MSC group was injected with male rat MSC solution of 0.5 ml (2.5×10(6) cells) via the tail vein after intratracheal instillation of bleomycin. Six rats from each group were killed on day 7, 14 and 28 of the experiments. BrdU labeling rate was measured before MSC transplantation. Lung tissue specimens were obtained for pathological examination, hydroxyproline content measurement, and detection of the expression of type II alveolar cell (ATII) specific marker-pulmonary surfactant protein-C (SP-C) in BrdU labeled MSC using dual immunofluorescence method. RT-PCR method was used to detect SP-C mRNA expression in the lung tissue and the bone marrow at different stages. The bone marrow mobilization involved in repair of type II alveolar cells after lung injury was observed. RESULTS: The final concentration of BrdU labeled MSC at 48 h was 10 µmol/L, while the labeling efficiency was>98%, and the passage cells could be continuously labeled. In the MSC group, BrdU labeled MSCs with expression of SP-C were observed in all frozen sections of lung tissue at day 7, 14, and 28. By day 28, the lung fibrosis scores of the MSC group and the BLM group were (2.17 ± 0.26) and (2.83 ± 0.24), respectively, the lung tissue hydroxyproline contents were (138 ± 21) mg/g and (184 ± 19) mg/g, respectively, and the lung tissue SP-C mRNA expressions were (0.98 ± 0.15) and (0.59 ± 0.14), respectively. For both groups the SP-C mRNA expressions in the bone marrow at different stages were significantly increased as compared to the control group. CONCLUSIONS: Marrow mesenchymal stem cells could be transplanted into lung tissues of rats, and transformed into type II alveolar cells and was shown to prevent the development of pulmonary fibrosis. The damage-induced enhancement of host bone marrow mobilization was also involved in the repair process. PMID: 23158067 [PubMed - indexed for MEDLINE]
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Related Articles Irreversible leukoencephalopathy after reduced-intensity stem cell transplantation in a dyskeratosis congenita patient with TINF2 mutation. J Pediatr Hematol Oncol. 2013 May;35(4):e178-82 Authors: Isoda T, Mitsuiki N, Ohkawa T, Kaneko S, Endo A, Ono T, Aoki Y, Tomizawa D, Kajiwara M, Araki S, Nagasawa M, Morio T, Takagi M, Mizutani S Abstract Hematopoietic stem cell transplantation (HSCT) for dyskeratosis congenita (DC) is challenging due to severe treatment-related adverse effects. Development of pulmonary fibrosis or veno-occlusive disease is well described in DC. However, neurological complication after HSCT has not been reported. A 9-year-old Japanese male with DC harboring the TINF2 mutation received reduced-intensity HSCT. Unfortunately, patient developed posterior reversible encephalopathy syndrome-like symptoms plausibly result by combination of thrombotic microangiopathy, graft-versus-host disease, and persistent hypertension and has been persisted mental retardation. Therefore, to decrease risk in DC cases after HSCT, strict control of hypertension, graft-versus-host disease, and thrombotic microangiopathy is required. PMID: 23242325 [PubMed - indexed for MEDLINE]
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Related Articles Mesenchymal stem cells and idiopathic pulmonary fibrosis. Potential for clinical testing. Am J Respir Crit Care Med. 2013 Jul 15;188(2):133-40 Authors: Toonkel RL, Hare JM, Matthay MA, Glassberg MK Abstract Idiopathic pulmonary fibrosis (IPF) is a progressive, debilitating, and fatal lung disease characterized by interstitial fibrosis with decreasing lung volumes and hypoxemic respiratory failure. The prognosis for patients with IPF is poor and the quest to find effective therapies has been unsuccessful. Despite several clinical trials over the past decade, there are no U.S. Food and Drug Administration-approved treatments for patients with IPF and thus no standard of care. In terms of pathogenesis, IPF is characterized by alveolar epithelial cell injury and activation with interstitial inflammation, fibroblast proliferation with extracellular matrix collagen deposition, and loss of lung function. Because mesenchymal stem cells (MSCs) home to sites of injury, inhibit inflammation, and contribute to epithelial tissue repair, their use has been suggested as a therapy for the treatment of IPF. MSCs have potential as a novel therapeutic agent in multiple diseases and they have been safely administered in a number of clinical trials. Some, but not all, preclinical studies in animal models of lung fibrosis suggest that MSCs might be effective in the treatment of IPF. Given the safety and ease of MSC administration in other patient populations, the results in preclinical animal models of IPF, and the major need for novel therapeutic options in this devastating disease, we propose that carefully designed clinical trials of MSCs for the treatment of patients with IPF are appropriate. Establishing safety in the setting of IPF is the first priority in early clinical trials followed by clinical and biological measures of efficacy. PMID: 23306542 [PubMed - indexed for MEDLINE]
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Related Articles Primary myelofibrosis: 2013 update on diagnosis, risk-stratification, and management. Am J Hematol. 2013 Feb;88(2):141-50 Authors: Tefferi A Abstract DISEASE OVERVIEW: Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by stem cell-derived clonal myeloproliferation, abnormal cytokine expression, bone marrow fibrosis, anemia, splenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, leukemic progression, and shortened survival. DIAGNOSIS: Diagnosis is based on bone marrow morphology. The presence of fibrosis, JAK2/MPL mutation, or +9/13q- cytogenetic abnormality is supportive but not essential for diagnosis. Prefibrotic PMF mimics essential thrombocythemia in its presentation and the distinction is prognostically relevant. Differential diagnosis of myelofibrosis should include chronic myeloid leukemia, myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia. RISK STRATIFICATION: The Dynamic International Prognostic Scoring System-plus (DIPSS-plus) prognostic model for PMF can be applied at any point during the disease course and uses eight independent predictors of inferior survival: age >65 years, hemoglobin <10 g/dL, leukocytes >25 × 10⁹/L, circulating blasts ≥ 1%, constitutional symptoms, red cell transfusion dependency, platelet count <100 × 10⁹/L, and unfavorable karyotype (i.e., complex karyotype or sole or two abnormalities that include +8, -7/7q-, i(17q), inv(3), -5/5q-, 12p-, or 11q23 rearrangement). The presence of 0, 1, "2 or 3," and ≥ 4 adverse factors defines low, intermediate-1, intermediate-2, and high-risk disease with median survivals of approximately 15.4, 6.5, 2.9, and 1.3 years, respectively. A >80% two-year mortality is predicted by monosomal karyotype, inv(3)/i(17q) abnormalities, or any two of circulating blasts >9%, leukocytes ≥ 40 × 10⁹/L or other unfavorable karyotype. Most recently, mutations involving ASXL1, SRSF2, EZH2, and IDH1/2 or increased plasma IL-2R, IL-8, or serum-free light chain levels have been shown to adversely affect survival. RISK-ADAPTED THERAPY: Observation alone is adequate for asymptomatic low/intermediate-1 risk disease. Allogeneic stem cell transplantation (ASCT) is often considered for high risk disease. Conventional or experimental drug therapy is reasonable for symptomatic intermediate-1 or intermediate-2 risk disease; however, ASCT is an acceptable treatment option for such patients in the presence of ASXL1 or other prognostically adverse mutations. Splenectomy and low-dose radiotherapy are used for drug-refractory splenomegaly. Radiotherapy is also used for the treatment of non-hepatosplenic EMH, PMF-associated pulmonary hypertension, and extremity bone pain. PMID: 23349007 [PubMed - indexed for MEDLINE]
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Related Articles Mesenchymal stem cells promote alveolar epithelial cell wound repair in vitro through distinct migratory and paracrine mechanisms. Respir Res. 2013;14:9 Authors: Akram KM, Samad S, Spiteri MA, Forsyth NR Abstract BACKGROUND: Mesenchymal stem cells (MSC) are in clinical trials for widespread indications including musculoskeletal, neurological, cardiac and haematological disorders. Furthermore, MSC can ameliorate pulmonary fibrosis in animal models although mechanisms of action remain unclear. One emerging concept is that MSCs may have paracrine, rather than a functional, roles in lung injury repair and regeneration. METHODS: To investigate the paracrine role of human MSC (hMSC) on pulmonary epithelial repair, hMSC-conditioned media (CM) and a selected cohort of hMSC-secretory proteins (identified by LC-MS/MS mass spectrometry) were tested on human type II alveolar epithelial cell line A549 cells (AEC) and primary human small airway epithelial cells (SAEC) using an in vitro scratch wound repair model. A 3D direct-contact wound repair model was further developed to assess the migratory properties of hMSC. RESULTS: We demonstrate that MSC-CM facilitates AEC and SAEC wound repair in serum-dependent and -independent manners respectively via stimulation of cell migration. We also show that the hMSC secretome contains an array of proteins including Fibronectin, Lumican, Periostin, and IGFBP-7; each capable of influencing AEC and SAEC migration and wound repair stimulation. In addition, hMSC also show a strong migratory response to AEC injury as, supported by the observation of rapid and effective AEC wound gap closure by hMSC in the 3D model. CONCLUSION: These findings support the notion for clinical application of hMSCs and/or their secretory factors as a pharmacoregenerative modality for the treatment of idiopathic pulmonary fibrosis (IPF) and other fibrotic lung disorders. PMID: 23350749 [PubMed - indexed for MEDLINE]
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Related Articles Stem cell treatment for chronic lung diseases. Respiration. 2013;85(3):179-92 Authors: Tzouvelekis A, Ntolios P, Bouros D Abstract Chronic lung diseases such as idiopathic pulmonary fibrosis and cystic fibrosis or chronic obstructive pulmonary disease and asthma are leading causes of morbidity and mortality worldwide with a considerable human, societal and financial burden. In view of the current disappointing status of available pharmaceutical agents, there is an urgent need for alternative more effective therapeutic approaches that will not only help to relieve patient symptoms but will also affect the natural course of the respective disease. Regenerative medicine represents a promising option with several fruitful therapeutic applications in patients suffering from chronic lung diseases. Nevertheless, despite relative enthusiasm arising from experimental data, application of stem cell therapy in the clinical setting has been severely hampered by several safety concerns arising from the major lack of knowledge on the fate of exogenously administered stem cells within chronically injured lung as well as the mechanisms regulating the activation of resident progenitor cells. On the other hand, salient data arising from few 'brave' pilot investigations of the safety of stem cell treatment in chronic lung diseases seem promising. The main scope of this review article is to summarize the current state of knowledge regarding the application status of stem cell treatment in chronic lung diseases, address important safety and efficacy issues and present future challenges and perspectives. In this review, we argue in favor of large multicenter clinical trials setting realistic goals to assess treatment efficacy. We propose the use of biomarkers that reflect clinically inconspicuous alterations of the disease molecular phenotype before rigid conclusions can be safely drawn. PMID: 23364286 [PubMed - indexed for MEDLINE]
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Related Articles Induced pluripotent stem cells mediate the release of interferon gamma-induced protein 10 and alleviate bleomycin-induced lung inflammation and fibrosis. Shock. 2013 Mar;39(3):261-70 Authors: How CK, Chien Y, Yang KY, Shih HC, Juan CC, Yang YP, Chiou GY, Huang PI, Chang YL, Chen LK, Wang CY, Hsu HS, Chiou SH, Lee CH Abstract Chronic lung diseases cause serious morbidity and mortality, and effective treatments are limited. Induced pluripotent stem cells (iPSCs) lacking the reprogramming factor c-Myc (3-gene iPSCs) can be used as ideal tools for cell-based therapy because of their low level of tumorigenicity. In this study, we investigated whether 3-gene iPSC transplantation could rescue bleomycin-induced pulmonary fibrosis. After the induction of pulmonary inflammation and fibrosis via intratracheal delivery of bleomycin sulfate, mice were i.v. injected with 3-gene iPSCs or conditioned medium (iPSC-CM) at 24 h after bleomycin treatment. Administration of either 3-gene iPSCs or iPSC-CM significantly attenuated collagen content and myeloperoxidase activity, diminished neutrophil accumulation, and rescued pulmonary function and recipient survival after bleomycin treatment. Notably, both treatments reduced the levels of inflammatory cytokines and chemokines, including interleukin 1 (IL-1), IL-2, IL-10, tumor necrosis factor-α, and monocyte chemotactic protein 1 yet increased the production of the antifibrotic chemokine interferon-γ-induced protein 10 (IP-10) in bleomycin-injured lungs. Furthermore, IP-10 neutralization via treatment with IP-10-neutralizing antibodies ameliorated the reparative effect of either 3-gene iPSCs or iPSC-CM on collagen content, neutrophil and monocyte accumulation, pulmonary fibrosis, and recipient survival. Intravenous delivery of 3-gene iPSCs/iPSC-CM alleviated the severity of histopathologic and physiologic impairment in bleomycin-induced lung fibrosis. The protective mechanism was partially mediated by the early moderation of inflammation, reduced levels of cytokines and chemokines that mediate inflammation and fibrosis, and an increased production of antifibrotic IP-10 in the injured lungs. PMID: 23364435 [PubMed - indexed for MEDLINE]
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Related Articles Small molecule inhibitors of CXCR4. Theranostics. 2013;3(1):47-75 Authors: Debnath B, Xu S, Grande F, Garofalo A, Neamati N Abstract CXCR4 is a G-protein-coupled receptor involved in a number of physiological processes in the hematopoietic and immune systems. The SDF-1/CXCR4 axis is significantly associated with several diseases, such as HIV, cancer, WHIM syndrome, rheumatoid arthritis, pulmonary fibrosis and lupus. For example, CXCR4 is one of the major co-receptors for HIV entry into target cells, while in cancer it plays an important role in tumor cell metastasis. Several promising CXCR4 antagonists have been developed to block SDF-1/CXCR4 interactions that are currently under different stages of development. The first in class CXCR4 antagonist, plerixafor, was approved by the FDA in 2008 for the mobilization of hematopoietic stem cells and several other drugs are currently in clinical trials for cancer, HIV, and WHIM syndrome. While the long-term safety data for the first generation CXCR4 antagonists are not yet available, several new compounds are under preclinical development in an attempt to provide safer and more efficient treatment options for HIV and cancer patients. PMID: 23382786 [PubMed - indexed for MEDLINE]
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Related Articles Essential role of stem cell factor-c-Kit signalling pathway in bleomycin-induced pulmonary fibrosis. J Pathol. 2013 Jun;230(2):205-14 Authors: Ding L, Dolgachev V, Wu Z, Liu T, Nakashima T, Wu Z, Ullenbruch M, Lukacs NW, Chen Z, Phan SH Abstract Stem cell factor (SCF) and its receptor c-Kit have been implicated in tissue remodelling and fibrosis. Alveolar fibroblasts from patients with diffuse interstitial fibrosis secrete more SCF. However, its precise role remains unclear. In this study the potential role of the SCF-c-Kit axis in pulmonary fibrosis was examined. Fibrosis was induced by intratracheal instillation of bleomycin (BLM), which caused increased SCF levels in plasma, bronchoalveolar lavage fluid (BALF) and lung tissue, as well as increased expression by lung fibroblasts. These changes were accompanied by increased numbers of bone marrow-derived c-Kit(+) cells in the lung, with corresponding depletion in bone marrow. Both recombinant SCF and lung extracts from BLM-treated animals induced bone-marrow cell migration, which was blocked by c-Kit inhibitor. The migrated cells promoted myofibroblast differentiation when co-cultured with fibroblasts, suggesting a paracrine pathogenic role. Interestingly, lung fibroblast cultures contained a subpopulation of cells that expressed functionally active c-Kit, which were significantly greater and more responsive to SCF induction when isolated from fibrotic lungs, including those from patients with idiopathic pulmonary fibrosis (IPF). This c-Kit(+) subpopulation was αSMA-negative and expressed lower levels of collagen I but significantly higher levels of TGFβ than c-Kit-negative cells. SCF deficiency achieved by intratracheal treatment with neutralizing anti-SCF antibody or by use of Kitl(Sl)/Kitl(Sl-d) mutant mice in vivo resulted in significant reduction in pulmonary fibrosis. Taken together, the SCF-c-Kit pathway was activated in BLM-injured lung and might play a direct role in pulmonary fibrosis by the recruitment of bone marrow progenitor cells capable of promoting lung myofibroblast differentiation. PMID: 23401096 [PubMed - indexed for MEDLINE]
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Related Articles Telomeres and age-related disease: how telomere biology informs clinical paradigms. J Clin Invest. 2013 Mar 1;123(3):996-1002 Authors: Armanios M Abstract Telomere length shortens with age and predicts the onset of replicative senescence. Recently, short telomeres have been linked to the etiology of degenerative diseases such as idiopathic pulmonary fibrosis, bone marrow failure, and cryptogenic liver cirrhosis. These disorders have recognizable clinical manifestations, and the telomere defect explains their genetics and informs the approach to their treatment. Here, I review how telomere biology has become intimately connected to clinical paradigms both for understanding pathophysiology and for individualizing therapy decisions. I also critically examine nuances of interpreting telomere length measurement in clinical studies. PMID: 23454763 [PubMed - indexed for MEDLINE]
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Related Articles BMP signaling regulates the differentiation of mouse embryonic stem cells into lung epithelial cell lineages. In Vitro Cell Dev Biol Anim. 2013 Mar;49(3):230-7 Authors: Ninomiya N, Michiue T, Asashima M, Kurisaki A Abstract Somatic stem/progenitor cells are known to be present in most adult tissues. However, those in the lung have limited abilities for tissue regeneration after serious damage as a result of chronic disease. Therefore, regenerative medicine using exogenous stem cells has been suggested for the treatment of progressive lung diseases such as chronic obstructive pulmonary disease and pulmonary fibrosis. Embryonic stem (ES) cells and induced pluripotent stem cells, with their potent differentiation abilities, are promising sources for the generation of various tissue cells. In this study, we investigated the effects of various differentiation-inducing growth factors on the differentiation of lung cells from ES cells in vitro. Several factors, including activin, nodal, and noggin, significantly promoted the induction of Nkx2.1-positive lung progenitor cells when cells were cultured as embryoid bodies. Bone morphogenetic protein (BMP) 4 signaling controls the lineage commitment of lung cells along the proximal-distal axis. BMP4 promotes the induction of distal cell lineages of alveolar bud, such as Clara cells and mucus-producing goblet cells. These results suggest that several developmentally essential factors, including nodal/activin and BMP signaling, are important in the control of the differentiation of lung epithelial cells from mouse ES cells in vitro. PMID: 23468359 [PubMed - indexed for MEDLINE]
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Related Articles [Inhibition of liver fibrosis by IL-10 gene-modified BMSCs in a rat model]. Zhonghua Gan Zang Bing Za Zhi. 2012 Dec;20(12):908-11 Authors: Tu YZ, Zhang J, Liu HP, Yu W Abstract OBJECTIVE: To investigate the potential curative effects of bone marrow mesenchymal stem cells (BMSCs) overexpressing IL-10 for treating liver fibrosis by using a CCl4-induced rat model. METHODS: BMSCs were cultured and marked by DAPI staining of the cells' nuclei. Meanwhile, 60 Wistar rats were treated with CCl4 to induce liver fibrosis and randomly divided into three groups: A: injected with DAPI-marked BMSCs transfected with pcDNA3.0-IL-10; B: injected with DAPI-marked BMSCs; C: injected with phosphate-buffered saline. Histological analysis of excised livers was conducted to observe BMSCs (by DAPI marker) and fibrosis (by Masson's stain). Western blotting was used to detect IL-10 expression in BMSCs. Effects on expression of tumor necrosis factor-alpha (TNFa) were analyzed by enzyme-linked immunosorbent assay, and on hydroxyproline (HYP) levels were analyzed by the acid hydrolysis method. RESULTS: Following CCl4-inducement, rat livers showed the characteristic pathological changes of fibrosis and DAPI-marked cells (BMSCs) were observed. Compared with group C (pulmonary fibrosis score: 3.15+/-0.96; HYP level: 1.89+/-1.03 mug/mg), the extent of liver fibrosis was significantly lower in group A (pulmonary fibrosis score: 1.01+/-0.35; HYP level: 0.73+/-0.29 mug/mg) and group B (pulmonary fibrosis score: 1.34+/-0.65; HYP level: 1.21+/-0.78 mug/mg). The therapeutic effects were significantly greater in group A than group B (q=-4.73, P less than 0.05). TNFa protein expression was significantly lower in group A (275.21+/-86.35) and group B (321.76+/-98.49) than in group C (476.23+/-126.43). The TNFa expression was significantly lower in group A than group B (q=-7.43, P less than 0.05). CONCLUSION: IL-10 gene-modified BMSCs are effective for treating liver fibrosis in a CCl4-induced rat model. PMID: 23522251 [PubMed - indexed for MEDLINE]
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Related Articles Human Amnion-Derived Cells: Prospects for the Treatment of Lung Diseases. Curr Stem Cell Res Ther. 2013 Apr 15; Authors: Carbone A, Paracchini V, Castellani S, Di Gioia S, Seia M, Colombo C, Conese M Abstract Lung diseases represent a significant burden of morbidity and mortality worldwide. Current therapies have not proven adequate in the long term and are often associated with significant side effects. There has been recent interest in the regenerative/reparative potential of cell-based therapies, including cells derived from the placental tissues. Amnion-derived cells are fetal-derived and characterized by expression profile and differentiative capacity of pluripotent cells. Moreover, because placenta is discarded after delivery, they represent an ethical source for the purposes of regenerative medicine. Amnion-derived cells are endowed with immunomodulatory, anti-inflammatory, anti-scarring and antibacterial properties, which may explain many of the beneficial effects observed with administration of the cells in animal models for a large number of inflammatory diseases. Both human amniotic epithelial cells (hAEC) and mesenchymal stromal cells (hAMSC) have been shown to acquire in vitro and in vivo some characteristics of epithelial cells, i.e. CFTR (cystic fibrosis transmembrane conductance regulator) and surfactant proteins. Administration of hAEC or hAMSC in vivo in the bleomycin-induced lung injury model has proven their therapeutic effects in term of reduction of pulmonary fibrosis and inflammation, as well as recovery of lung mechanical function. Many biological and clinical informations have to be gathered before proposing amnion-derived cells in the clinic for the treatment of acute and chronic lung diseases. PMID: 23597268 [PubMed - as supplied by publisher]
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Related Articles The potential for resident lung mesenchymal stem cells to promote functional tissue regeneration: understanding microenvironmental cues. Cells. 2012 Dec;1(4):874 Authors: Foronjy RF, Majka SM Abstract Tissue resident mesenchymal stem cells (MSCs) are important regulators of tissue repair or regeneration, fibrosis, inflammation, angiogenesis and tumor formation. Bone marrow derived mesenchymal stem cells (BM-MSCs) and endothelial progenitor cells (EPC) are currently being considered and tested in clinical trials as a potential therapy in patients with such inflammatory lung diseases including, but not limited to, chronic lung disease, pulmonary arterial hypertension (PAH), pulmonary fibrosis (PF), chronic obstructive pulmonary disease (COPD)/emphysema and asthma. However, our current understanding of tissue resident lung MSCs remains limited. This review addresses how environmental cues impact on the phenotype and function of this endogenous stem cell pool. In addition, it examines how these local factors influence the efficacy of cell-based treatments for lung diseases. PMID: 23626909 [PubMed]
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Related Articles Prognostic value of telomere attrition in patients with aplastic anemia. Int J Hematol. 2013 May;97(5):553-7 Authors: Scheinberg P Abstract The decision to pursue hematopoietic stem cell transplantation or immunosuppression as first therapy in severe aplastic anemia is currently based on age and availability of a histocompatible donor. The ability to predict hematologic response, relapse and clonal evolution could improve treatment allocation. In the past 15 years, telomeres have been implicated in clinical diseases such as aplastic anemia, pulmonary fibrosis, cirrhosis and cancer development. The clinical relevance of varying telomere lengths (TL) and/or mutations in genes of the telomerase complex (TERC, TERT) is evolving in aplastic anemia. A large retrospective analysis suggests that baseline TL associate with late events of hematologic relapse and clonal evolution in aplastic anemia patients treated initially with anti-thymocyte globulin-based therapy. Further laboratory experiments propose possible mechanistic insight into genomic instability of bone marrow cells derived from patients with critically short telomeres and/or mutation in telomerase genes. The possibility of modulating telomere attrition rate with sex hormones could positively affect clonal evolution rates in humans. This review will summarize studies in marrow failure that explore the association between telomeres and aplastic anemia outcomes. PMID: 23636667 [PubMed - indexed for MEDLINE]
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Related Articles Antifibrotic effects of focal adhesion kinase inhibitor in bleomycin-induced pulmonary fibrosis in mice. Am J Respir Cell Mol Biol. 2013 Oct;49(4):536-43 Authors: Kinoshita K, Aono Y, Azuma M, Kishi J, Takezaki A, Kishi M, Makino H, Okazaki H, Uehara H, Izumi K, Sone S, Nishioka Y Abstract Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase involved in various biological functions, including cell survival, proliferation, migration, and adhesion. FAK is an essential factor for transforming growth factor β to induce myofibroblast differentiation. In the present study, we investigated whether the targeted inhibition of FAK by using a specific inhibitor, TAE226, has the potential to regulate pulmonary fibrosis. TAE226 showed inhibitory activity of autophosphorylation of FAK at tyrosine 397 in lung fibroblasts. The addition of TAE226 inhibited the proliferation of lung fibroblasts in response to various growth factors, including platelet-derived growth factor and insulin-like growth factor I, in vitro. TAE226 strongly suppressed the production of type I collagen by lung fibroblasts. Furthermore, treatment of fibroblasts with TAE226 reduced the expression of α-smooth muscle actin induced by transforming growth factor β, indicating the inhibition of differentiation of fibroblasts to myofibroblasts. Administration of TAE226 ameliorated the pulmonary fibrosis induced by bleomycin in mice even when used late in the treatment. The number of proliferating mesenchymal cells was reduced in the lungs of TAE226-treated mice. These data suggest that FAK signal plays a significant role in the progression of pulmonary fibrosis and that it can become a promising target for therapeutic approaches to pulmonary fibrosis. PMID: 23642017 [PubMed - indexed for MEDLINE]
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Related Articles Paracrine effects and heterogeneity of marrow-derived stem/progenitor cells: relevance for the treatment of respiratory diseases. Cells Tissues Organs. 2013;197(6):445-73 Authors: Conese M, Carbone A, Castellani S, Di Gioia S Abstract Stem cell-based treatment may represent a hope for the treatment of acute lung injury and pulmonary fibrosis, and other chronic lung diseases, such as cystic fibrosis, asthma and chronic obstructive pulmonary disease (COPD). It is well established in preclinical models that bone marrow-derived stem and progenitor cells exert beneficial effects on inflammation, immune responses and repairing of damage in virtually all lung-borne diseases. While it was initially thought that the positive outcome was due to a direct engraftment of these cells into the lung as endothelial and epithelial cells, paracrine factors are now considered the main mechanism through which stem and progenitor cells exert their therapeutic effect. This knowledge has led to the clinical use of marrow cells in pulmonary hypertension with endothelial progenitor cells (EPCs) and in COPD with mesenchymal stromal (stem) cells (MSCs). Bone marrow-derived stem cells, including hematopoietic stem/progenitor cells, MSCs, EPCs and fibrocytes, encompass a wide array of cell subsets with different capacities of engraftment and injured tissue-regenerating potential. The characterization/isolation of the stem cell subpopulations represents a major challenge to improve the efficacy of transplantation protocols used in regenerative medicine and applied to lung disorders. PMID: 23652321 [PubMed - indexed for MEDLINE]
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Related Articles Treating skin and lung fibrosis in systemic sclerosis: a future filled with promise? Curr Opin Pharmacol. 2013 Jun;13(3):455-62 Authors: Antic M, Distler JH, Distler O Abstract Systemic sclerosis (SSc) is a rare autoimmune disorder characterized by immune activation, vascular damage and an excessive accumulation of extracellular matrix proteins in the skin and internal organs. Despite its high morbidity and increased mortality, currently available treatment options for fibrotic manifestations of SSc remain limited and their clinical antifibrotic effects are borderline. In this review, novel insights from recently published clinical trials in SSc on treatment concepts such as mycophenolate mofetil, oral type I collagen, recombinant human relaxin and autologous hematopoietic stem cell transplantation are discussed. In the past decade the most significant progress in this field has been made by the identification of a large number of cellular and molecular key players in the pathogenesis of fibrotic disease manifestations. This has led to the identification of novel candidates as molecular targets for treatment of fibrotic diseases. On the basis of their level of evidence from preclinical studies and based on the availability of first clinical results, the most promising targets are presented including inhibitors of B-cells, tyrosine kinases, 5-hydroxytryptamin receptors, interleukin-6 and Wnt signalling. PMID: 23747024 [PubMed - indexed for MEDLINE]
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Related Articles Effects of mesenchymal stem cell therapy on the time course of pulmonary remodeling depend on the etiology of lung injury in mice. Crit Care Med. 2013 Nov;41(11):e319-33 Authors: Maron-Gutierrez T, Silva JD, Asensi KD, Bakker-Abreu I, Shan Y, Diaz BL, Goldenberg RC, Mei SH, Stewart DJ, Morales MM, Rocco PR, Dos Santos CC Abstract OBJECTIVE: Recent evidence suggests that mesenchymal stem cells may attenuate lung inflammation and fibrosis in acute lung injury. However, so far, no study has investigated the effects of mesenchymal stem cell therapy on the time course of the structural, mechanical, and remodeling properties in pulmonary or extrapulmonary acute lung injury. DESIGN: Prospective randomized controlled experimental study. SETTING: University research laboratory. SUBJECTS: One hundred forty-three females and 24 male C57BL/6 mice. INTERVENTIONS: Control mice received saline solution intratracheally (0.05 mL, pulmonary control) or intraperitoneally (0.5 mL, extrapulmonary control). Acute lung injury mice received Escherichia coli lipopolysaccharide intratracheally (2 mg/kg in 0.05 mL of saline/mouse, pulmonary acute lung injury) or intraperitoneally (20 mg/kg in 0.5 mL of saline/mouse, extrapulmonary acute lung injury). Mesenchymal stem cells were intravenously injected (IV, 1 × 10 cells in 0.05 mL of saline/mouse) 1 day after lipopolysaccharide administration. MEASUREMENTS AND MAIN RESULTS: At days 1, 2, and 7, static lung elastance and the amount of alveolar collapse were similar in pulmonary and extrapulmonary acute lung injury groups. Inflammation was markedly increased at day 2 in both acute lung injury groups as evidenced by neutrophil infiltration and levels of cytokines in bronchoalveolar lavage fluid and lung tissue. Conversely, collagen deposition was only documented in pulmonary acute lung injury. Mesenchymal stem cell mitigated changes in elastance, alveolar collapse, and inflammation at days 2 and 7. Compared with extrapulmonary acute lung injury, mesenchymal stem cell decreased collagen deposition only in pulmonary acute lung injury. Furthermore, mesenchymal stem cell increased metalloproteinase-8 expression and decreased expression of tissue inhibitor of metalloproteinase-1 in pulmonary acute lung injury, suggesting that mesenchymal stem cells may have an effect on the remodeling process. This change may be related to a shift in macrophage phenotype from M1 (inflammatory and antimicrobial) to M2 (wound repair and inflammation resolution) phenotype. CONCLUSIONS: Mesenchymal stem cell therapy improves lung function through modulation of the inflammatory and remodeling processes. In pulmonary acute lung injury, a reduction in collagen fiber content was observed associated with a balance between metalloproteinase-8 and tissue inhibitor of metalloproteinase-1 expressions. PMID: 23760104 [PubMed - indexed for MEDLINE]
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Related Articles Historical perspective on effects and treatment of sulfur mustard injuries. Chem Biol Interact. 2013 Dec 5;206(3):512-22 Authors: Graham JS, Schoneboom BA Abstract Sulfur mustard (2,2'-dichlorodiethyl sulfide; SM) is a potent vesicating chemical warfare agent that poses a continuing threat to both military and civilian populations. Significant SM injuries can take several months to heal, necessitate lengthy hospitalizations, and result in long-term complications affecting the skin, eyes, and lungs. This report summarizes initial and ongoing (chronic) clinical findings from SM casualties from the Iran-Iraq War (1980-1988), with an emphasis on cutaneous injury. In addition, we describe the cutaneous manifestations and treatment of several men recently and accidentally exposed to SM in the United States. Common, chronic cutaneous problems being reported in the Iranian casualties include pruritis (the primary complaint), burning, pain, redness, desquamation, hyperpigmentation, hypopigmentation, erythematous papular rash, xerosis, multiple cherry angiomas, atrophy, dermal scarring, hypertrophy, and sensitivity to mechanical injury with recurrent blistering and ulceration. Chronic ocular problems include keratitis, photophobia, persistent tearing, sensation of foreign body, corneal thinning and ulceration, vasculitis of the cornea and conjunctiva, and limbal stem cell deficiency. Chronic pulmonary problems include decreases in lung function, bronchitis with hyper-reactive airways, bronchiolitis, bronchiectasis, stenosis of the trachea and other large airways, emphysema, pulmonary fibrosis, decreased total lung capacity, and increased incidences of lung cancer, pulmonary infections, and tuberculosis. There are currently no standardized or optimized methods of casualty management; current treatment strategy consists of symptomatic management and is designed to relieve symptoms, prevent infections, and promote healing. New strategies are needed to provide for optimal and rapid healing, with the goals of (a) returning damaged tissue to optimal appearance and normal function in the shortest period of time, and (b) ameliorating chronic effects. Further experimental research and clinical trials will be needed to prevent or mitigate the acute clinical effects of SM exposure and to reduce or eliminate the long-term manifestations. PMID: 23816402 [PubMed - indexed for MEDLINE]
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Related Articles Therapeutic effect of exogenous bone marrow‑derived mesenchymal stem cell transplantation on silicosis via paracrine mechanisms in rats. Mol Med Rep. 2013 Sep;8(3):741-6 Authors: Zhao MM, Cui JZ, Cui Y, Li R, Tian YX, Song SX, Zhang J, Gao JL Abstract Silicosis is a well-known occupational disease, characterized by epithelial injury, fibroblast proliferation, expansion of the lung matrix and dyspnea. At present, no effective treatment methods for silicosis have been identified. The present study aimed to investigate the protective potential of exogenous bone marrow-derived mesenchymal stem cell (BMSC) transplantation on experimental silica-induced pulmonary fibrosis in rats and analyze the underlying paracrine mechanisms associated with its therapeutic effects. BMSCs were isolated, cultured and passaged from male Sprague-Dawley (SD) rat bone marrow. Third-generation BMSCs were identified by flow cytometry using FITC staining. Following the successful establishment of the silicosis model, exogenous BMSCs were infused into female adult SD rats via the tail vein. Lungs were evaluated using hematoxylin and eosin (H&E) staining. The expression of interleukin-1 receptor antagonist (IL‑1RA), interleukin-1 (IL-1) and tumor necrosis factor α (TNF-α) protein was detected by immunohistochemistry and western blot analysis. Co-localization of sex determining region Y (SRY) and IL-1RA expression was determined by double-label immunofluorescence. The distribution of transplanted BMSCs was tracked by monitoring the expression of SRY in rats. Treatment with BMSCs was found to protect the lungs against injury and fibrosis by the suppression of upregulated IL-1 and TNF-α protein, via triggering IL-1RA secretion. This mechanism was hypothesized to be mediated by paracrine signaling. These results indicate that the release of IL‑1RA from BMSCs via paracrine mechanisms significantly blocks the production and/or activity of IL-1 and TNF-α. The present study provides an experimental basis for cellular therapy in silicosis. PMID: 23842733 [PubMed - indexed for MEDLINE]
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Related Articles A prospective, non-randomized, no placebo-controlled, phase Ib clinical trial to study the safety of the adipose derived stromal cells-stromal vascular fraction in idiopathic pulmonary fibrosis. J Transl Med. 2013;11:171 Authors: Tzouvelekis A, Paspaliaris V, Koliakos G, Ntolios P, Bouros E, Oikonomou A, Zissimopoulos A, Boussios N, Dardzinski B, Gritzalis D, Antoniadis A, Froudarakis M, Kolios G, Bouros D Abstract INTRODUCTION: Regenerative medicine and particular adult stem cells represent an alternative option with several fruitful therapeutic applications in patients suffering from chronic lung diseases including idiopathic pulmonary fibrosis (IPF). Nevertheless, lack of knowledge regarding the origin and the potential of mesenchymal stem cells (MSCs) to differentiate into fibroblasts has limited their use for the treatment of this dismal disease. PATIENTS AND METHODS: To this end, we conducted a phase Ib, non-randomized, clinical trial to study the safety of three endobronchial infusions of autologous adipose derived stromal cells (ADSCs)-stromal vascular fraction (SVF) (0.5 million cells per kgr of body weight per infusion) in patients with IPF (n=14) of mild to moderate disease severity (forced vital capacity -FVC>50% predicted value and diffusion lung capacity for carbon monoxide-DLCO>35% of predicted value). Our primary end-point was incidence of treatment emergent adverse events within 12 months. Alterations of functional, exercise capacity and quality of life parameters at serial time points (baseline, 6 and 12 months after first infusion) were exploratory secondary end-points. RESULTS: No cases of serious or clinically meaningful adverse events including short-term infusional toxicities as well as long-term ectopic tissue formation were recorded in all patients. Detailed safety monitoring through several time-points indicated that cell-treated patients did not deteriorate in both functional parameters and indicators of quality of life. CONCLUSIONS: The clinical trial met its primary objective demonstrating an acceptable safety profile of endobronchially administered autologous ADSCs-SVF. Our findings accelerate the rapidly expanded scientific knowledge and indicate a way towards future efficacy trials. PMID: 23855653 [PubMed - indexed for MEDLINE]
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Related Articles Cell therapy trials for lung diseases: progress and cautions. Am J Respir Crit Care Med. 2013 Jul 15;188(2):123-5 Authors: Weiss DJ, Ortiz LA PMID: 23855686 [PubMed - indexed for MEDLINE]
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Related Articles Steep barriers to overcome for successful application of stem cell treatment in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2013 Jul 15;188(2):251-2 Authors: Tzouvelekis A, Bouros D PMID: 23855695 [PubMed - indexed for MEDLINE]
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Related Articles Idiopathic pulmonary fibrosis: a degenerative disease requiring a regenerative approach. Am J Respir Crit Care Med. 2013 Jul 15;188(2):252-3 Authors: Chambers DC, Hopkins PM PMID: 23855696 [PubMed - indexed for MEDLINE]
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Related Articles Reply: idiopathic pulmonary fibrosis: a degenerative disease requiring a regenerative approach. Am J Respir Crit Care Med. 2013 Jul 15;188(2):253-4 Authors: Glassberg MK, Hare JM, Toonkel RL, Matthay MA PMID: 23855697 [PubMed - indexed for MEDLINE]
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Related Articles Inhibition of Wnt/β-catenin signaling promotes engraftment of mesenchymal stem cells to repair lung injury. J Cell Physiol. 2014 Feb;229(2):213-24 Authors: Sun Z, Gong X, Zhu H, Wang C, Xu X, Cui D, Qian W, Han X Abstract We sought to explore the treatment effects and the repair mechanisms of bone marrow derived mesenchymal stem cells (MSCs) during HCl-induced acute lung injury (ALI). MSCs were delivered through the tail veins of rats 24 h after intranasal instillation of HCl. The results showed that MSCs did not ameliorate the histopathologic changes of ALI and pulmonary fibrosis. We found that the activated Wnt/β-catenin signaling may regulate the differentiation of MSCs and is associated with lung fibroblasts activation, pulmonary fibrosis and tissue repair process in ALI rats. Immunofluorescence and histology analysis indicated that activated canonical Wnt/β-catenin signaling induced most MSCs to differentiate into myofibroblasts or fibroblasts in vivo. However, inhibition of Wnt/β-catenin signaling by Dickkopf-1 (DKK1) promotes epithelial differentiation of MSCs induced by native alveolar epithelial cells which are beneficial to repair the injured lung epithelium. Inhibition of Wnt/β-catenin signaling after MSCs transplantation ameliorated pulmonary fibrosis and improved pulmonary function which attenuated the lung injury. In vitro study, activation of the Wnt/β-catenin signaling stimulated MSCs to express myofibroblasts markers, which was attenuated by DKK1. Furthermore, Wnt3α activated Wnt/β-catenin signaling in lung fibroblasts to enhance the expression of collagen I, vimentin and α-smooth muscle actin, but DKK1 attenuated these proteins expression. These findings demonstrated that canonical Wnt/β-catenin signaling plays a key role in regulating differentiation of MSCs in vivo or in vitro and the pathogenesis of fibrotic diseases. Our study suggested that inhibition of abnormal activated Wnt/β-catenin signaling would promote MSCs epithelial differentiation to repair lung injury and reduce pulmonary fibrosis. PMID: 23881674 [PubMed - indexed for MEDLINE]
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Related Articles Cell therapy for cystic fibrosis. J Tissue Eng Regen Med. 2013 Jul 25; Authors: Murphy SV, Atala A Abstract Currently there is no cure for cystic fibrosis (CF). Treatments are focused on addressing the disease symptoms, with varying degrees of success. Regenerative medicine holds the promise of regenerating dysfunctional or damaged tissues and to enhance the body's own endogenous repair mechanisms. The discovery of endogenous and exogenous stem cells has provided valuable tools for development of novel treatments for CF. The ability of stem cells to differentiate into functional pulmonary cells, modulate inflammatory responses and contribute to pulmonary function has provided researchers with multiple approaches to develop effective treatment strategies. Several approaches show promise to produce viable therapeutic treatments to treat the underlying cause of CF, reduce the symptoms and mitigate long-term damage, and generate functional replacement organs for end-stage transplantation. This review provides an overview of the rapidly progressing field of cell therapy for CF, focusing on the various cell types utilized and current strategies that show promise to improve life expectancy and quality of life for CF patients. Copyright © 2013 John Wiley & Sons, Ltd. PMID: 23894126 [PubMed - as supplied by publisher]
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Related Articles p90 ribosomal S6 kinase 3 contributes to cardiac insufficiency in α-tropomyosin Glu180Gly transgenic mice. Am J Physiol Heart Circ Physiol. 2013 Oct 1;305(7):H1010-9 Authors: Passariello CL, Gayanilo M, Kritzer MD, Thakur H, Cozacov Z, Rusconi F, Wieczorek D, Sanders M, Li J, Kapiloff MS Abstract Myocardial interstitial fibrosis is an important contributor to the development of heart failure. Type 3 p90 ribosomal S6 kinase (RSK3) was recently shown to be required for concentric myocyte hypertrophy under in vivo pathological conditions. However, the role of RSK family members in myocardial fibrosis remains uninvestigated. Transgenic expression of α-tropomyosin containing a Glu180Gly mutation (TM180) in mice of a mixed C57BL/6:FVB/N background induces a cardiomyopathy characterized by a small left ventricle, interstitial fibrosis, and diminished systolic and diastolic function. Using this mouse model, we now show that RSK3 is required for the induction of interstitial fibrosis in vivo. TM180 transgenic mice were crossed to RSK3 constitutive knockout (RSK3(-/-)) mice. Although RSK3 knockout did not affect myocyte growth, the decreased cardiac function and mild pulmonary edema associated with the TM180 transgene were attenuated by RSK3 knockout. The improved cardiac function was consistent with reduced interstitial fibrosis in the TM180;RSK3(-/-) mice as shown by histology and gene expression analysis, including the decreased expression of collagens. The specific inhibition of RSK3 should be considered as a potential novel therapeutic strategy for improving cardiac function and the prevention of sudden cardiac death in diseases in which interstitial fibrosis contributes to the development of heart failure. PMID: 23913705 [PubMed - indexed for MEDLINE]
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Related Articles Protection against hyperoxia-induced lung fibrosis by KGF-induced MSCs mobilization in neonatal rats. Pediatr Transplant. 2013 Nov;17(7):676-82 Authors: Yao L, Liu CJ, Luo Q, Gong M, Chen J, Wang LJ, Huang Y, Jiang X, Xu F, Li TY, Shu C Abstract MSCs have been shown to improve functional and pathological outcome in lung fibrosis. However, low in vivo cell engraftment of the transplanted cells limits their overall effectiveness. KGF (also known as FGF-7) is a critical mediator of pulmonary epithelial repair through stimulation of epithelial cell proliferation. However, the role of KGF in MSCs and its therapeutic effects have not been identified. In this study, we investigated the effect of KGF on MSCs and its preventive role in hyperoxia-induced fibrosis in neonatal rats. Neonatal rats exposed to normoxia or hyperoxia were randomly assigned to receive intraperitoneal injections of normal saline (PL), MSCs, or KGF pretreated MSCs on the fourth day of exposure. Our results showed that as compared to PL, while MSCs attenuated lung fibrosis, KGF pretreated MSCs exhibited enhanced preventive effect against lung fibrosis. This effect was partly attributed to enhanced mobilization of MSCs to the fibrotic lungs. In addition, the SHH signaling pathway, which is associated with the differentiation of stem cells was activated by KGF. Our data suggest that MSCs, especially KGF preconditioned MSCs, can attenuate lung fibrosis and KGF may regulate the MSCs behavior by activating SHH pathway. PMID: 23919829 [PubMed - indexed for MEDLINE]
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Related Articles Amniotic fluid stem cells inhibit the progression of bleomycin-induced pulmonary fibrosis via CCL2 modulation in bronchoalveolar lavage. PLoS One. 2013;8(8):e71679 Authors: Garcia O, Carraro G, Turcatel G, Hall M, Sedrakyan S, Roche T, Buckley S, Driscoll B, Perin L, Warburton D Abstract The potential for amniotic fluid stem cell (AFSC) treatment to inhibit the progression of fibrotic lung injury has not been described. We have previously demonstrated that AFSC can attenuate both acute and chronic-fibrotic kidney injury through modification of the cytokine environment. Fibrotic lung injury, such as in Idiopathic Pulmonary Fibrosis (IPF), is mediated through pro-fibrotic and pro-inflammatory cytokine activity. Thus, we hypothesized that AFSC treatment might inhibit the progression of bleomycin-induced pulmonary fibrosis through cytokine modulation. In particular, we aimed to investigate the effect of AFSC treatment on the modulation of the pro-fibrotic cytokine CCL2, which is increased in human IPF patients and is correlated with poor prognoses, advanced disease states and worse fibrotic outcomes. The impacts of intravenous murine AFSC given at acute (day 0) or chronic (day 14) intervention time-points after bleomycin injury were analyzed at either day 3 or day 28 post-injury. Murine AFSC treatment at either day 0 or day 14 post-bleomycin injury significantly inhibited collagen deposition and preserved pulmonary function. CCL2 expression increased in bleomycin-injured bronchoalveolar lavage (BAL), but significantly decreased following AFSC treatment at either day 0 or at day 14. AFSC were observed to localize within fibrotic lesions in the lung, showing preferential targeting of AFSC to the area of fibrosis. We also observed that MMP-2 was transiently increased in BAL following AFSC treatment. Increased MMP-2 activity was further associated with cleavage of CCL2, rendering it a putative antagonist for CCL2/CCR2 signaling, which we surmise is a potential mechanism for CCL2 reduction in BAL following AFSC treatment. Based on this data, we concluded that AFSC have the potential to inhibit the development or progression of fibrosis in a bleomycin injury model during both acute and chronic remodeling events. PMID: 23967234 [PubMed - indexed for MEDLINE]
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Related Articles Mesenchymal stem cell therapy in lung disorders: pathogenesis of lung diseases and mechanism of action of mesenchymal stem cell. Exp Lung Res. 2013 Oct;39(8):315-27 Authors: Inamdar AC, Inamdar AA Abstract Lung disorders such as asthma, acute respiratory distress syndrome (ARDS), chronic obstructive lung disease (COPD), and interstitial lung disease (ILD) show a few common threads of pathogenic mechanisms: inflammation, aberrant immune activity, infection, and fibrosis. Currently no modes of effective treatment are available for ILD or emphysema. Being anti-inflammatory, immunomodulatory, and regenerative in nature, the administration of mesenchymal stem cells (MSCs) has shown the capacity to control immune dysfunction and inflammation in the lung. The intravenous infusion of MSCs, the common mode of delivery, is followed by their entrapment in lung vasculature before MSCs reach to other organ systems thus indicating the feasible and promising approach of MSCs therapy for lung diseases. In this review, we discuss the mechanistic basis for MSCs therapy for asthma, ARDS, COPD, and ILD. PMID: 23992090 [PubMed - indexed for MEDLINE]
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Related Articles [Treatment and course of a man with systemic sclerosis before and after hematopoetic blood stem cell transplantation]. Dtsch Med Wochenschr. 2013 Sep;138(37):1824-7 Authors: Blank N, Lorenz HM Abstract HISTORY AND ADMISSION FINDINGS: A 66-year-old patient presented in our clinic with increasing painful swelling of his hands, whole body stiffness, weight loss and dyspnoea upon exercise. EXAMINATIONS: The physical examination revealed a marked skin sclerosis of hands, extremities and the face. Fist closure was impossible. Pulmonary CT scan showed lung fibrosis and ground glass opacities. Antinuclear antibodies and antibodies against Scl70 were positive. CRP, LDH, NT-Pro-BNP were elevated. DIAGNOSIS, TREATMENT AND COURSE: A diffuse cutaneous systemic sclerosis with an active interstitial pneumonia and lung fibrosis was diagnosed. Three pulses of cyclophosphamide 1.4 g every three weeks were ineffective to halt the progression of skin sclerosis, joint contractures and decline of pulmonary function. Mobilisation chemotherapy was initialized and blood stem cells were harvested. Blood stem cells were reinfused after myeloablative chemotherapy with melphalan. A maintainance therapy with mycophenolic acid was initiated after recovery of hematopoiesis. Six months after blood stem cell transplantation a decrease of skin sclerosis and an increasing recovery of joint mobility and physical strength was observed. CONCLUSION: Patients with a progressive systemic sclerosis and further risk factors should be treated with high-dose chemotherapy with blood stem cell transplantation before organ function is severely compromised. In cases with contraindications against cyclophosphamide or anti-thymocyte-globulin melphalan can be discussed as an alternative. PMID: 24006162 [PubMed - indexed for MEDLINE]
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Related Articles Lung bone marrow-derived hematopoietic progenitor cells enhance pulmonary fibrosis. Am J Respir Crit Care Med. 2013 Oct 15;188(8):976-84 Authors: Nakashima T, Liu T, Yu H, Ding L, Ullenbruch M, Hu B, Wu Z, Oguro H, Phan SH Abstract RATIONALE: Bone marrow (BM)-derived cells have been implicated in pulmonary fibrosis. However, their precise role in pathogenesis is incompletely understood. OBJECTIVES: To elucidate roles of BM-derived cells in bleomycin-induced pulmonary fibrosis, and clarify their potential relationship to lung hematopoietic progenitor cells (LHPCs). METHODS: GFP BM-chimera mice treated with or without bleomycin were used to assess the BM-derived cells. MEASUREMENTS AND MAIN RESULTS: GFP(+) cells in the chimera lung were found to be comprised of two distinct phenotypes: GFP(hi) and GFP(low) cells. The GFP(hi), but not GFP(low), population was significantly increased after bleomycin treatment. Flow-cytometric analysis and quantitative real-time polymerase chain reaction revealed that GFP(hi) cells exhibited phenotypic characteristics of CD11c(+) dendritic cells and macrophages. GFP(hi) cell conditioned media were chemotactic for fibroblasts obtained from fibrotic but not normal lung in vitro. Moreover, adoptive transfer of GFP(hi) cells exacerbated fibrosis in recipient mice, similar to that seen on adoptive transfer of BM-derived CD11c(+) cells from donor bleomycin-treated mice. Next, we evaluated the potential of LHPCs as the source of GFP(hi) cells. Isolation of LHPCs by flow sorting revealed enrichment in cKit(+)/Sca1(-)/Lin(-) cells, most of which were GFP(+) indicating their BM origin. The number of LHPCs increased rapidly after bleomycin treatment. Furthermore, stem cell factor induced LHPC proliferation, whereas granulocyte-macrophage-colony stimulating factor induced differentiation to GFP(hi) cells. CONCLUSIONS: BM-derived LHPCs with a novel phenotype could differentiate into GFP(hi) cells, which enhanced pulmonary fibrosis. Targeting this mobilized LHPCs might represent a novel therapeutic approach in chronic fibrotic lung diseases. PMID: 24010731 [PubMed - indexed for MEDLINE]
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Related Articles [Interests and potentials of adipose tissue in scleroderma]. Rev Med Interne. 2013 Dec;34(12):763-9 Authors: Daumas A, Eraud J, Hautier A, Sabatier F, Magalon G, Granel B Abstract Systemic sclerosis is a disorder involving the connective tissue, arterioles and microvessels. It is characterized by skin and visceral fibrosis and ischemic phenomena. Currently, therapy is limited and no antifibrotic treatment has proven its efficacy. Beyond some severe organ lesions (pulmonary arterial hypertension, pulmonary fibrosis, scleroderma renal crisis), which only concern a minority of patients, the skin sclerosis of hands and face and the vasculopathy lead to physical and psychological disability in most patients. Thus, functional improvement of hand motion and face represents a priority for patient therapy. Due to its easy obtention by fat lipopaspirate and adipocytes survival, re injection of adipose tissue is a common therapy used in plastic surgery for its voluming effect. Identification and characterization of the adipose tissue-derived stroma vascular fraction, mainly including mesenchymal stem cells, have revolutionized the science showing that adipose tissue is a valuable source of multipotent stem cells, able to migrate to site of injury and to differentiate according to the receiver tissue's needs. Due to easy harvest by liposuction, its abundance in mesenchymal cells far higher that the bone marrow, and stroma vascular fraction's ability to differentiate and secrete growth angiogenic and antiapoptotic factors, the use of adipose tissue is becoming more attractive in regenerative medicine. We here present the interest of adipose tissue use in the treatment of the hands and face in scleroderma. PMID: 24050783 [PubMed - indexed for MEDLINE]
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Related Articles Cardiac matrix: a clue for future therapy. Biochim Biophys Acta. 2013 Dec;1832(12):2271-6 Authors: Mishra PK, Givvimani S, Chavali V, Tyagi SC Abstract Cardiac muscle is unique because it contracts ceaselessly throughout the life and is highly resistant to fatigue. The marvelous nature of the cardiac muscle is attributed to its matrix that maintains structural and functional integrity and provides ambient micro-environment required for mechanical, cellular and molecular activities in the heart. Cardiac matrix dictates the endothelium myocyte (EM) coupling and contractility of cardiomyocytes. The matrix metalloproteinases (MMPs) and their tissue inhibitor of metalloproteinases (TIMPs) regulate matrix degradation that determines cardiac fibrosis and myocardial performance. We have shown that MMP-9 regulates differential expression of micro RNAs (miRNAs), calcium cycling and contractility of cardiomyocytes. The differential expression of miRNAs is associated with angiogenesis, hypertrophy and fibrosis in the heart. MMP-9, which is involved in the degradation of cardiac matrix and induction of fibrosis, is also implicated in inhibition of survival and differentiation of cardiac stem cells (CSC). Cardiac matrix is distinct because it renders mechanical properties and provides a framework essential for differentiation of cardiac progenitor cells (CPC) into specific lineage. Cardiac matrix regulates myocyte contractility by EM coupling and calcium transients and also directs miRNAs required for precise regulation of continuous and synchronized beating of cardiomyocytes that is indispensible for survival. Alteration in the matrix homeostasis due to induction of MMPs, altered expression of specific miRNAs or impaired signaling for contractility of cardiomyocytes leads to catastrophic effects. This review describes the mechanisms by which cardiac matrix regulates myocardial performance and suggests future directions for the development of treatment strategies in cardiovascular diseases. PMID: 24055000 [PubMed - indexed for MEDLINE]
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Related Articles [Experimental treatment of pulmonary interstitial fibrosis with human umbilical cord blood mesenchymal stem cells]. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi. 2013 Sep;31(9):675-80 Authors: Wang HY, Liu C, Wang Y, Zhang LL, Liu XR, Liu HL Abstract OBJECTIVE: To investigate the therapeutic effect and possible action mechanism of human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) in the treatment of bleomycin-induced pulmonary fibrosis in rats. METHODS: The second generation of hUCB-MSCs was cultured to the fourth generation. Sixty healthy male Sprague-Dawley rats (clean grade) were randomly and equally divided into 4 groups: bleomycin group, stem cell treatment group, dexamethasone treatment group, and negative control group. A pulmonary fibrosis model was established by intratracheal instillation of bleomycin in the bleomycin group, stem cell treatment group, and dexamethasone treatment group. The stem cell treatment group was injected with stem cells labeled with 5-bromo-2-deoxyuridine (Brdu) via the caudal vein immediately after the model was established. The dexamethasone treatment group was intraperitoneally injected with dexamethasone for 7 d from the next day after the model was established. The negative control group was given an equal volume of normal saline by intra-tracheal instillation. In each group, 5 rats were sacrificed in the 7th, 14th, and 28th days. The expression of transforming growth factor β1 (TGF-β1) and Brdu-labeled stem cells were observed by HE and Masson staining and immunohistochemistry. Lung hydroxyproline content was determined by acid hydrolysis. RESULTS: The stem cell treatment groups had Brdu-labeled stem cells seen in lung tissue in the 7th, 14th, and 28th days. Compared with the negative control group, the bleomycin group, stem cell treatment group, and dexamethasone treatment group had significantly increased scores of alveolitis and pulmonary fibrosis (P < 0.05). In the 7th, 14th, and 28th days, the scores of alveolitis in stem cell treatment group and dexamethasone treatment group were significantly lower than those in bleomycin group (P < 0.05); in the 28th day, the scores of pulmonary fibrosis in stem cell treatment group and dexamethasone treatment group were significantly lower than that in bleomycin group (P < 0.05). There were no significant differences in scores of alveolitis and pulmonary fibrosis between the dexamethasone treatment group and stem cell treatment group (P > 0.05). Compared with the bleomycin group, the stem cell treatment group and dexamethasone treatment group had significantly decreased number of TGF-β1-positive cells and hydroxyproline content in lung tissue at all time points (P < 0.05). There were no significant differences in number of TGF-β1-positive cells and hydroxyproline content in lung tissue between the stem cell treatment group and dexamethasone treatment group (P > 0.05). CONCLUSION: hUCB-MSCs can be transplanted into damaged lung tissue and effectively reduce alveolitis and pulmonary fibrosis in the early stage of pulmonary fibrosis. The action mechanism of hUCB-MSCs may involve inhibiting the expression of TGF-β1 and reducing the formation of collagen. PMID: 24064124 [PubMed - indexed for MEDLINE]
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Related Articles Oxidative stress elicits platelet/leukocyte inflammatory interactions via HMGB1: a candidate for microvessel injury in sytemic sclerosis. Antioxid Redox Signal. 2014 Mar 1;20(7):1060-74 Authors: Maugeri N, Rovere-Querini P, Baldini M, Baldissera E, Sabbadini MG, Bianchi ME, Manfredi AA Abstract AIMS: An abnormal generation of reactive oxygen species (ROS) is thought to contribute to systemic sclerosis (SSc), fostering autoimmunity, fibrosis, and vascular inflammation. The function of the prototypic damage-associated molecular pattern, high mobility group box 1 (HMGB1), depends on its redox status. Here we investigate whether oxidative stress regulates the cross-talk between leukocytes and platelets via HMGB1, thus contributing to vessel inflammation in SSc. RESULTS: The oxidation of HMGB1 amplified its ability to activate neutrophils, as detected assessing the redistribution of primary granule molecules and the transactivation of the β2 integrin chain CD18. Activated platelets are a source of bioactive HMGB1 and via P-selectin stimulated neutrophils to generate ROS. Oxidized extracellular HMGB1, soluble or associated to platelet membrane or to platelet-derived microparticles (PDμPs), further increased leukocyte activation. Leukocyte activation abated in the presence of inhibitors of HMGB1 or of catalase, which catalyzes the dismutation of hydrogen peroxide into water and molecular oxygen. The redistribution of the content of primary granules and the transactivation of β2 integrins characterized blood leukocytes of SSc patients and membrane HMGB1 was significantly higher in patients with pulmonary hypertension or with diffuse SSc. HMGB1(+) microparticles (μPs) purified from SSc patients, but not HMGB1(-) μPs purified from control subjects, activated in vitro healthy neutrophils, and HMGB1 inhibitors reversed the effects of μPs. INNOVATION AND CONCLUSION: ROS dramatically increase the ability of extracellular HMGB1 to activate blood leukocytes. This event might contribute to maintain the microvascular injury of patients with SSc. PMID: 24070090 [PubMed - in process]
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Related Articles Hepatocyte growth factor regulates immune reactions caused by transplantation and autoimmune diseases. Yakugaku Zasshi. 2013;133(11):1159-67 Authors: Iwasaki T, Shibasaki S Abstract Hepatocyte growth factor (HGF) was first identified and cloned as a mitogenic protein for hepatocytes, and subsequent studies revealed that HGF has multiple biological effects on a wide variety of cells, including mitogenic, motogenic, morphogenic, anti-apoptotic, and angiogenic activities. It plays roles in organizing tissues during development and regeneration. HGF may be applied for the treatment of acute onset diseases such as fulminant hepatitis, myocardial infarction, acute renal failure, cerebral infarction, and chronic diseases like liver cirrhosis, chronic renal failure, pulmonary fibrosis, cardiomyopathy, and arteriosclerosis obliterans. HGF also has immunomodulatory activities and we previously demonstrated that its administration inhibited acute graft-versus-host disease (GVHD) after treatment with hematopoietic stem cell transplantation. We also demonstrated that HGF inhibited lupus nephritis induced by chronic GVHD and dermal sclerosis in systemic sclerosis using model mice. More than 7 hundred thousand patients suffer from rheumatoid arthritis (RA) in Japan. Although the prognosis of these patients has improved by the treatment of biological agents such as TNF-α and IL-6 blockers, there remain many for whom these agents have not proved beneficial. Recently, using RA model mice, we demonstrated that the HGF antagonist, NK4, can block disease progression of RA through its anti-angiogenic and immunomodulatory actions. In this review article, we discuss the possible roles of HGF signaling for the treatment of immunological reactions in transplantation and autoimmune diseases. PMID: 24189557 [PubMed - in process]
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Related Articles Inhibition of the CXCL12/CXCR4-axis as preventive therapy for radiation-induced pulmonary fibrosis. PLoS One. 2013;8(11):e79768 Authors: Shu HK, Yoon Y, Hong S, Xu K, Gao H, Hao C, Torres-Gonzalez E, Nayra C, Rojas M, Shim H Abstract BACKGROUND: A devastating late injury caused by radiation is pulmonary fibrosis. This risk may limit the volume of irradiation and compromise potentially curative therapy. Therefore, development of a therapy to prevent this toxicity can be of great benefit for this patient population. Activation of the chemokine receptor CXCR4 by its ligand stromal cell-derived factor 1 (SDF-1/CXCL12) may be important in the development of radiation-induced pulmonary fibrosis. Here, we tested whether MSX-122, a novel small molecule and partial CXCR4 antagonist, can block development of this fibrotic process. METHODOLOGY/PRINCIPAL FINDINGS: The radiation-induced lung fibrosis model used was C57BL/6 mice irradiated to the entire thorax or right hemithorax to 20 Gy. Our parabiotic model involved joining a transgenic C57BL/6 mouse expressing GFP with a wild-type mouse that was subsequently irradiated to assess for migration of GFP+ bone marrow-derived progenitor cells to the irradiated lung. CXCL12 levels in the bronchoalveolar lavage fluid (BALF) and serum after irradiation were determined by ELISA. CXCR4 and CXCL12 mRNA in the irradiated lung was determined by RNase protection assay. Irradiated mice were treated daily with AMD3100, an established CXCR4 antagonist; MSX-122; and their corresponding vehicles to determine impact of drug treatment on fibrosis development. Fibrosis was assessed by serial CTs and histology. After irradiation, CXCL12 levels increased in BALF and serum with a corresponding rise in CXCR4 mRNA within irradiated lungs consistent with recruitment of a CXCR4+ cell population. Using our parabiotic model, we demonstrated recruitment of CXCR4+ bone marrow-derived mesenchymal stem cells, identified based on marker expression, to irradiated lungs. Finally, irradiated mice that received MSX-122 had significant reductions in development of pulmonary fibrosis while AMD3100 did not significantly suppress this fibrotic process. CONCLUSIONS/SIGNIFICANCE: CXCR4 inhibition by drugs such as MSX-122 may alleviate potential radiation-induced lung injury, presenting future therapeutic opportunities for patients requiring chest irradiation. PMID: 24244561 [PubMed - in process]
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Related Articles Lysophosphatidic acid accelerates lung fibrosis by inducing differentiation of mesenchymal stem cells into myofibroblasts. J Cell Mol Med. 2014 Jan;18(1):156-69 Authors: Tang N, Zhao Y, Feng R, Liu Y, Wang S, Wei W, Ding Q, An MS, Wen J, Li L Abstract Lung fibrosis is characterized by vascular leakage and myofibroblast recruitment, and both phenomena are mediated by lysophosphatidic acid (LPA) via its type-1 receptor (LPA1). Following lung damage, the accumulated myofibroblasts activate and secrete excessive extracellular matrix (ECM), and form fibrotic foci. Studies have shown that bone marrow-derived cells are an important source of myofibroblasts in the fibrotic organ. However, the type of cells in the bone marrow contributing predominantly to the myofibroblasts and the involvement of LPA-LPA1 signalling in this is yet unclear. Using a bleomycin-induced mouse lung-fibrosis model with an enhanced green fluorescent protein (EGFP) transgenic mouse bone marrow replacement, we first demonstrated that bone marrow derived-mesenchymal stem cells (BMSCs) migrated markedly to the bleomycin-injured lung. The migrated BMSC contributed significantly to α-smooth muscle actin (α-SMA)-positive myofibroblasts. By transplantation of GFP-labelled human BMSC (hBMSC) or EGFP transgenic mouse BMSC (mBMSC), we further showed that BMSC might be involved in lung fibrosis in severe combined immune deficiency (SCID)/Beige mice induced by bleomycin. In addition, using quantitative-RT-PCR, western blot, Sircol collagen assay and migration assay, we determined the underlying mechanism was LPA-induced BMSC differentiation into myofibroblast and the secretion of ECM via LPA1. By employing a novel LPA1 antagonist, Antalpa1, we then showed that Antalpa1 could attenuate lung fibrosis by inhibiting both BMSC differentiation into myofibroblast and the secretion of ECM. Collectively, the above findings not only further validate LPA1 as a drug target in the treatment of pulmonary fibrosis but also elucidate a novel pathway in which BMSCs contribute to the pathologic process. PMID: 24251962 [PubMed - indexed for MEDLINE]
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Related Articles Phase I clinical trial of cell therapy in patients with advanced chronic obstructive pulmonary disease: follow-up of up to 3 years. Rev Bras Hematol Hemoter. 2013;35(5):352-7 Authors: Stessuk T, Ruiz MA, Greco OT, Bilaqui A, Ribeiro-Paes MJ, Ribeiro-Paes JT Abstract BACKGROUND: Chronic obstructive pulmonary disease is a major inflammatory disease of the airways and an enormous therapeutic challenge. Within the spectrum of chronic obstructive pulmonary disease, pulmonary emphysema is characterized by the destruction of the alveolar walls with an increase in the air spaces distal to the terminal bronchioles but without significant pulmonary fibrosis. Therapeutic options are limited and palliative since they are unable to promote morphological and functional regeneration of the alveolar tissue. In this context, new therapeutic approaches, such as cell therapy with adult stem cells, are being evaluated. OBJECTIVE: This article aims to describe the follow-up of up to 3 years after the beginning of a phase I clinical trial and discuss the spirometry parameters achieved by patients with advanced pulmonary emphysema treated with bone marrow mononuclear cells. METHODS: Four patients with advanced pulmonary emphysema were submitted to autologous infusion of bone marrow mononuclear cells. Follow-ups were performed by spirometry up to 3 years after the procedure. RESULTS: The results showed that autologous cell therapy in patients having chronic obstructive pulmonary disease is a safe procedure and free of adverse effects. There was an improvement in laboratory parameters (spirometry) and a slowing down in the process of pathological degeneration. Also, patients reported improvements in the clinical condition and quality of life. CONCLUSIONS: Despite being in the initial stage and in spite of the small sample, the results of the clinical protocol of cell therapy in advanced pulmonary emphysema as proposed in this study, open new therapeutic perspectives in chronic obstructive pulmonary disease. It is worth emphasizing that this study corresponds to the first study in the literature that reports a change in the natural history of pulmonary emphysema after the use of cell therapy with a pool of bone marrow mononuclear cells. PMID: 24255620 [PubMed]
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Related Articles Human embryonic stem cells recover in vivo acute lung inflammation bleomycin-induced. Sarcoidosis Vasc Diffuse Lung Dis. 2013 Oct;30(3):177-85 Authors: Sangiuolo F, Spitalieri P, Quitadamo MC, Orlandi A, Puxeddu E, Curradi G, Sangiuolo F Abstract Idiopathic pulmonary fibrosis (IPF)  is characterized by alveolar epithelial cell injury, type II cell activation, apoptosis and bronchiolar epithelial cell proliferation, accumulation of extracellular matrix and fibroblasts. No current animal model recapitulates all of these cardinal manifestation of the human disease. However, bleomycin instillation in mice lung by intranasal way (ITN) represents the best experimental model of pulmonary fibrosis in which alveolar pneumocytes type II (ATII) are usually depleted. The aim of this study was to test the possibility to recover acute lung fibrosis after transplantation of human embryonic type II derived-pneumocytes in a murine model of bleomycin-induced damage. Our results indicate the striking "clinical" beneficial effect of differentiated HUES-3 cells into ATII in terms of lung function, weight loss and mortality in injured mice, suggesting this stem cell therapy as a promising, systemic and specific treatment of human pulmonary fibrosis. PMID: 24284290 [PubMed - in process]
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Related Articles MSC Microvesicles for the Treatment of Lung Disease: A New Paradigm for Cell-Free Therapy. Antioxid Redox Signal. 2014 Feb 24; Authors: Sdrimas K, Kourembanas S Abstract Abstract Significance: Bronchopulmonary dysplasia (BPD), also known as chronic lung disease of infancy, is a major complication of preterm birth that, despite improvements in neonatal respiratory support and perinatal care, remains an important cause of morbidity and mortality, often with severe adverse neurodevelopmental sequelae. Even with major advances in our understanding of the pathogenesis of this disease, BPD remains essentially without adequate treatment. Recent Advances: Cell-based therapies arose as a promising treatment for acute and chronic lung injury in many experimental models of disease. Currently, more than 3000 human clinical trials employing cell therapy for the treatment of diverse diseases, including cardiac, neurologic, immune, and respiratory conditions, are ongoing or completed. Among the treatments, mesenchymal stem cells (MSCs) are the most studied and have been extensively tested in experimental models of BPD, pulmonary hypertension, pulmonary fibrosis, and acute lung injury. Critical Issues: Despite the promising potential, MSC therapy for human lung disease still remains at an experimental stage and optimal transplantation conditions need to be determined. Although the mechanism of MSC action can be manifold, accumulating evidence suggests a predominant paracrine, immunomodulatory, and cytoprotective effect. Future Directions: The current review summarizes the effect of MSC treatment in models of lung injury, including BPD, and focuses on the MSC secretome and, specifically, MSC-derived microvesicles as potential key mediators of therapeutic action that can be the focus of future therapies. Antioxid. Redox Signal. 00, 000-000. PMID: 24382303 [PubMed - as supplied by publisher]
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Related Articles A health plan that isn't worth keeping. Mod Healthc. 2013 Nov 25;43(47):22 Authors: Goozner M PMID: 24416869 [PubMed - indexed for MEDLINE]
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Related Articles Neuroepithelial body increases in bleomycin-treated mice. Respir Physiol Neurobiol. 2014 Mar 1;193:52-4 Authors: Liu J, Song N, Tian S, Yu J Abstract Neuroepithelial bodies (NEBs) serve a niche for lung stem cells and proliferate in a variety of pulmonary diseases. We hypothesize that NEBs play an important role in lung injury repair processes, such as during pulmonary fibrosis. To test this hypothesis, we examined NEBs in a bleomycin-induced lung fibrosis mouse model. We divided FVB/NJ mice into bleomycin-treated (BL) and normal saline-treated (NS) groups. Two weeks after intravenous treatment, we immune-stained NEBs with anti-calcitonin gene-related peptide (CGRP) in whole mount preparations and found that the number of NEBs per unit area of airway almost tripled in the BL group (1.11±0.28 number/mm(2); n=5) compared with the NS group (0.32±0.14 number/mm(2); n=4, p=0.001). The size of NEBs increased significantly in the BL group. Our findings support that NEBs play an important role in the pathogenesis of pulmonary fibrosis. PMID: 24418354 [PubMed - in process]
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Related Articles Non-invasive airway health assessment: synchrotron imaging reveals effects of rehydrating treatments on mucociliary transit in-vivo. Sci Rep. 2014;4:3689 Authors: Donnelley M, Morgan KS, Siu KK, Farrow NR, Stahr CS, Boucher RC, Fouras A, Parsons DW Abstract To determine the efficacy of potential cystic fibrosis (CF) therapies we have developed a novel mucociliary transit (MCT) measurement that uses synchrotron phase contrast X-ray imaging (PCXI) to non-invasively measure the transit rate of individual micron-sized particles deposited into the airways of live mice. The aim of this study was to image changes in MCT produced by a rehydrating treatment based on hypertonic saline (HS), a current CF clinical treatment. Live mice received HS containing a long acting epithelial sodium channel blocker (P308); isotonic saline; or no treatment, using a nebuliser integrated within a small-animal ventilator circuit. Marker particle motion was tracked for 20 minutes using PCXI. There were statistically significant increases in MCT in the isotonic and HS-P308 groups. The ability to quantify in vivo changes in MCT may have utility in pre-clinical research studies designed to bring new genetic and pharmaceutical treatments for respiratory diseases into clinical trials. PMID: 24418935 [PubMed - in process]
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Related Articles Myelofibrosis-associated complications: pathogenesis, clinical manifestations, and effects on outcomes. Int J Gen Med. 2014;7:89-101 Authors: Mughal TI, Vaddi K, Sarlis NJ, Verstovsek S Abstract Myelofibrosis (MF) is a rare chronic BCR-ABL1 (breakpoint cluster region-Abelson murine leukemia viral oncogene homologue 1)-negative myeloproliferative neoplasm characterized by progressive bone marrow fibrosis, inefficient hematopoiesis, and shortened survival. The clinical manifestations of MF include splenomegaly, consequent to extramedullary hematopoiesis, cytopenias, and an array of potentially debilitating abdominal and constitutional symptoms. Dysregulated Janus kinase (JAK)-signal transducer and activator of transcription signaling underlies secondary disease-associated effects in MF, such as myeloproliferation, bone marrow fibrosis, constitutional symptoms, and cachexia. Common fatal complications of MF include transformation to acute leukemia, thrombohemorrhagic events, organ failure, and infections. Potential complications from hepatosplenomegaly include portal hypertension and variceal bleeding, whereas extramedullary hematopoiesis outside the spleen and liver - depending on the affected organ - may result in intracranial hypertension, spinal cord compression, pulmonary hypertension, pleural effusions, lymphadenopathy, skin lesions, and/or exacerbation of abdominal symptoms. Although allogeneic stem cell transplantation is the only potentially curative therapy, it is suitable for few patients. The JAK1/JAK2 inhibitor ruxolitinib is effective in improving splenomegaly, MF-related symptoms, and quality-of-life measures. Emerging evidence that ruxolitinib may be associated with a survival benefit in intermediate- or high-risk MF suggests the possibility of a disease-modifying effect. Consequently, ruxolitinib could provide a treatment backbone to which other (conventional and novel) therapies may be added for the prevention and effective management of specific MF-associated complications. PMID: 24501543 [PubMed]
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Related Articles New drug therapies for COPD. Clin Chest Med. 2014 Mar;35(1):219-39 Authors: Ross CL, Hansel TT Abstract Clinical trials with new drugs for chronic obstructive pulmonary disease (COPD) have been performed. Viruses exacerbate COPD and bacteria may play a part in severe COPD; therefore, antibiotic and antiviral approaches have a sound rationale. Antiinflammatory approaches have been studied. Advances in understanding the molecular basis of other processes have resulted in novel drugs to target reactive oxidant species, mucus, proteases, fibrosis, cachexia, and muscle wasting, and accelerated aging. Studies with monoclonal antibodies have been disappointing, highlighting the tendency for infections and malignancies during treatment. Promising future directions are lung regeneration with retinoids and stem cells. PMID: 24507848 [PubMed - indexed for MEDLINE]
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Related Articles Novel therapeutic strategies for lung disorders associated with airway remodelling and fibrosis. Pharmacol Ther. 2014 Mar;141(3):250-260 Authors: Royce SG, Moodley Y, Samuel CS Abstract Inflammatory cell infiltration, cytokine release, epithelial damage, airway/lung remodelling and fibrosis are central features of inflammatory lung disorders, which include asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome and idiopathic pulmonary fibrosis. Although the lung has some ability to repair itself from acute injury, in the presence of ongoing pathological stimuli and/or insults that lead to chronic disease, it no longer retains the capacity to heal, resulting in fibrosis, the final common pathway that causes an irreversible loss of lung function. Despite inflammation, genetic predisposition/factors, epithelial-mesenchymal transition and mechanotransduction being able to independently contribute to airway remodelling and fibrosis, current therapies for inflammatory lung diseases are limited by their ability to only target the inflammatory component of the disease without having any marked effects on remodelling (epithelial damage and fibrosis) that can cause lung dysfunction independently of inflammation. Furthermore, as subsets of patients suffering from these diseases are resistant to currently available therapies (such as corticosteroids), novel therapeutic approaches are required to combat all aspects of disease pathology. This review discusses emerging therapeutic approaches, such as trefoil factors, relaxin, histone deacetylase inhibitors and stem cells, amongst others that have been able to target airway inflammation and airway remodelling while improving related lung dysfunction. A better understanding of the mode of action of these therapies and their possible combined effects may lead to the identification of their clinical potential in the setting of lung disease, either as adjunct or alternative therapies to currently available treatments. PMID: 24513131 [PubMed - as supplied by publisher]
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Related Articles Mesenchymal stem cell trials for pulmonary diseases. J Cell Biochem. 2014 Jun;115(6):1023-32 Authors: Antunes MA, Laffey JG, Pelosi P, Rocco PR Abstract All adult tissues, including the lung, have some capacity to self-repair or regenerate through the replication and differentiation of stem cells resident within these organs. While lung resident stem cells are an obvious candidate cell therapy for lung diseases, limitations exist regarding our knowledge of the biology of these cells. In contrast, there is considerable interest in the therapeutic potential of exogenous cells, particularly mesenchymal stem/stromal cells (MSCs), for lung diseases. Bone marrow derived-MSCs are the most studied cell therapy for these diseases. Preclinical studies demonstrate promising results using MSCs for diverse lung disorders, including emphysema, bronchopulmonary dysplasia, fibrosis, and acute respiratory distress syndrome. This mini-review will summarize ongoing clinical trials using MSCs in lung diseases, critically examine the data supporting their use for this purpose, and discuss the next steps in the translational pathway for MSC therapy of lung diseases. PMID: 24515922 [PubMed - in process]
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Related Articles Cystic fibrosis: toward personalized therapies. Int J Biochem Cell Biol. 2014 Jul;52:192-200 Authors: Ikpa PT, Bijvelds MJ, de Jonge HR Abstract Cystic fibrosis (CF), the most common, life-threatening monogenetic disease in Caucasians, is caused by mutations in the CFTR gene, encoding a cAMP- and cGMP-regulated epithelial chloride channel. Symptomatic therapies treating end-organ manifestations have increased the life expectancy of CF patients toward a mean of 40 years. The recent development of CFTR-targeted drugs that emerged from high-throughput screening and are capable of correcting the basic defect promises to transform the therapeutic landscape from a trial-and-error prescription to personalized medicine. This stratified approach is tailored to a specific functional class of mutations in CFTR, but can be refined further to an individual level by exploiting recent advances in ex vivo drug testing methods. These tests range from CFTR functional measurements in rectal biopsies donated by a CF patient to the use of patient-derived intestinal or pulmonary organoids. Such organoids may serve as an inexhaustible source of epithelial cells that can be stored in biobanks and allow medium- to high-throughput screening of CFTR activators, correctors and potentiators on the basis of a simple microscopic assay monitoring organoid swelling. Thus the recent breakthrough in stem cell biology allowing the culturing of mini-organs from individual patients is not only relevant for future stem cell therapy, but may also allow the preclinical testing of new drugs or combinations that are optimally suited for an individual patient. PMID: 24561283 [PubMed - in process]
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Related Articles Hematopoietic and mesenchymal stem cells for the treatment of chronic respiratory diseases: role of plasticity and heterogeneity. ScientificWorldJournal. 2014;2014:859817 Authors: Conese M, Piro D, Carbone A, Castellani S, Di Gioia S Abstract Chronic lung diseases, such as cystic fibrosis (CF), asthma, and chronic obstructive pulmonary disease (COPD) are incurable and represent a very high social burden. Stem cell-based treatment may represent a hope for the cure of these diseases. In this paper, we revise the overall knowledge about the plasticity and engraftment of exogenous marrow-derived stem cells into the lung, as well as their usefulness in lung repair and therapy of chronic lung diseases. The lung is easily accessible and the pathophysiology of these diseases is characterized by injury, inflammation, and eventually by remodeling of the airways. Bone marrow-derived stem cells, including hematopoietic stem/progenitor cells (HSPCs) and mesenchymal stromal (stem) cells (MSCs), encompass a wide array of cell subsets with different capacities of engraftment and injured tissue regenerating potential. Proof-of-principle that marrow cells administered locally may engraft and give rise to specialized epithelial cells has been given, but the efficiency of this conversion is too limited to give a therapeutic effect. Besides the identification of plasticity mechanisms, the characterization/isolation of the stem cell subpopulations represents a major challenge to improving the efficacy of transplantation protocols used in regenerative medicine for lung diseases. PMID: 24563632 [PubMed - in process]
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Related Articles Activated Wnt signaling induces myofibroblast differentiation of mesenchymal stem cells, contributing to pulmonary fibrosis. Int J Mol Med. 2014 May;33(5):1097-109 Authors: Sun Z, Wang C, Shi C, Sun F, Xu X, Qian W, Nie S, Han X Abstract Acute lung injury may lead to fibrogenesis. However, no treatment is currently available. This study was conducted to determine the effects of bone marrow-derived mesenchymal stem cells (MSCs) in a model of HCl-induced acute lung injury in Sprague-Dawley (SD) rats. Stromal cell-derived factor (SDF)-1 and its receptor CXC chemokine receptor (CXCR)4 have been shown to participate in mobilizing MSCs. Adenovirus carrying the CXCR4 gene was used to transfect MSCs in order to increase the engraftment numbers of MSCs at injured sites. Histological examination data demonstrated that the engraftment of MSCs did not attenuate lung injury and pulmonary fibrosis. The results showed that engraftment of MSCs almost differentiated into myofibroblasts, but rarely differentiated into lung epithelial cells. Additionally, it was demonstrated that activated canonical Wnt/β-catenin signaling in injured lung tissue regulated the myofibroblast differentiation of MSCs in vivo. The in vitro study results demonstrated that activation of the Wnt/β-catenin signaling stimulated MSCs to express myofibroblast markers; however, this process was attenuated by Wnt antagonist DKK1. Therefore, the results demonstrated that the aberrant activation of Wnt signaling induces the myofibroblast differentiation of engrafted MSCs, thus contributing to pulmonary fibrosis following lung injury. PMID: 24573542 [PubMed - in process]
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Related Articles Long-term results of total body irradiation in adults with acute lymphoblastic leukemia. Strahlenther Onkol. 2014 May;190(5):453-8 Authors: Marnitz S, Zich A, Martus P, Budach V, Jahn U, Neumann O, Arnold R Abstract PURPOSE: The aim of this chart review of adult patients treated for acute lymphoblastic leukemia (ALL) with total body irradiation (TBI) was to evaluate early and late toxicity and long-term outcome. PATIENTS AND METHODS: A total of 110 adult patients (34 ± 12 years) with ALL underwent TBI (6 fractions of  2 Gy for a total of 12 Gy) as a part of the treatment regimen before transplantation. Treatment-related toxicity, mortality, and hematologic outcome are reported. RESULTS: Mean follow-up was 70 months. The 2- and 5-year leukemia-free survival rates were 78 and 72%, respectively. In all, 29% (32/110) patients suffered from medullary recurrence after a median time of 7 months. Gender was the only statistically significant prognostic factor in terms of overall survival in favor of female patients. Treatment-related mortality and overall survival after 2 and 5 years were 16 and 22%, and 60 and 52.7%, respectively. The most frequent late reaction wascGVHD of the skin (n = 33, 30%). In addition, 15.5% (17/110 patients) suffered pulmonary symptoms, and 6 patients developed lung fibrosis. Eyes were frequently affected by the radiation (31/110 = 28%); 12 of 110 patients (11%) presented with symptoms from osteoporosis, 5 of 110 patients (4.5%) developed hypothyreosis and 2 patients diabetes mellitus. Of the male patients, 11% reported erectile dysfunction or loss of libido, while 2 of 36 women reported menopausal syndrome at the mean time of 28 months after treatment with requirement for substitution. No women became pregnant after treatment. No acute or late cardiac toxicities were documented in our patients. No secondary malignancies were documented. CONCLUSION: Although hematologic outcome was in the upper range of that reported in the literature, treatment-related mortality (TRM) and medullary recurrences remain a challenge. Sophisticated radiation techniques allow for decreasing toxicity to certain organs and/or dose escalation to the bone marrow in highly selected patients in order to improve therapeutic breadth. PMID: 24595415 [PubMed - indexed for MEDLINE]
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Related Articles Therapeutic use of stem cell transplantation for cell replacement or cytoprotective effect of microvesicle released from mesenchymal stem cell. Mol Cells. 2014 Feb;37(2):133-9 Authors: Choi M, Ban T, Rhim T Abstract Idiopathic pulmonary fibrosis (IPF) is the most common and severe type of idiopathic interstitial pneumonias (IIP), and which is currently no method was developed to restore normal structure and function. There are several reports on therapeutic effects of adult stem cell transplantations in animal models of pulmonary fibrosis. However, little is known about how mesenchymal stem cell (MSC) can repair the IPF. In this study, we try to provide the evidence to show that transplanted mesenchymal stem cells directly replace fibrosis with normal lung cells using IPF model mice. As results, transplanted MSC successfully integrated and differentiated into type II lung cell which express surfactant protein. In the other hand, we examine the therapeutic effects of microvesicle treatment, which were released from mesenchymal stem cells. Though the therapeutic effects of MV treatment is less than that of MSC treatment, MV treatment meaningfully reduced the symptom of IPF, such as collagen deposition and inflammation. These data suggest that stem cell transplantation may be an effective strategy for the treatment of pulmonary fibrosis via replacement and cytoprotective effect of microvesicle released from MSCs. PMID: 24598998 [PubMed - in process]
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Related Articles Intratracheal administration of umbilical cord blood-derived mesenchymal stem cells in a patient with acute respiratory distress syndrome. J Korean Med Sci. 2014 Mar;29(3):438-40 Authors: Chang Y, Park SH, Huh JW, Lim CM, Koh Y, Hong SB Abstract Umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) have been introduced as a possible therapy in acute lung injury and acute respiratory distress syndrome (ARDS). This case history is reported of a 59-yr-old man who was treated with MSCs in the course of ARDS and subsequent pulmonary fibrosis. He received a long period of mechanical ventilation and weaning proved difficult. On hospital day 114, he underwent the intratracheal administration of UCB-derived MSCs at a dose of 1 × 10(6)/kg. After cell infusion, an immediate improvement was shown in his mental status, his lung compliance (from 22.7 mL/cmH2O to 27.9 mL/cmH2O), PaO2/FiO2 ratio (from 191 mmHg to 334 mmHg) and his chest radiography over the course of three days. Even though he finally died of repeated pulmonary infection, our current findings suggest the possibility of using MSCs therapy in an ARDS patient. It is the first clinical case of UCB-derived MSCs therapy ever reported. PMID: 24616596 [PubMed - in process]
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Related Articles The effect of adipose stem cell therapy on pulmonary fibrosis induced by repetitive intratracheal bleomycin in mice. Exp Lung Res. 2014 Apr;40(3):117-25 Authors: Lee SH, Lee EJ, Lee SY, Kim JH, Shim JJ, Shin C, In KH, Kang KH, Uhm CS, Kim HK, Yang KS, Park S, Kim HS, Kim YM, Yoo TJ Abstract Adipose stem cells (ASCs) are detectable in the parenchyma and large airways of lungs after systemic administration, and ameliorate inflammatory infiltration and cell death in animal models of emphysema. We evaluated whether ASC treatment could attenuate lung fibrosis induced by repetitive intratracheal bleomycin administration. Male 8-week-old C57BL/6J mice (control group, bleomycin-only group, and bleomycin-plus-ASC group) were used. Eight biweekly doses of bleomycin were injected intratracheally via an intubation procedure at a dose of 0.04 units in a total volume of 100 μL of sterile saline. During the latter 2 months of the 4-month bleomycin exposure, human ASCs (3 × 10(5) cells) were administered repeatedly via intraperitoneal injection at the same time as bleomycin. Lung tissues were evaluated for histology, collagen content, TUNEL staining, and TGF-β levels. Bronchoalveolar lavage (BAL) was performed for cell counting. Administrations of ASCs ameliorated the deleterious effects of repetitive intratracheal instillation of bleomycin, namely hyperplasia of Club cells (Clara cells) and cuboidal alveolar epithelial cells, infiltration of the perialveolar ducts by inflammatory cells, septal thickening, enlarged alveoli, and extensive fibrosis. Addition of ASC led to suppression of bleomycin-induced epithelial cell apoptosis and expression of TGF-β. These results suggest a useful therapeutic effect of ASCs on pulmonary fibrosis induced by repetitive bleomycin administration. Further studies will be required to evaluate the efficacy of ASC therapy for the treatment of idiopathic pulmonary fibrosis. PMID: 24624895 [PubMed - in process]
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Related Articles Effects of bone marrow-derived mononuclear cells from healthy or acute respiratory distress syndrome donors on recipient lung-injured mice. Crit Care Med. 2014 Jul;42(7):e510-24 Authors: Silva JD, Paredes BD, Araújo IM, Lopes-Pacheco M, Oliveira MV, Suhett GD, Faccioli LA, Assis E, Castro-Faria-Neto HC, Goldenberg RC, Capelozzi VL, Morales MM, Pelosi P, Xisto DG, Rocco PR Abstract OBJECTIVE: The advantage of using autologous bone marrow-derived mononuclear cells to treat acute respiratory distress syndrome patients is to prevent immunological rejection. However, bone marrow-derived mononuclear cells may be altered by different acute respiratory distress syndrome etiologies, resulting in questionable efficacy and thus limited clinical application. We aimed to investigate the effects of bone marrow-derived mononuclear cells obtained from healthy and acute respiratory distress syndrome donors on pulmonary and extrapulmonary acute respiratory distress syndrome. DESIGN: Prospective, randomized, controlled experimental study. SETTING: University research laboratory. SUBJECTS: Two hundred and twenty-five C57BL/6 mice. INTERVENTIONS: Acute respiratory distress syndrome was induced by Escherichia coli lipopolysaccharide intratracheally (ARDSp) or intraperitoneally (ARDSexp). Control mice (Healthy) received saline solution intratracheally (Cp) or intraperitoneally (Cexp). After 24 hours, whole bone marrow cells were analyzed in vitro: 1) colony-forming unit-fibroblasts and 2) hematopoietic stem cells, neutrophils, T helper lymphocytes, B lymphocytes, and nonhematopoietic precursors. After cell characterization, all groups received saline or bone marrow-derived mononuclear cells (2 × 10), obtained from Cp, Cexp, ARDSp, and ARDSexp donor mice, IV, on day 1. MEASUREMENTS AND MAIN RESULTS: On day 1, in ARDSp, different patterns of colony formation were found, with nonstromal cells (mainly neutrophils) predominating over fibroblastoid colonies. In ARDSexp, irregular colony-forming unit-fibroblasts morphology with dispersed proliferating colonies and a greater number of hematopoietic stem cells were observed. In ARDSp, colony-forming unit-fibroblasts count was higher but not measurable in ARDSexp. In ARDSp, monocytes and T lymphocytes were increased and hematopoietic precursor cells reduced, with no significant changes in ARDSexp. On day 7, bone marrow-derived mononuclear cells improved survival and attenuated changes in lung mechanics, alveolar collapse, inflammation, pulmonary fibrosis, and apoptosis in the lung and distal organs, regardless of donor type. CONCLUSIONS: Bone marrow-derived mononuclear cells from ARDSp and ARDSexp donors showed different characteristics but were as effective as cells obtained from healthy donors in reducing inflammation and remodeling, suggesting the utility of autologous transplant of bone marrow-derived mononuclear cells in the clinical setting. PMID: 24633189 [PubMed - indexed for MEDLINE]
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Related Articles Regulation of transplanted mesenchymal stem cells by the lung progenitor niche in rats with chronic obstructive pulmonary disease. Respir Res. 2014;15:33 Authors: Zhang WG, He L, Shi XM, Wu SS, Zhang B, Mei L, Xu YJ, Zhang ZX, Zhao JP, Zhang HL Abstract BACKGROUND: Stem cell transplantation is a promising method for the treatment of chronic obstructive pulmonary disease (COPD), and mesenchymal stem cells (MSCs) have clinical potential for lung repair/regeneration. However, the rates of engraftment and differentiation are generally low following MSC therapy for lung injury. In previous studies, we constructed a pulmonary surfactant-associated protein A (SPA) suicide gene system, rAAV-SPA-TK, which induced apoptosis in alveolar epithelial type II (AT II) cells and vacated the AT II cell niche. We hypothesized that this system would increase the rates of MSC engraftment and repair in COPD rats. METHODS: The MSC engraftment rate and morphometric changes in lung tissue in vivo were investigated by in situ hybridization, hematoxylin and eosin staining, Masson's trichrome staining, immunohistochemistry, and real-time PCR. The expression of hypoxia inducible factor (HIF-1α) and stromal cell-derived factor-1 (SDF-1), and relationship between HIF-1α and SDF-1 in a hypoxic cell model were analyzed by real-time PCR, western blotting, and enzyme-linked immunosorbent assay. RESULTS: rAAV-SPA-TK transfection increased the recruitment of MSCs but induced pulmonary fibrosis in COPD rats. HIF-1α and SDF-1 expression were enhanced after rAAV-SPA-TK transfection. Hypoxia increased the expression of HIF-1α and SDF-1 in the hypoxic cell model, and SDF-1 expression was augmented by HIF-1α under hypoxic conditions. CONCLUSIONS: Vacant AT II cell niches increase the homing and recruitment of MSCs to the lung in COPD rats. MSCs play an important role in lung repair and promote collagen fiber deposition after induction of secondary damage in AT II cells by rAAV-SPA-TK, which involves HIF-1α and SDF-1 signaling. PMID: 24661402 [PubMed - in process]
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Related Articles Outcomes of lung transplantation after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2014 Aug;20(8):1169-75 Authors: Cheng GS, Edelman JD, Madtes DK, Martin PJ, Flowers ME Abstract Other than lung transplantation (LT), no specific therapies exist for end-stage lung disease resulting from hematopoietic stem cell transplantation (HCT)-related complications, such as bronchiolitis obliterans syndrome (BOS). We report the indications and outcomes in patients who underwent LT after HCT for hematologic disease from a retrospective case series at our institution and a review of the medical literature. We identified a total of 70 cases of LT after HCT, including 9 allogeneic HCT recipients from our institution who underwent LT between 1990 and 2010. In our cohort, the median age was 16 years (range, 10 to 35 years) at the time of HCT and 34 years (range, 17 to 44 years) at the time of LT, with a median interval between HCT and LT of 10 years (range, 2.9 to 27 years). Indications for LT-included pulmonary fibrosis (n = 4), BOS (n = 3), interstitial pneumonitis related to graft-versus-host disease (GVHD) (n = 1), and primary pulmonary hypertension (n = 1). Median survival was 49 months (range, 2 weeks to 87 months), and 1 patient remains alive at more than 3 years after LT. Survival at 1 year and 5 years after LT was 89% and 37%, respectively. In the medical literature between 1992 and July 2013, we identified 20 articles describing 61 cases of LT after HCT from various centers in the United States, Europe, and Asia. Twenty-six of the 61 cases (43%) involved patients age <18 years at the time of LT. BOS and GVHD of the lung were cited as the indication for LT in the majority of cases (80%; n = 49), followed by pulmonary fibrosis and interstitial lung disease (20%; n = 12). In publications reporting 3 or more cases with a follow-up interval ranging from the immediate postoperative period to 16 years, the survival rate was 71% (39 of 55). Most deaths were attributed to long-term complications of the lung allograft, including infections and BOS. Two deaths were related to recurrent or relapsed hematologic malignancy. LT can prolong survival in some patients who suffer from end-stage pulmonary complications after HCT. Patient factors that likely improve the chances of a good long-term outcome include young age, at least 2 years post-HCT free of relapse from the original hematologic malignancy, and lack of other end-organ dysfunction or manifestations of chronic GVHD that require treatment with immunosuppressive agents. PMID: 24727334 [PubMed - in process]
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Related Articles Mitochondrial Transfer of Induced Pluripotent Stem Cells-derived MSCs to Airway Epithelial Cells Attenuates Cigarette Smoke-induced Damage. Am J Respir Cell Mol Biol. 2014 Apr 16; Authors: Li X, Zhang Y, Yeung SC, Liang Y, Liang X, Ding Y, Ip MS, Tse HF, Mak JC, Lian Q Abstract Transplantation of mesenchymal stem cells (MSCs) holds great promise in the repair of cigarette smoke (CS)-induced lung damage in chronic obstructive pulmonary disease (COPD). As cigarette smoke leads to mitochondrial dysfunction, we therefore aimed to investigate the potential benefit of mitochondrial transfer from human-induced pluripotent stem cell-derived mesenchymal stem cells (iPSC-MSCs) to CS-exposed airway epithelial cells in vitro and in vivo. Rats were exposed to 4% CS for one hour daily for 56 days. At day 29 and day 43, human iPSC-MSCs or adult bone marrow-MSCs (BM-MSCs) were administered intravenously to CS-exposed rats. CS-exposed rats exhibited severe alveolar destruction with a higher mean linear intercept (Lm) than sham air-exposed rats (p < 0.001) that was attenuated in the presence of iPSC-MSCs or BM-MSCs (p < 0.01). The attenuation of Lm value and the severity of fibrosis was greater in the iPSC-MSC-treated group than the BM-MSC-treated group (p<0.05). This might be contributed to the novel observation of mitochondrial transfer from MSCs to rat airway epithelial cells in lung sections exposed to CS. In vitro studies further revealed that transfer of mitochondria from iPSC-MSCs to bronchial epithelial cells (BEAS-2B) was more effective than from BM-MSCs with preservation of adenosine triphosphate contents. This distinct mitochondrial transfer occurred via the formation of tunneling nanotubes (TNT). Inhibition of TNT formation blocked mitochondrial transfer. Our findings indicate a higher mitochondrial transfer capacity of iPSC-MSCs than BM-MSCs to rescue CS-induced mitochondrial damage. iPSC-MSCs may thus hold promise for the development of cell therapy in COPD. PMID: 24738760 [PubMed - as supplied by publisher]
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Related Articles Lung transplantation following hematopoietic stem cell transplantation: report of two cases and systematic review of literature. Clin Transplant. 2014 Jul;28(7):776-82 Authors: Soubani AO, Kingah P, Alshabani K, Muma G, Haq A Abstract BACKGROUND: Non-infectious pulmonary complications following hematopoietic stem cell transplantation (HSCT) are major cause of morbidity and mortality with limited treatment options. Lung transplantation (LT) has been rarely reported as a treatment option for selected HSCT recipients with these problems. OBJECTIVE: Describe the outcome of HSCT recipients who underwent LT. METHODS: Two cases of LT following HSCT from our institution are presented. Cases reported in literature were identified using English language PubMed/MEDLINE with keywords hematopoietic stem cell transplantation, bone marrow transplantation, or bronchiolitis obliterans cross-referenced with lung transplantation. We extracted data on baseline characteristics and survival data following LT. RESULTS: Total of 84 patients are analyzed. Age at time of LT was median of 22 yr (range 1-66). Seventy-nine patients were recipients of allogeneic HSCT. The indications for LT were bronchiolitis obliterans syndrome (BOS; 63 patients), pulmonary fibrosis (13 patients), BOS/pulmonary fibrosis (five patients), and graft-versus-host-disease (GVHD) of lung (three patients). The median time between HSCT and LT was 52.3 months (range 6-240). The median follow-up after LT was 36 months (range 0-168). During this time, BOS was documented in 25 patients. Relapse of hematological malignancy was reported in two patients, and new malignancy developed in four patients. At the end of follow-up, 60 patients were alive and 24 patients died. The probability of survival following LT at 24 and 36 months was 0.88 (95% CI 0.78-0.93) and 0.79 (95% CI 0.67-0.87), respectively. CONCLUSION: LT is a potential therapeutic option in selected patients with severe chronic pulmonary disease following HSCT. Further studies are needed to determine the appropriate timing and the outcome of this approach. PMID: 24754643 [PubMed - in process]
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Related Articles Differentiation of mouse induced pluripotent stem cells into alveolar epithelial cells in vitro for use in vivo. Stem Cells Transl Med. 2014 Jun;3(6):675-85 Authors: Zhou Q, Ye X, Sun R, Matsumoto Y, Moriyama M, Asano Y, Ajioka Y, Saijo Y Abstract Alveolar epithelial cells (AECs) differentiated from induced pluripotent stem cells (iPSCs) represent new opportunities in lung tissue engineering and cell therapy. In this study, we modified a two-step protocol for embryonic stem cells that resulted in a yield of ∼9% surfactant protein C (SPC)(+) alveolar epithelial type II (AEC II) cells from mouse iPSCs in a 12-day period. The differentiated iPSCs showed morphological characteristics similar to those of AEC II cells. When differentiated iPSCs were seeded and cultured in a decellularized mouse lung scaffold, the cells reformed an alveolar structure and expressed SPC or T1α protein (markers of AEC II or AEC I cells, respectively). Finally, the differentiated iPSCs were instilled intratracheally into a bleomycin-induced mouse acute lung injury model. The transplanted cells integrated into the lung alveolar structure and expressed SPC and T1α. Significantly reduced lung inflammation and decreased collagen deposition were observed following differentiated iPSC transplantation. In conclusion, we report a simple and rapid protocol for in vitro differentiation of mouse iPSCs into AECs. Differentiated iPSCs show potential for regenerating three-dimensional alveolar lung structure and can be used to abrogate lung injury. PMID: 24763685 [PubMed - indexed for MEDLINE]
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Related Articles Effect of immobilized hyaluronidase on stem and progenitor cells in pulmonary fibrosis. Bull Exp Biol Med. 2014 Feb;156(4):590-4 Authors: Dygai AM, Skurikhin EG, Khmelevskaya ES, Ermakova NN, Reztsova AM, Pershina OV, Krupin VA, Stepanova IE, Reztsova VM, Artamonov AV, Bekarev AA, Madonov PG, Kinsht DN Abstract The effect of immobilized hyaluronidase on stem and progenitor cells of the lungs was studied on the model of partially reversible toxic bleomycin-induced pulmonary fibrosis in C57Bl/6 mice. During the inflammation phase, immobilized hyaluronidase reduced infiltration of alveolar interstitium with hemopoietic stem cells Sca-1(+), c-Kit(+), CD34(-), (CD3, CD45R (B220), Ly6C, Ly6G (Gr1), CD11b (Mac1), TER-119)(-). Improvement of histological parameters of bleomycin lungs during the phase of collagen fiber deposition after the treatment was accompanied by accumulation of mesenchymal multipotent stromal cells (CD31(-), CD34(-), CD45(-), CD44(+), CD73(+), CD90(+), CD106(+)decrease in the population of pan-hemopoietic cells (CD45(+)), accelerated restoration of the content of endothelial cells, and inhibition of clonal activity of fibroblast precursors (CD45(-)). PMID: 24771454 [PubMed - in process]
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Related Articles The scaffold protein muscle A-kinase anchoring protein β orchestrates cardiac myocyte hypertrophic signaling required for the development of heart failure. Circ Heart Fail. 2014 Jul;7(4):663-72 Authors: Kritzer MD, Li J, Passariello CL, Gayanilo M, Thakur H, Dayan J, Dodge-Kafka K, Kapiloff MS Abstract BACKGROUND: Cardiac myocyte hypertrophy is regulated by an extensive intracellular signal transduction network. In vitro evidence suggests that the scaffold protein muscle A-kinase anchoring protein β (mAKAPβ) serves as a nodal organizer of hypertrophic signaling. However, the relevance of mAKAPβ signalosomes to pathological remodeling and heart failure in vivo remains unknown. METHODS AND RESULTS: Using conditional, cardiac myocyte-specific gene deletion, we now demonstrate that mAKAPβ expression in mice is important for the cardiac hypertrophy induced by pressure overload and catecholamine toxicity. mAKAPβ targeting prevented the development of heart failure associated with long-term transverse aortic constriction, conferring a survival benefit. In contrast to 29% of control mice (n=24), only 6% of mAKAPβ knockout mice (n=31) died in the 16 weeks of pressure overload (P=0.02). Accordingly, mAKAPβ knockout inhibited myocardial apoptosis and the development of interstitial fibrosis, left atrial hypertrophy, and pulmonary edema. This improvement in cardiac status correlated with the attenuated activation of signaling pathways coordinated by the mAKAPβ scaffold, including the decreased phosphorylation of protein kinase D1 and histone deacetylase 4 that we reveal to participate in a new mAKAP signaling module. Furthermore, mAKAPβ knockout inhibited pathological gene expression directed by myocyte-enhancer factor-2 and nuclear factor of activated T-cell transcription factors that associate with the scaffold. CONCLUSIONS: mAKAPβ orchestrates signaling that regulates pathological cardiac remodeling in mice. Targeting of the underlying physical architecture of signaling networks, including mAKAPβ signalosome formation, may constitute an effective therapeutic strategy for the prevention and treatment of pathological remodeling and heart failure. PMID: 24812305 [PubMed - in process]
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Related Articles Coupled cellular therapy and magnetic targeting for airway regeneration. Biochem Soc Trans. 2014 Jun;42(3):657-61 Authors: Ordidge KL, Gregori M, Kalber TL, Lythgoe MF, Janes SM, Giangreco A Abstract Airway diseases including COPD (chronic obstructive pulmonary disease), cystic fibrosis and lung cancer are leading causes of worldwide morbidity and mortality, with annual healthcare costs of billions of pounds. True regeneration of damaged airways offers the possibility of restoring lung function and protecting against airway transformation. Recently, advances in tissue engineering have allowed the development of cadaveric and biosynthetic airway grafts. Although these have produced encouraging results, the ability to achieve long-term functional airway regeneration remains a major challenge. To promote regeneration, exogenously delivered stem and progenitor cells are being trialled as cellular therapies. Unfortunately, current evidence suggests that only small numbers of exogenously delivered stem cells engraft within lungs, thereby limiting their utility for airway repair. In other organ systems, magnetic targeting has shown promise for improving long-term robust cell engraftment. This technique involves in vitro cell expansion, magnetic actuation and magnetically guided cell engraftment to sites of tissue damage. In the present paper, we discuss the utility of coupling stem cell-mediated cellular therapy with magnetic targeting for improving airway regeneration. PMID: 24849234 [PubMed - in process]
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Related Articles Inhibition of Wnt/β-catenin signaling promotes epithelial differentiation of mesenchymal stem cells and repairs bleomycin-induced lung injury. Am J Physiol Cell Physiol. 2014 Aug 1;307(3):C234-44 Authors: Wang C, Zhu H, Sun Z, Xiang Z, Ge Y, Ni C, Luo Z, Qian W, Han X Abstract Idiopathic pulmonary fibrosis is a progressive lung disorder of unknown etiology. Previous studies have shown that aberrant activation of the Wnt/β-catenin signaling cascade occurs in lungs of patients with idiopathic pulmonary fibrosis. Given the important roles of the Wnt/β-catenin signaling pathway in the development of pulmonary fibrosis, we targeted this pathway for the intervention of pulmonary fibrosis with XAV939, a small molecule that specifically inhibits Tankyrase 1/2, eventually leading to the degradation of β-catenin and suppression of the Wnt/β-catenin signaling pathway. Our results demonstrated that XAV939 significantly inhibited the activation of Wnt/β-catenin signaling and attenuated bleomycin-induced lung fibrosis in mice, and thus improved the survival of mice with lung injury. Interestingly, previous investigations have confirmed that endogenous and exogenous mesenchymal stem cells could be recruited to the injured lung, although the exact effects of these cells are debatable. To determine the effect of Wnt/β-catenin signaling in the epithelial differentiation of bone marrow-derived mesenchymal stem cells (BM-MSCs), we established a coculture system that contains BM-MSCs and alveolar type II epithelial cells. The in vitro experiments demonstrated that XAV939 could promote the differentiation of BM-MSCs into an epithelium-like phenotype in the coculture system. We also found that XAV939 could inhibit the proliferation and myofibroblast differentiation of NIH/3T3 fibroblasts. This work supports that inhibition of the Wnt/β-catenin signaling pathway may be exploited for the treatment of idiopathic pulmonary fibrosis for which effective treatment strategies are still lacking. PMID: 24898581 [PubMed - in process]
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Related Articles Comparative Study between Intravenous and Intraperitoneal Stem Cell Therapy in Amiodarone Induced Lung Injury in Rat. Int J Stem Cells. 2014 May;7(1):1-11 Authors: Zickri MB, Fadl SG, Metwally HG Abstract BACKGROUND AND OBJECTIVES: The fibrosing form of lung injury (occupational, environmental, infective or drug induced) is associated with significant morbidity and mortality. Amiodarone (AM), often prescribed for control of arrhythmias is considered a potential cause. No effective treatment was confirmed, except lung transplantation. Intravenous (IV) stem cell therapy may produce pulmonary emboli or infarctions. Despite being commonly used in clinical practice, the intraperitoneal (IP.) route has been rarely used for cell delivery. The present study aimed at investigating and comparing the possible effect of IP stem cell therapy (SCT) on pulmonary toxicity versus the intravenous route in a rat model of amiodarone induced lung damage. METHODS AND RESULTS: 36 adult male albino rats were divided into 4 groups. Rats of AM group were given 30 mg/kg daily orally for 4 weeks. Rats of IV SCT group were injected with stem cells in the tail vein. Rats of IP SCT group received IP cell therapy. Histological, histochemical, immunohistochemical and morphometric studies were performed. Obstructed bronchioles, overdistended alveoli, reduced type I pneumocytes, increased thickness of alveolar septa and vessels wall besides increased area% of collagen fibers regressed in response to IV and IP SCT. The improvement was more obvious in IV group. The area% of Prussion blue +ve and CD105 +ve cells was significantly higher in IV group. CONCLUSIONS: Cord blood MSC therapy proved definite amelioration of lung injury ending in fibrosis. The effect of IP SCT was slightly inferior to that of IV SCT, which may be overwhelmed by repeated IP injection. PMID: 24921022 [PubMed]
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Related Articles Histolgical and immunohistochemical study on the effect of stem cell therapy on bleomycin induced pulmonary fibrosis in albino rat. Int J Stem Cells. 2014 May;7(1):33-42 Authors: Sabry MM, Elkalawy SA, Abo-Elnour RK, Abd-El-Maksod DF Abstract AIM OF WORK: To demonstrate the bleomycin induced histological changes in the lung and the possible protective and/or therapeutic effect of stem cell therapy. MATERIALS AND METHODS: Study was carried out on 36 adult male albino rats, classified into 4 groups: group I (control), group II (bleomycin treated group), group III (early stem cell treated group: immediately after bleomycin), group IV (late stem cell treated group: 7 days after bleomycin). Sections were taken at the 14(th) day of experiment. stained with Hematoxylin and Eosin, Masson's trichrome, immunohistochemichal stains for α-SMA & PCNA. Sections were examined by light & immunofluroscent microscopy. Area percent of collagen fibers, area percent & optical density of α-SMA immunopositive cells were measured as well as the number of H&E and PCNA stained pneumocytes type II was counted. RESULTS: Group II showed, thickening of septa, extravasation of blood, dividing pneumocytes type II cells with acinar formation, cellular infiltration, fibroblast cells, almost complete loss of normal lung architecture in certain fields, consolidation and replacement of the lung tissue with fibrous tissue in other fields. Restoring of lung tissue with significant decrease in mean area % of collagen fibers, α-SMA immunopositive cells were detected in group III. CONCLUSIONS: Early treatment with bone marrow derived mesenchymal stem cells (BMSCs) immediately after bleomycin administration showed a significant reduction in fibrotic changes, however the late treatment with BMSCs (7 days) after bleomycin administration showed non significant results. PMID: 24921026 [PubMed]
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Related Articles A phase 1b study of placenta-derived mesenchymal stromal cells in patients with idiopathic pulmonary fibrosis. Respirology. 2014 Jul 9; Authors: Chambers DC, Enever D, Ilic N, Sparks L, Whitelaw K, Ayres J, Yerkovich ST, Khalil D, Atkinson KM, Hopkins PM Abstract BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a degenerative disease characterized by fibrosis following failed epithelial repair. Mesenchymal stromal cells (MSC), a key component of the stem cell niche in bone marrow and possibly other organs including lung, have been shown to enhance epithelial repair and are effective in preclinical models of inflammation-induced pulmonary fibrosis, but may be profibrotic in some circumstances. METHODS: In this single centre, non-randomized, dose escalation phase 1b trial, patients with moderately severe IPF (diffusing capacity for carbon monoxide (DLCO ) ≥ 25% and forced vital capacity (FVC) ≥ 50%) received either 1 × 10(6) (n = 4) or 2 × 10(6) (n = 4) unrelated-donor, placenta-derived MSC/kg via a peripheral vein and were followed for 6 months with lung function (FVC and DLCO ), 6-min walk distance (6MWD) and computed tomography (CT) chest. RESULTS: Eight patients (4 female, aged 63.5 (57-75) years) with median (interquartile range) FVC 60 (52.5-74.5)% and DLCO 34.5 (29.5-40)% predicted were treated. Both dose schedules were well tolerated with only minor and transient acute adverse effects. MSC infusion was associated with a transient (1% (0-2%)) fall in SaO2 after 15 min, but no changes in haemodynamics. At 6 months FVC, DLCO , 6MWD and CT fibrosis score were unchanged compared with baseline. There was no evidence of worsening fibrosis. CONCLUSIONS: Intravenous MSC administration is feasible and has a good short-term safety profile in patients with moderately severe IPF. PMID: 25039426 [PubMed - as supplied by publisher]
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Related Articles ABCG2pos Lung Mesenchymal Stem Cells are a Novel Pericyte Subpopulation that Contributes to Fibrotic Remodeling. Am J Physiol Cell Physiol. 2014 Aug 13; Authors: Marriott S, Baskir RS, Gaskill C, Menon S, Carrier EJ, Williams J, Talati M, Helm K, Alford CE, Kropski JA, Loyd J, Wheeler L, Johnson J, Austin E, Nozik-Grayck E, Meyrick BO, West JD, Klemm DJ, Majka SM Abstract Genesis of myofibroblasts is obligatory for the development of pathology in many adult lung diseases. Adult lung tissue contains a population of perivascular ABCG2(pos) mesenchymal stem cells (MSC) that are precursors of myofibroblasts and distinct from NG2 pericytes. We hypothesized that these MSC participate in deleterious remodeling associated with pulmonary fibrosis (PF) and associated hypertension (PH). To test this hypothesis, resident lung MSC were quantified in lung samples from control subjects and PF patients. ABCG2(pos) cell numbers were decreased in human PF and interstitial lung disease compared to control samples. Genetic labeling of lung MSC in mice enabled determination of terminal lineage and localization of ABCG2 cells following intratracheal administration of bleomycin to elicit fibrotic lung injury. Fourteen days following bleomycin injury eGFP labeled lung MSC-derived cells were increased in number and localized to interstitial areas of fibrotic and microvessel remodeling. Finally, gene expression analysis was evaluated to define the response of MSC to bleomycin injury in vivo using ABCG2(pos) MSC isolated during the inflammatory phase post injury and in vitro bleomycin or TGFβ1 treated cells. MSC responded to bleomycin treatment in vivo with a pro-fibrotic gene program which was not recapitulated in vitro with bleomycin treatment. However, TGFβ1 treatment induced the appearance of a pro-fibrotic myofibroblast phenotype in vitro. Additionally, when exposed to the profibrotic stimulus, TGFβ1, ABCG2 and NG2 pericytes demonstrated distinct responses. Our data highlight ABCG2(pos) lung MSC as a novel cell population that contributes to detrimental myofibroblast-mediated remodeling during PF. PMID: 25122876 [PubMed - as supplied by publisher]
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Related Articles Moving stem cell therapy to patients with idiopathic pulmonary fibrosis. Respirology. 2014 Aug 14; Authors: Glassberg MK, Toonkel RL PMID: 25124287 [PubMed - as supplied by publisher]
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Related Articles Primary myelofibrosis: 2014 update on diagnosis, risk-stratification, and management. Am J Hematol. 2014 Sep;89(9):915-25 Authors: Tefferi A Abstract DISEASE OVERVIEW: Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by stem cell-derived clonal myeloproliferation, abnormal cytokine expression, bone marrow fibrosis, anemia, splenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, leukemic progression, and shortened survival. DIAGNOSIS: DIAGNOSIS is based on bone marrow morphology. The presence of JAK2, CALR, or MPL mutation is supportive but not essential for diagnosis; approximately 90% of patients carry one of these mutations and 10% are "triple-negative." None of these mutations are specific to PMF and are also seen in essential thrombocythemia (ET). Prefibrotic PMF mimics ET in its presentation and the distinction, enabled by careful bone marrow morphological examination, is prognostically relevant. Differential diagnosis also includes chronic myeloid leukemia, myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia. RISK STRATIFICATION: The Dynamic International Prognostic Scoring System-plus (DIPSS-plus) uses eight predictors of inferior survival: age >65 years, hemoglobin <10 g/dL, leukocytes >25 × 10(9) /L, circulating blasts ≥1%, constitutional symptoms, red cell transfusion dependency, platelet count <100 × 10(9) /L, and unfavorable karyotype (i.e., complex karyotype or sole or two abnormalities that include +8, -7/7q-, i(17q), inv(3), -5/5q-, 12p-, or 11q23 rearrangement). The presence of 0, 1, "2 or 3," and ≥4 adverse factors defines low, intermediate-1, intermediate-2, and high-risk disease with median survivals of approximately 15.4, 6.5, 2.9, and 1.3 years, respectively. High risk disease is also defined by CALR(-) /ASXL1(+) mutational status. RISK-ADAPTED THERAPY: Observation alone is adequate for asymptomatic low/intermediate-1 risk disease, especially with CALR(+) /ASXL1(-) mutational status. Stem cell transplant is considered for DIPSS-plus high risk disease or any risk disease with CALR(-) /ASXL1(+) mutational status. Investigational drug therapy is reasonable for symptomatic intermediate-1 or intermediate-2 risk disease. Splenectomy is considered for drug-refractory splenomegaly. Involved field radiotherapy is most useful for post-splenectomy hepatomegaly, non-hepatosplenic EMH, PMF-associated pulmonary hypertension, and extremity bone pain. Am. J. Hematol. 89:916-925, 2014. © 2014 Wiley Periodicals, Inc. PMID: 25124313 [PubMed - in process]
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Related Articles IL-6/STAT3 promotes regeneration of airway ciliated cells from basal stem cells. Proc Natl Acad Sci U S A. 2014 Aug 18; Authors: Tadokoro T, Wang Y, Barak LS, Bai Y, Randell SH, Hogan BL Abstract The pseudostratified airway epithelium of the lung contains a balanced proportion of multiciliated and secretory luminal cells that are maintained and regenerated by a population of basal stem cells. However, little is known about how these processes are modulated in vivo, and about the potential role of cytokine signaling between stem and progenitor cells and their niche. Using a clonal 3D organoid assay, we found that IL-6 stimulated, and Stat3 inhibitors reduced, the generation of ciliated vs. secretory cells from basal cells. Gain-of-function and loss-of-function studies with cultured mouse and human basal cells suggest that IL-6/Stat3 signaling promotes ciliogenesis at multiple levels, including increases in multicilin gene and forkhead box protein J1 expression and inhibition of the Notch pathway. To test the role of IL-6 in vivo genetically, we followed the regeneration of mouse tracheal epithelium after ablation of luminal cells by inhaled SO2. Stat3 is activated in basal cells and their daughters early in the repair process, correlating with an increase in Il-6 expression in platelet-derived growth factor receptor alpha(+) mesenchymal cells in the stroma. Conditional deletion in basal cells of suppressor of cytokine signaling 3, encoding a negative regulator of the Stat3 pathway, results in an increase in multiciliated cells at the expense of secretory and basal cells. By contrast, Il-6 null mice regenerate fewer ciliated cells and an increased number of secretory cells after injury. The results support a model in which IL-6, produced in the reparative niche, functions to enhance the differentiation of basal cells, and thereby acts as a "friend" to promote airway repair rather than a "foe." PMID: 25136113 [PubMed - as supplied by publisher]
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