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 Muscarinic receptor subtypes in neuronal and non-neuronal cholinergic function. Auton Autacoid Pharmacol. 2006 Jul;26(3):219-33 Authors: Eglen RM Abstract 1 Muscarinic M1-M5 receptors mediate the metabotropic actions of acetylcholine in the nervous system. A growing body of data indicate they also mediate autocrine functions of the molecule. The availability of novel and selective muscarinic agonists and antagonists, as well as in vivo gene disruption techniques, has clarified the roles of muscarinic receptors in mediating both functions of acetylcholine. 2 Selective M1 agonists or mixed M1 agonists/M2 antagonists may provide an approach to the treatment of cognitive disorders, while M3 antagonism, or mixed M2/M3 antagonists, are approved for the treatment of contractility disorders including overactive bladder and chronic obstructive pulmonary disease. Preclinical data suggest that selective agonism of the M4 receptor will provide novel anti-nociceptive agents, while therapeutics-based upon agonism or antagonism of the muscarinic M5 receptor have yet to be reported. 3 The autocrine functions of muscarinic receptors broadly fall into two areas - control of cell growth or proliferation and mediation of the release of chemical mediators from epithelial cells, ultimately causing muscle relaxation. The former particularly are involved in embryological development, oncogenesis, keratinocyte function and immune responsiveness. The latter regulate contractility of smooth muscle in the vasculature, airways and urinary bladder. 4 Most attention has focused on muscarinic M1 or M3 receptors which mediate lymphocyte immunoresponsiveness, cell migration and release of smooth muscle relaxant factors. Muscarinic M4 receptors are implicated in the regulation of keratinocyte adhesion and M2 receptors in stem cell proliferation and development. Little data are available concerning the M5 receptor, partly due to the difficulties in defining the subtype pharmacologically. 5 The autocrine functions of acetylcholine, like those in the nervous system, involve activation of several muscarinic receptor subtypes. Consequently, the role of these subtypes in autocrine, as well neuronal cholinergic systems, significantly expands their importance in physiology and pathophysiology. PMID: 16879488 [PubMed - indexed for MEDLINE]
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Related Articles [A case of follicular lymphoma complicated with lethal pemphigus]. Gan To Kagaku Ryoho. 2006 Nov;33(11):1677-80 Authors: Imataki O, Tamai Y, Abe Y, Ito I, Yoshikawa S, Kawakami K Abstract Paraneoplastic pemphigus (PNP) is a rare autoimmune bullous disease associated with neoplasm, which is clinically characterized by mucocutaneous lesions resembling pemphigus vulgaris or erythema multiforme. A case presented with PNP refractory to chemotherapy including rituximab, predonisolone and cyclophosphamide (RCHOP regimen). A 36-year-old man, who had been diagnosed as extended follicular lymphoma, presented with a polymorphous skin eruption of the trunk, sclera conjunctivitis, and severe mucosal erosions of the lips and oral cavity. He was diagnosed as pemphigus pathologically by a biopsy of the oral mucosa. However, 3 courses of rituximab and CHOP therapy, which exert a partial response with lymphoma lesions, did not prove effective for oral stomatitis due to pemphigus. He received corticosteroid therapy (prednisolone 40 mg/day) and went into a state of temporally remission regarding pemphigus. However, the mucosal lesions were again exacerbated despite control of the lymphoma status after chemotherapy. Oral stomatitis extended to the upper respiratory system through the larynx and resulted in bronchiolitis obliterance clinically presented likely as severe chronic obstructive pulmonary disease (COPD). Because it is known that PNP refractory to long-term steroid and cytoreductive therapy has a progressive character and poor prognosis, supportive care would be warranted for these patients. PMID: 17108741 [PubMed - indexed for MEDLINE]
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Related Articles Chronic GVHD and pretransplantation abnormalities in pulmonary function are the main determinants predicting worsening pulmonary function in long-term survivors after stem cell transplantation. Biol Blood Marrow Transplant. 2006 Dec;12(12):1261-9 Authors: Savani BN, Montero A, Srinivasan R, Singh A, Shenoy A, Mielke S, Rezvani K, Karimpour S, Childs R, Barrett AJ Abstract Pulmonary function (PF) was studied in 69 consecutive patients with hematologic diseases, with a minimum 5-year (range, 5-13 years) follow-up after allogeneic stem cell transplantation from an HLA-matched sibling. Fifty-six patients (81%) received total body irradiation based myeloablative stem cell transplantation (MT) and 13 (19%) underwent nonmyeloablative stem cell transplantation (NST). Thirty-one patients (45%) developed a late decrease in PF from baseline, 25 with a restrictive and 6 with an obstructive pattern PF abnormality. Twelve patients (17%) were symptomatic, 8 with a severe restrictive PF defect, but none required supplemental oxygen. The incidence of developing a late PF abnormality was comparable in MT (24 of 56) and NST (5 of 13; P = .51). In multivariate analysis, chronic graft-versus-host disease (relative risk, 16) and pretransplantation diffusion capacity for carbon monoxide or forced expiratory volume in the first second <80% predicted were independently associated with a late decrease in PF from baseline (relative risk, 7). Our results indicate that late PF abnormality is common after MT and NST. Patients with a low pretransplantation diffusion capacity for carbon monoxide of or forced expiratory volume in the first second who developed chronic graft-versus-host disease were most severely affected. Longer follow-up is needed to determine whether PF will continue to decrease or reach a plateau and whether more patients with PF abnormality will eventually become symptomatic. PMID: 17162207 [PubMed - indexed for MEDLINE]
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Related Articles [Cell based therapy for COPD]. Nihon Rinsho. 2007 Apr;65(4):740-7 Authors: Kubo H Abstract To develop a new cell based therapy for chronic obstructive pulmonary disease (COPD), we need to understand 1) the role of tissue-specific and bone marrow-derived stem cells, 2) extracellular matrix, and 3) growth factors. Recently, bronchioalveolar stem cells were identified in murine distal lungs. Impairment of these stem cells may cause improper lung repair after inflammation, resulting in pulmonary emphysema. Bone marrow-derived cells are necessary to repair injured lungs. However, the long term role of these cells is not understood yet. Although we need more careful analysis and additional experiments, growth factors, such as hepatocyte growth factor, are good candidates for the new cell based therapy for COPD. Lung was believed as a non-regenerative organ. Based on these recent reports about lung regeneration and stem cells, however, new strategies to treat COPD and a new point of view to understand the pathophysiology of COPD are rising. PMID: 17419397 [PubMed - indexed for MEDLINE]
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Related Articles Alpha one antitrypsin deficiency: from gene to treatment. Respiration. 2007;74(5):481-92 Authors: Wood AM, Stockley RA Abstract Alpha1-antitrypsin deficiency is a genetic disorder which contributes to the development of chronic obstructive pulmonary disease, bronchiectasis, liver cirrhosis and panniculitis. The discovery of alpha1-antitrypsin and its function as an antiprotease led to the protease-antiprotease hypothesis, which goes some way to explaining the pathogenesis of emphysema. This article will review the clinical features of alpha1-antitrypsin deficiency, the genetic mutations known to cause it, and how they do so at a molecular level. Specific treatments for the disorder based on this knowledge will be reviewed, including alpha1-antitrypsin replacement, gene therapy and possible future therapies, such as those based on stem cells. PMID: 17671403 [PubMed - indexed for MEDLINE]
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Related Articles Tissue regeneration as next-generation therapy for COPD--potential applications. Int J Chron Obstruct Pulmon Dis. 2008;3(4):509-14 Authors: Ohnishi S, Nagaya N Abstract COPD is a major cause of chronic morbidity and mortality worldwide, and there is a need to develop more effective therapeutic strategies to replace specialized treatment such as lung transplantation. Recent studies suggest that recognition of apoptotic lung epithelial or endothelial cells may result in growth factors to stimulate cell replacement, and defects in these processes may contribute to the pathogenesis of COPD. Furthermore, recent animal and human studies have revealed that tissue-specific stem cells and bone marrow-derived cells contribute to lung tissue regeneration and protection, and thus administration of exogenous stem/progenitor cells or humoral factors responsible for activation of endogenous stem/progenitor cells may be a potent next-generation therapy for COPD. PMID: 19281069 [PubMed - indexed for MEDLINE]
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Related Articles Deriving respiratory cell types from stem cells. Curr Stem Cell Res Ther. 2007 Sep;2(3):197-208 Authors: Olsson F, Denham M, Cole TJ, Hooper SB, Mollard R Abstract The reported pluripotential capabilities of many human stem cell types has made them an attractive area of research, given the belief they may hold considerable therapeutic potential for treating a wide range of human diseases and injuries. Although the bulk of stem cell based research has focused on developing procedures for the treatment of pancreatic, neural, cardiovascular and haematopoietic diseases, the potential for deriving respiratory cell types from stem cells for treatment of respiratory specific diseases has also been explored. It is suggested that stem cell derivatives may be used for lung replacement/regeneration therapeutics and high though-put pharmacological screening strategies for a variety of respiratory injuries and diseases including: cystic fibrosis, chronic obstructive pulmonary disease, respiratory distress syndrome, pulmonary fibrosis and pulmonary edema. This review will explore recent progress in characterizing adult respiratory and bone marrow derived stem cells with respiratory potential as well as the endogenous mechanisms directing the homing of these cells to the diseased and injured lung. In addition, the potential for embryonic stem cell based therapies in this domain as well as the histological, anatomical and molecular aspects of respiratory development will be summarized. PMID: 18220903 [PubMed - indexed for MEDLINE]
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Related Articles Elastase-induced lung emphysema in rats is not reduced by hematopoietic growth factors when applied preventionally. Virchows Arch. 2008 Jun;452(6):675-88 Authors: Schmiedl A, Lempa T, Hoymann HG, Rittinghausen S, Popa D, Tschernig T, Fehrenbach H, Pabst R, Hoeper MM, Hohlfeld JM Abstract We hypothesized that formation of pulmonary emphysema could be diminished after previous activation of stem cells. Animals received either a daily dose of the hematopoietic growth factors (GF; recombinant rat stem cell factor plus recombinant granulocyte colony stimulating factor; n=6, Elastase/GF group) or vehicle (n=9, Elastase/Sham group) starting 3 days before intratracheal instillation of elastase or vehicle and continued for another 25 days. Control animals were treated with NaCl (n=9, Sham/Sham group). On day 25, in all animals, a 2-mL pump was implanted subcutaneously that delivered 200 microg/h 5-bromo-2-desoxyuridine (BrdU) until study termination. Compared to controls, the Elastase/Sham group exhibited elevated total lung capacity (TLC) and functional residual capacity (FRC), significantly increased mean free alveolar pathway, alveolar volume, and decreased septal density. The Elastase/GF group showed (1) a significant increase of TLC and FRC, (2) a significant increase in alveolar size and volume, (3) a significant reduction of septal density, volume, and thickness. Proliferation in lung parenchyma and in terminal bronchioles remained significantly decreased in the Elastase/Sham group and the Elastase/GF group. Blood cell number has significantly increased in the Elastase/GF group. The application of GF-enhanced pulmonary emphysema, presumable because of increased inflammatory activity, was a result of a preventive treatment. PMID: 18437418 [PubMed - indexed for MEDLINE]
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Related Articles [Effects of bone marrow mesenchymal stem cells transplantation on the apoptosis of alveolar wall cells in papain and Co60-induced pulmonary emphysema rats]. Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2008 May;24(2):210-4 Authors: Liu HM, Zhen GH, Zhang ZX, Zhang HL, Cao Y, Wang T, Gu NB, Xu YJ Abstract AIM: To study the effects of bone marrow MSCs transplantation on the apoptosis of alveolar wall cells and the expression of Bcl-2 and Bax of lung tissue in papain and Co60-induced pulmonary emphysema rats. METHODS: Female Lewis rats were randomly divided into three groups: control group, emphysema group, emphysema + MSCs transplantation group. Rats were sacrificed at days 14 and 28 after treatment. Morphologic analysis of the lung tissue was performed. The apoptosis of the lung cells was assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. The expression of Bcl-2 and Bax were determined by immunohistochemical staining. RESULTS: Emphysematous changes of the lung tissue were observed in emphysema group and emphysema + MSCs transplantation group. However, the emphysematous change in emphysema + MSCs transplantation group was improved compared with the emphysema group. There was significant difference in the number of alveolar counted per unit area (MAN), mean alveoli area (MAA) and mean linear interval(MLI) between emphysema group and emphysema + MSCs transplantation group. The apoptotic index of the alveolar wall cells in emphysema + MSCs transplantation group was less than that in the emphysema group. The percentage of Bcl-2 positive cells in emphysema + MSCs transplantation group was significantly higher than that in the emphysema group. The percentage of Bax positive cells in emphysema + MSCs transplantation group was significantly lower than that in the emphysema group. The ratio of Bcl-2/Bax of emphysema + MSCs transplantation group was significantly higher than that in the emphysema group. CONCLUSION: Bone marrow MSCs transplantation inhibits the apoptosis of alveolar wall cells, upregulates the expression of Bcl-2 and downregulates the expression of Bax. This may be part of the reason that bone marrow MSCs transplantation improves the papain and Co60-induced pulmonary emphysema. PMID: 21141529 [PubMed - indexed for MEDLINE]
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Related Articles [Activation of satellite cells in the intercostal muscles of patients with chronic obstructive pulmonary disease]. Arch Bronconeumol. 2008 May;44(5):239-44 Authors: Martínez-Llorens J, Casadevall C, Lloreta J, Orozco-Levi M, Barreiro E, Broquetas J, Gea J Abstract OBJECTIVE: The respiratory muscles of patients with chronic obstructive pulmonary disease (COPD) display evidence of structural damage in parallel with signs of adaptation. We hypothesized that this can only be explained by the simultaneous activation of satellite cells. The aim of this study was to analyze the number and activation of those cells along with the expression of markers of microstructural damage that are frequently associated with regeneration. PATIENTS AND METHODS: The study included 8 patients with severe COPD (mean [SD] forced expiratory volume in 1 second, 33% [9%] of predicted) and 7 control subjects in whom biopsies were performed of the external intercostal muscle. The samples were analyzed by light microscopy to assess muscle fiber phenotype, electron microscopy to identify satellite cells, and real-time polymerase chain reaction to analyze the expression of the following markers: insulin-like growth factor 1, mechano growth factor, and embryonic and perinatal myosin heavy chains (MHC) as markers of microstructural damage; Pax-7 and m-cadherin as markers of the presence and activation of satellite cells, respectively; and MHC-I, IIa, and IIx as determinants of muscle fiber phenotype. RESULTS: The patients had larger fibers than healthy subjects (54 [6] vs 42 [4] microm(2); P< .01) with a similar or slightly increased proportion of satellite cells, as measured by ultrastructural analysis (4.3% [1%] vs 3.7% [3.5%]; P>.05) or expression of Pax-7 (5.5 [4.1] vs 1.6 [0.8] arbitrary units [AU]; P< .05). In addition, there was greater activation of satellite cells in the patients, as indicated by increased expression of m-cadherin (3.8 [2.1] vs 1.0 [1.2] AU; P=.05). This was associated with increased expression of markers of microstructural damage: insulin-like growth factor 1, 0.35 (0.34) vs 0.09 (0.08) AU (P< .05); mechano growth factor, 0.45 (0.55) vs 0.13 (0.17) AU (P=.05). CONCLUSIONS: The intercostal muscles of patients with severe COPD show indirect signs of microstructural damage accompanied by satellite cell activation. This suggests the presence of ongoing cycles of lesion and repair that could partially explain the maintenance of the structural properties of the muscle. PMID: 18448014 [PubMed - indexed for MEDLINE]
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Related Articles Mesenchymal stem cells transplantation protects against rat pulmonary emphysema. Front Biosci. 2008;13:3415-22 Authors: Zhen G, Liu H, Gu N, Zhang H, Xu Y, Zhang Z Abstract Pulmonary emphysema is characterized by loss of alveolar structure. Bone marrow mesenchymal stem cells (MSCs) have been shown to differentiate into alveolar epithelial cells. However, the effect of MSCs transplantation on pulmonary emphysema is unknown. To address this question, cultured bone marrow MSCs from male donor rats were infused into female recipients treated with irradiation and instillation of papain. We found that the emphysematous changes in rats received MSCs transplantation were ameliorated when compared with the rats without MSCs transplantation. Y chromosome fluorescent in situ hybridization (FISH) and immunohistochemical staining for SP-C, confirmed that MSCs engrafted in recipient lungs and differentiated into type II alveolar epithelial cells. Additionally, MSCs transplantation reduced the extent of irradiation and papain-induced alveolar cell apoptosis, likely due to the up-regulation of the expression of Bcl-2 and Bax gene. We conclude that MSCs transplantation protects against the irradiation and papain-induced pulmonary emphysema. The mechanisms of protection may involve the engraftment of MSCs in the lungs, differentiation of MSCs into type II alveolar epithelial cells and suppression of alveolar cell apoptosis. PMID: 18508443 [PubMed - indexed for MEDLINE]
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Related Articles Second donation of hematopoietic stem cells from unrelated donors for patients with relapse or graft failure after allogeneic transplantation. Haematologica. 2008 Aug;93(8):1276-8 Authors: Platzbecker U, Binder M, Schmid C, Rutt C, Ehninger G, Bornhäuser M PMID: 18519515 [PubMed - indexed for MEDLINE]
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Related Articles Intranasal HGF administration ameliorates the physiologic and morphologic changes in lung emphysema. Mol Ther. 2008 Aug;16(8):1417-26 Authors: Hegab AE, Kubo H, Yamaya M, Asada M, He M, Fujino N, Mizuno S, Nakamura T Abstract Hepatocyte growth factor (HGF) has multiple biological effects on stem cells, epithelial proliferation, and wound healing. In this study, we investigated a possible therapeutic benefit of intranasal HGF on elastase-induced emphysema, and assessed the role of stem/progenitor cells in this process. HGF was given twice a week for 1-4 weeks after the establishment of emphysema in mice. HGF inhalation significantly ameliorated the enlargement of airspaces and alveolar wall destruction. Also, elevated static lung compliance returned to control levels within 2 weeks of HGF treatment. The expressions of stem-cell markers, c-kit, stem-cell antigen 1 (Sca-1), and CD34 were also significantly influenced by HGF. Most of the c-kit(+) cells were bone marrow derived, while most Sca-1(+) were lung endogenous cells. CD34(+) cells were from both sources, and a portion of the endogenous CD34(+) cells was also Sca-1(+). Further, HGF increased the expression levels of proliferating cell nuclear antigen (PCNA) and cytokeratin-19. Also, their immunohistochemical staining patterns were colocalized, indicative of epithelial multiplication. The results of the study show that intranasal treatment with HGF reverses both the physiological and morphometric changes of lung emphysema, possibly through stem-cell mobilization and alveolar regeneration, providing a nonsurgical treatment and suggesting the possibility of achieving a similar effect in humans. PMID: 18560414 [PubMed - indexed for MEDLINE]
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Related Articles Epithelial cell-extracellular matrix interactions and stem cells in airway epithelial regeneration. Proc Am Thorac Soc. 2008 Aug 15;5(6):689-94 Authors: Coraux C, Roux J, Jolly T, Birembaut P Abstract In healthy subjects, the respiratory epithelium forms a continuous lining to the airways and to the environment, and plays a unique role as a barrier against external deleterious agents to protect the airways from the insults. In respiratory diseases such as cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), chronic bronchitis, or asthma, the airway epithelium is frequently remodeled and injured, leading to the impairment of its defense functions. The rapid restoration of the epithelial barrier is crucial for these patients. The complete regeneration of the airway epithelium is a complex phenomenon, including not only the epithelial wound repair but also the epithelial differentiation to reconstitute a fully well differentiated and functional epithelium. The regeneration implies two partners: the epithelial stem/progenitor cells and factors able to regulate this process. Among these factors, epithelial cells-extracellular matrix (ECM) interactions play a crucial role. The secretion of a provisional ECM, the cell-ECM relationships through epithelial receptors, and the remodeling of the ECM by proteases (mainly matrix metalloproteinases) contribute not only to airway epithelial repair by modulating epithelial cell migration and proliferation, but also to the differentiation of repairing cells leading to the complete restoration of the wounded epithelium. A better characterization of resident stem cells and of effectors of the regeneration process is an essential prerequisite to propose new regenerative therapeutics to patients suffering from infectious/inflammatory respiratory diseases. PMID: 18684718 [PubMed - indexed for MEDLINE]
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Related Articles Intrinsic and synaptic long-term depression of NTS relay of nociceptin- and capsaicin-sensitive cardiopulmonary afferents hyperactivity. Pflugers Arch. 2009 Mar;457(5):1147-59 Authors: Bantikyan A, Song G, Feinberg-Zadek P, Poon CS Abstract The nucleus tractus solitarius (NTS) in the caudal medulla is a gateway for a variety of cardiopulmonary afferents important for homeostatic regulation and defense against airway and cardiovascular insults and is a key central target potentially mediating the response habituation to these inputs. Here, whole-cell and field population action potential recordings and infrared imaging in rat brainstem slices in vitro revealed a compartmental pain-pathway-like organization of capsaicin-facilitated vs. nocistatin-facilitated/nociceptin-suppressed neuronal clusters in an NTS region, which receives cardiopulmonary A- and C-fiber afferents with differing capsaicin sensitivities. All capsaicin-sensitive neurons and a fraction of nociceptin-sensitive neurons expressed N-methyl-D: -aspartate (NMDA) receptor-dependent synaptic long-term depression (LTD) following afferent stimulation. All neurons also expressed activity-dependent decrease of excitability (intrinsic LTD), which converted to NMDA receptor-dependent intrinsic long-term potentiation after GABA(A) receptor blockade. Thus, distinct intrinsic and synaptic LTD mechanisms in the NTS specific to the relay of A- or C-fiber afferents may underlie the response habituation to persistent afferents hyperactivity that are associated with varying physiologic challenges and cardiopulmonary derangements-including hypertension, chronic cough, asthmatic bronchoconstriction, sustained elevated lung volume in chronic obstructive pulmonary disease or in continuous positive-airway-pressure therapy for sleep apnea, metabolic acidosis, and prolonged exposure to hypoxia at high altitude. PMID: 18704488 [PubMed - indexed for MEDLINE]
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Related Articles Human metapneumovirus infection in adults. Pediatr Infect Dis J. 2008 Oct;27(10 Suppl):S80-3 Authors: Falsey AR Abstract Human metapneumovirus (hMPV) was first identified in 2001 in Dutch children with bronchiolitis. The virus is an RNA virus in the Pneumovirinae subfamily and is most closely related to respiratory syncytial virus. hMPV has been shown to have worldwide circulation with nearly universal infection by age 5. Similar to influenza and respiratory syncytial virus, activity is greatest during the winter in temperate climates. Most of the available data on the clinical manifestations of hMPV infection are from studies of children where the virus causes upper respiratory tract infections, bronchiolitis, and pneumonia. Reinfections with hMPV occur throughout adult life and hMPV infection has been documented in 1-9% of adults each year using RT-PCR and serology for diagnosis. Illness is generally mild in young adults with serologic evidence of asymptomatic infection in many cases. Adults at highest risk of serious sequelae as a result of hMPV include the elderly, adults with underlying pulmonary disease, and those who are immunocompromised. Outbreaks of hMPV have been documented in long term care facilities with mortality of up to 50% in frail elderly residents. In addition, 6-12% of exacerbations of chronic obstructive pulmonary disease have been associated with hMPV and underlying lung disease is common in patients hospitalized with hMPV. Lastly, hMPV has been linked with severe idiopathic pneumonia in recipients of hematopoietic stem cell transplants. Although the true spectrum of adult hMPV remains to be defined, it is clear that hMPV can result in severe illness the frail elderly and adults with underlying diseases. PMID: 18820584 [PubMed - indexed for MEDLINE]
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Related Articles Stem cell therapy: the great promise in lung disease. Ther Adv Respir Dis. 2008 Jun;2(3):173-7 Authors: Siniscalco D, Sullo N, Maione S, Rossi F, D'Agostino B Abstract Lung injuries are leading causes of morbidity and mortality worldwide. Pulmonary diseases such as asthma or chronic obstructive pulmonary disease characterized by loss of lung elasticity, small airway tethers, and luminal obstruction with inflammatory mucoid secretions, or idiopathic pulmonary fibrosis characterized by excessive matrix deposition and destruction of the normal lung architecture, have essentially symptomatic treatments and their management is costly to the health care system.Regeneration of tissue by stem cells from endogenous, exogenous, and even genetically modified cells is a promising novel therapy. The use of adult stem cells to help with lung regeneration and repair could be a newer technology in clinical and regenerative medicine. In fact, different studies have shown that bone marrow progenitor cells contribute to repair and remodeling of lung in animal models of progressive pulmonary hypertension.Therefore, lung stem cell biology may provide novel approaches to therapy and could represent a great promise for the future of molecular medicine. In fact, several diseases can be slowed or even blocked by stem cell transplantation. PMID: 19124369 [PubMed - indexed for MEDLINE]
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Related Articles Short and long-term safety of lenograstim administration in healthy peripheral haematopoietic progenitor cell donors: a single centre experience. Bone Marrow Transplant. 2009 Aug;44(3):163-8 Authors: Martino M, Console G, Dattola A, Callea I, Messina G, Moscato T, Massara E, Irrera G, Fedele R, Gervasi A, Bresolin G, Iacopino P Abstract Healthy donors (HDs) who were mobilized using lenograstim (LENO) and who were undergoing peripheral haematopoietic progenitor cell collection with apheresis (HPC-A) were enrolled in a surveillance protocol. In all, 184 HDs have been assessed with a median follow-up of 62 months (range 2-155). HDs received LENO at a median dose of 10 microg/kg (range 5-15). Bone pain was reported as the most frequent short-term adverse event (71.2%). Other commonly observed short-term symptoms included fatigue (19.0%), fever (5.4%), headache (27.7%), nausea (12.0%) and insomnia (22.3%). Spleen size increased in 4.3% of the donors. No vascular disorders or cardiac disease occurred. Long-term follow-up included monitoring of adverse events, neoplastic disease or other pathologies. Transit ischaemic attack occurred in one donor (39 months post-donation). One autoimmune event was reported at 28 months post-recombinant human granulocyte (rhG)-CSF (ankylosing spondylitis); one donor with a history of chronic obstructive pulmonary disease developed secondary polyglobulia (50 months post-rhG-CSF). One donor was diagnosed with lung cancer at 19 months post-donation. No haematological disease was observed. In conclusion, the short-term safety appears to be verified, whereas, although the study identified no increased risks of malignancy among HDs who received rhG-CSF, long-term safety requires more complete data sets, especially a longer follow-up and a larger number of HDs. PMID: 19182833 [PubMed - indexed for MEDLINE]
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Related Articles Cell therapy approaches for lung diseases: current status. Curr Opin Pharmacol. 2009 Jun;9(3):268-73 Authors: Sueblinvong V, Weiss DJ Abstract Recent findings suggest that embryonic stem cells and stem cells derived from adult tissues, including bone marrow and umbilical cord blood, could be utilized in repair and regeneration of injured or diseased lungs. This is an exciting and rapidly moving field that holds promise as a therapeutic approach for variety of lung diseases. Although initial emphasis was on engraftment of stem cells in lung, more recent studies demonstrate that mesenchymal stem cells (MSCs) can modulate local inflammatory and immune responses in mouse lung disease models including acute lung injury and pulmonary fibrosis. Further, on the basis of initial reports of safety and efficacy following allogeneic administration of MSCs to patients with Crohn's disease or with graft-versus-host disease, a recent trial has been initiated to study the effect of MSCs in patients with chronic obstructive pulmonary disease. Notably, several recent clinical trials have demonstrated potential benefit of autologous stem cell administration in patient with pulmonary hypertension. In this review, we will describe recent advances in cell therapy with the focus on MSCs and their potential roles in lung development and repair. PMID: 19349209 [PubMed - indexed for MEDLINE]
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Related Articles Mesenchymal stem cells and inflammatory lung diseases. Panminerva Med. 2009 Mar;51(1):5-16 Authors: Iyer SS, Co C, Rojas M Abstract Mesenchymal stem cells (MSCs) are emerging as a therapeutic modality in various inflammatory disease states. A number of ongoing randomized Phase I/II clinical trials are evaluating the effects of allogeneic MSC infusion in patients with multiple sclerosis, graft-versus-host disease, Crohn's disease, and severe chronic myocardial ischemia. MSCs are also being considered as a potential therapy in patients with inflammatory lung diseases. Several studies, including our own, have demonstrated compelling benefits from the administration of MSCs in animal models of lung injury. These studies are leading to growing interest in the therapeutic use of MSCs in inflammatory lung diseases. In this Review, we describe how the immunoregulatory effects of MSCs can confer substantial protection in the setting of lung diseases such as acute lung injury, chronic obstructive pulmonary disease, asthma, and pulmonary hypertension. We also address potential pitfalls related to the therapeutic use of MSCs in fibrotic lung diseases such as idiopathic pulmonary fibrosis. In addition, we identify emerging areas for MSC- based therapies in modulating oxidative stress and in attenuating inflammation in alcohol-related acute lung injury. PMID: 19352305 [PubMed - indexed for MEDLINE]
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Related Articles [Influence of comorbidities on decision caring of malignant haematological diseases]. Bull Cancer. 2009 May;96(5):563-70 Authors: Najman A, Andre K, Gorin NC Abstract Comorbidities are often present in adult patients treated for malignant hematological diseases. In older patients, these disabilities can have an influence on the natural course of the malignant disease, on the tolerance to treatment and clinical decision making. Moreover caring of patients with several illnesses may generate high costs. To evaluate their incidence and their influence on treatment decisions, we conducted a retrospective analysis of 330 charts of patients treated for malignant diseases in the Department of Hematology at Saint Antoine Hospital during 2003 and 2004. The median age was 61 years. Forty percent of the patients were treated for lymphomas, mainly non-Hodgkin lymphomas; 16% for myelomas, 16% for chronic lymphocytic leukemia, 16% for a myeloproliferative disorder and 8% for acute leukemia. Comorbidities were present in 84% of the patients: hypertension in 35%, coronary disease in 16%, diabetes and chronic obstructive pulmonary disease in 13%, renal failure, heart failure and arrhythmias in 10% respectively. Due to the presence of comorbidities, treatment was changed in 62/276 patients (22,46%). The diseases associated with a change were in a decreasing order: neurologic deficiency (out of stroke) (odds ratio [OR]: 4.86; 95% CI: [1.47-16.02]; P = 0.009), insulin-dependent diabetes (OR: 4.33; 95% CI: [1.40-13.31]; P = 0.01), chronic obstructive pulmonary disease (OR: 3.33; 95% CI: [1.37-8.08]; P = 0.007), renal failure (OR: 3.07; 95% CI: [1.27-7.43]; P = 0.01), coronary disease (OR: 2.89; 95% CI: [1.30-6.42]; P = 0.009) and hypertension (OR: 2.74; 95% CI: [1.39-5.38]; P = 0.003). Comorbidities are an important factor to define precisely patients with hematological malignant diseases and have to be integrated in any cost caring evaluation. Likewise, comorbidities have to be correctly assessed in oncological studies. PMID: 19467987 [PubMed - indexed for MEDLINE]
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Related Articles Effect of nartograstim, a recombinant human granulocyte colony-stimulating factor on elastase-induced emphysema in rats. Arzneimittelforschung. 2009;59(5):248-53 Authors: Yoshimatsu A, Nan-ya K, Miki I Abstract Granulocyte colony-stimulating factor (G-CSF) is known to mobilize stem cells to various organs and that it participates in tissue regeneration. Effect of the recombinant human G-CSF nartograstim (CAS 134088-74-7) was tested on elastase-induced emphysema. Porcine pancreas elastase (PPE) was administered intratracheally to male Sprague-Dawley rats to induce parenchymal destruction which was assessed by measuring the mean linear intercept (Lm) in tissue sections as an indicator of air space size. Lung alveoli were destructed and Lm value was significantly increased 2 weeks after PPE instillation. Increase in Lm was sustained for 8 weeks after PPE instillation. Two weeks after PPE instillation, 100 and 200 microg/kg of G-CSF injected for 5 d, followed by once and 3 injections a week for 5 weeks had reversed the increase in Lm by 28.7% (P = 0.02) and 35.2% (P = 0.004), respectively. Coadministration of 100 microg/kg x 5 injection of G-CSF with all-trans-retinoic acid (ATRA; 3 mg/ kg/d) for 3 weeks from 2 weeks after PPE instillation significantly inhibited the increase in Lm by 36% (p < 0.01), whereas administration of G-CSF or ATRA alone did not produce significant improvement. Preventive administration of G-CSF, which was treated for 4 weeks from 4 days after PPE instillation, did not improve enlargement of Lm. These data indicate that the administration of G-CSF is beneficial for the recovery of destructed alveoli. PMID: 19537526 [PubMed - indexed for MEDLINE]
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Related Articles Mortality, length of hospitalization, and costs associated with invasive fungal infections in high-risk patients. Am J Health Syst Pharm. 2009 Oct 1;66(19):1711-7 Authors: Menzin J, Meyers JL, Friedman M, Perfect JR, Langston AA, Danna RP, Papadopoulos G Abstract PURPOSE: The mortality, length of hospitalization, and costs associated with invasive fungal infections (IFIs) in hospitalized patients were studied. METHODS: This retrospective database study used data from the 2004 Healthcare Cost and Utilization Project Nationwide In-patient Sample. Patients were selected for inclusion based on diagnostic codes corresponding to an IFI. A control group was matched to the IFI group based on high-risk conditions (i.e., cancer, infection with human immunodeficiency virus, chronic obstructive pulmonary disease, diabetes mellitus, and solid-organ, hematopoietic stem cell, or bone marrow transplant), age, sex, and hospital region and teaching status. Excess mortality, length of hospital stay, and costs were estimated as the differences between the IFI and control groups. RESULTS: A total of 11,881 patients were identified with a discharge diagnosis of an IFI who could be matched to a control. Frequent infections included candidiasis (40.2%), other mycoses (36.3%), and aspergillosis (16.4%). Patients with IFIs had a significantly higher mortality rate (15% versus 5%), mean +/- S.E. length of stay (18.7 +/- 0.4 days versus 7.3 +/- 0.1 days), and mean +/- S.E. costs ($44,726 +/- $1,255 versus $15,445 +/- $404) (p < 0.001 for all comparisons) than did patients without IFIs. The burden of IFIs varied by high-risk condition (highest for transplant recipients and patients with cancer) and type of infection (highest for candidiasis, zygomycosis, and aspergillosis). CONCLUSION: Examination of a large database showed that, compared with high-risk patients without IFIs, those with IFIs had higher mortality, a longer hospital stay, and higher costs associated with their hospitalization. PMID: 19767376 [PubMed - indexed for MEDLINE]
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Related Articles Modulation of sensory nerve function and the cough reflex: understanding disease pathogenesis. Pharmacol Ther. 2009 Dec;124(3):354-75 Authors: Nasra J, Belvisi MG Abstract To cough is a protective defence mechanism that is vital to remove foreign material and secretions from the airways and which in the normal state serves its function appropriately. Modulation of the cough reflex pathway in disease can lead to inappropriate chronic coughing and an augmented cough response. Chronic cough is a symptom that can present in conjunction with a number of diseases including chronic obstructive pulmonary disease (COPD) and asthma, although often the cause of chronic cough may be unknown. As current treatments for cough have proved to exhibit little efficacy and are largely ineffective, there is a need to develop novel, efficacious and safe antitussive therapies. The underlying mechanisms of the cough reflex are complex and involve a network of events, which are not fully understood. It is accepted that the cough reflex is initiated following activation of airway sensory nerves. Therefore, in the hope of identifying novel antitussives, much research has focused on understanding the neural mechanisms of cough provocation. Experimentally this has been undertaken using chemical or mechanical tussive stimuli in conjunction with animal models of cough and clinical cough assessments. This review will discuss the neural mechanisms involved in the cough, changes that occur under pathophysiological conditions and and how current research may lead to novel therapeutic opportunities for the treatment of cough. PMID: 19818366 [PubMed - indexed for MEDLINE]
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Related Articles Lasers, stem cells, and COPD. J Transl Med. 2010;8:16 Authors: Lin F, Josephs SF, Alexandrescu DT, Ramos F, Bogin V, Gammill V, Dasanu CA, De Necochea-Campion R, Patel AN, Carrier E, Koos DR Abstract The medical use of low level laser (LLL) irradiation has been occurring for decades, primarily in the area of tissue healing and inflammatory conditions. Despite little mechanistic knowledge, the concept of a non-invasive, non-thermal intervention that has the potential to modulate regenerative processes is worthy of attention when searching for novel methods of augmenting stem cell-based therapies. Here we discuss the use of LLL irradiation as a "photoceutical" for enhancing production of stem cell growth/chemoattractant factors, stimulation of angiogenesis, and directly augmenting proliferation of stem cells. The combination of LLL together with allogeneic and autologous stem cells, as well as post-mobilization directing of stem cells will be discussed. PMID: 20158898 [PubMed - indexed for MEDLINE]
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Related Articles Mesenchymal stem cell therapy for the treatment of chronic obstructive pulmonary disease. Expert Opin Biol Ther. 2010 May;10(5):681-7 Authors: D'Agostino B, Sullo N, Siniscalco D, De Angelis A, Rossi F Abstract Recent studies have revealed that adult stem cells such as bone marrow-derived cells contribute to lung tissue regeneration and protection, and thus administration of exogenous stem/progenitor cells may be a potent next-generation therapy for COPD. Pathogenesis of COPD is characterized by an upregulation of inflammatory processes leading to irreversible events such as apoptosis of epithelial cells, proteolysis of the terminal air-space and lung extracellular matrix components. The available pharmacological treatments are essentially symptomatic, therefore, there is a need to develop more effective therapeutic strategies. It has been previously demonstrated that transplanted MSC home to the lung in response to lung injury and adopt phenotypes of alveolar epithelial cells, endothelial cells, fibroblasts and bronchial epithelial cells. However, engraftment and differentiation are now felt to be rare occurrences and other mechanisms might be involved and play a more important role. Importantly, MSCs protect lung tissue through suppression of proinflammatory cytokines, and through triggering production of reparative growth factors. Accordingly, it is not clear if and how these cells will be able to repair, to slow or to prevent the disease. This article reviews recent advances in regenerative medicine in COPD and highlights that their potential application although promising and very attractive, are still a far away opinion. PMID: 20384521 [PubMed - indexed for MEDLINE]
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Related Articles Mesenchymal stem cell transplantation increases expression of vascular endothelial growth factor in papain-induced emphysematous lungs and inhibits apoptosis of lung cells. Cytotherapy. 2010 Sep;12(5):605-14 Authors: Zhen G, Xue Z, Zhao J, Gu N, Tang Z, Xu Y, Zhang Z Abstract BACKGROUND: Pulmonary emphysema is characterized by loss of alveolar structures. We have found that bone marrow (BM) mesenchymal stem cell (MSC) transplantation ameliorates papain-induced pulmonary emphysema. However, the underlying mechanism is not completely understood. It has been shown that blocking the vascular endothelial growth factor (VEGF) signaling pathway leads to apoptosis of lung cells and pulmonary emphysema, and MSC are capable of secreting VEGF. We hypothesized that MSC transplantation may have a protective effect on pulmonary emphysema by increasing VEGF-A expression and inhibiting apoptosis of lung cells. METHODS: We examined the morphology and expression of VEGF-A in rat lung after papain treatment and MSC transplantation. We also used a co-culture system in which MSC and cells prepared from papain-treated lungs or control lungs were cultured together. The levels of VEGF-A in cells and culture medium were determined, and apoptosis of cultured lung cells was evaluated. RESULTS: VEGF-A expression in rat lungs was decreased after papain treatment, which was partly rescued by MSC transplantation. MSC production of VEGF-A was increased when MSC were co-cultured with cells prepared from papain-treated lungs. Furthermore, the apoptosis of papain-treated lung cells was inhibited when co-cultured with MSC. The induction of MSC production of VEGF-A by papain-treated lung cells was inhibited by adding anti-tumor necrosis factor (TNF)-alpha antibody to the medium. CONCLUSIONS: The protective effect of MSC transplantation on pulmonary emphysema may be partly mediated by increasing VEGF-A expression and inhibiting the apoptosis of lung cells. TNF-alpha released from papain-treated lung cells induces MSC to secret VEGF-A. PMID: 20429787 [PubMed - indexed for MEDLINE]
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Related Articles Aspergillus infections in the critically ill. Proc Am Thorac Soc. 2010 May;7(3):204-9 Authors: Dutkiewicz R, Hage CA Abstract Invasive aspergillosis is a common and devastating complication in severely immune-suppressed individuals with hematologic malignancies and in hematopoietic stem cell transplant recipients. With the increase use of immunosuppressive therapies, better intensive care, and prolonged patient survival, we are experiencing a surge in the incidence of invasive aspergillosis in our critically ill patients without malignancy. In this article we discuss the epidemiology, risk factors, and clinical spectrum of invasive aspergillosis in critically ill patients without malignancy. Diagnostic methods and recommended treatments are also presented. The emphasis is placed on early diagnosis and use of new and sensitive diagnostic tools. PMID: 20463249 [PubMed - indexed for MEDLINE]
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Related Articles Potential role of stem cells in management of COPD. Int J Chron Obstruct Pulmon Dis. 2010;5:81-8 Authors: Hackett TL, Knight DA, Sin DD Abstract Chronic obstructive pulmonary disease (COPD) is a worldwide epidemic affecting over 200 million people and accounting for more than three million deaths annually. The disease is characterized by chronic inflammation of the airways and progressive destruction of lung parenchyma, a process that in most cases is initiated by cigarette smoking. Unfortunately, there are no interventions that have been unequivocally shown to prolong survival in patients with COPD. Regeneration of lung tissue by stem cells from endogenous and exogenous sources is a promising therapeutic strategy. Herein we review the current literature on the characterization of resident stem and progenitor cell niches within the lung, the contribution of mesenchymal stem cells to lung regeneration, and advances in bioengineering of lung tissue. PMID: 20463889 [PubMed - indexed for MEDLINE]
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Related Articles Report from the 4th Advances Against Aspergillosis Conference. Future Microbiol. 2010 Jul;5(7):1001-4 Authors: Sheppard D, Grist LM Abstract Traditionally, the patients believed to be at highest risk of invasive aspergillosis (IA) are those who are neutropenic due to chemotherapy for hematological malignancy or those undergoing allogeneic hematopoietic stem cell transplantation. However, emerging data show that other patients are vulnerable to IA, even though some are not classically immunocompromised. These include: solid organ transplant recipients; patients with TB, chronic obstructive pulmonary disease and patients in the intensive care unit for other reasons. The conference highlighted the diagnostic and therapeutic challenges facing physicians treating this diverse group, not least of which include the unreliable estimates of IA incidence due to poor surveillance and inadequate data collection. Moreover, although there is now considerable experience of IA in neutropenic patients, much less is known about the management of those who are non-neutropenic. Nevertheless, approaches that have proven effective in neutropenic patients may also benefit others in this growing population. The meeting, attended by more than 500 delegates from almost 50 countries, also provided the opportunity to hear how basic scientific research may improve the understanding of the pathogenic mechanisms and therapy of IA. PMID: 20632800 [PubMed - indexed for MEDLINE]
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Related Articles The molecular and cellular biology of lung cancer: identifying novel therapeutic strategies. Br Med Bull. 2010;95:47-61 Authors: MacKinnon AC, Kopatz J, Sethi T Abstract INTRODUCTION: Lung cancer is the commonest fatal malignancy in the developed world. Survival rates for lung cancer have not changed significantly over the past 30 years. Sources of data This report is a systematic review of the literature on our current understanding of lung cancer biology. Searches were carried out using PUBMED. 1990-2010. AREAS OF AGREEMENT: A concerted effort to reduce cigarette smoking and nicotine addiction is required. A better understanding of the biology of lung cancer will lead to the identification of earlier diagnostic markers and improved therapy. AREAS OF CONTROVERSY: How chronic inflammatory disorders such as COPD and lung fibrosis contribute to lung cancer development is incompletely understood. GROWING POINTS: Developing novel biological agents to target lung cancer. New microarray-based technologies provide new methods for predicting prognosis and response to treatment. AREAS TIMELY FOR DEVELOPING RESEARCH: Developing strategies to target lung cancer stem cells may provide a novel approach for treating drug resistant disease. PMID: 20643690 [PubMed - indexed for MEDLINE]
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Related Articles Adipose stem cell treatment in mice attenuates lung and systemic injury induced by cigarette smoking. Am J Respir Crit Care Med. 2011 Jan 15;183(2):215-25 Authors: Schweitzer KS, Johnstone BH, Garrison J, Rush NI, Cooper S, Traktuev DO, Feng D, Adamowicz JJ, Van Demark M, Fisher AJ, Kamocki K, Brown MB, Presson RG, Broxmeyer HE, March KL, Petrache I Abstract RATIONALE: Adipose-derived stem cells express multiple growth factors that inhibit endothelial cell apoptosis, and demonstrate substantial pulmonary trapping after intravascular delivery. OBJECTIVES: We hypothesized that adipose stem cells would ameliorate chronic lung injury associated with endothelial cell apoptosis, such as that occurring in emphysema. METHODS: Therapeutic effects of systemically delivered human or mouse adult adipose stem cells were evaluated in murine models of emphysema induced by chronic exposure to cigarette smoke or by inhibition of vascular endothelial growth factor receptors. MEASUREMENTS AND MAIN RESULTS: Adipose stem cells were detectable in the parenchyma and large airways of lungs up to 21 days after injection. Adipose stem cell treatment was associated with reduced inflammatory infiltration in response to cigarette smoke exposure, and markedly decreased lung cell death and airspace enlargement in both models of emphysema. Remarkably, therapeutic results of adipose stem cells extended beyond lung protection by rescuing the suppressive effects of cigarette smoke on bone marrow hematopoietic progenitor cell function, and by restoring weight loss sustained by mice during cigarette smoke exposure. Pulmonary vascular protective effects of adipose stem cells were recapitulated by application of cell-free conditioned medium, which improved lung endothelial cell repair and recovery in a wound injury repair model and antagonized effects of cigarette smoke in vitro. CONCLUSIONS: These results suggest a useful therapeutic effect of adipose stem cells on both lung and systemic injury induced by cigarette smoke, and implicate a lung vascular protective function of adipose stem cell derived paracrine factors. PMID: 20709815 [PubMed - indexed for MEDLINE]
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Related Articles Clinical risk factors for invasive aspergillosis. Med Mycol. 2011 Apr;49 Suppl 1:S7-S12 Authors: Baddley JW Abstract Despite improvements in the antifungal armamentarium and diagnostic modalities, invasive aspergillosis (IA) remains an important cause of morbidity and mortality in immunocompromised patients. There is an emergence of non-traditional groups at risk for IA, including intensive care unit (ICU) patients, post-operative patients, those with chronic pulmonary diseases, patients with AIDS and patients on immunomodulating drugs (TNF-α inhibitors). Identification of clinical risk factors for IA may help in determining which patients require risk modification and other prevention measures. PMID: 20718606 [PubMed - indexed for MEDLINE]
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Related Articles Stem cells and cell therapy approaches in lung biology and diseases. Transl Res. 2010 Sep;156(3):188-205 Authors: Sueblinvong V, Weiss DJ Abstract Cell-based therapies with embryonic or adult stem cells, including induced pluripotent stem cells, have emerged as potential novel approaches for several devastating and otherwise incurable lung diseases, including emphysema, pulmonary fibrosis, pulmonary hypertension, and the acute respiratory distress syndrome. Although initial studies suggested engraftment of exogenously administered stem cells in lung, this is now generally felt to be a rare occurrence of uncertain physiologic significance. However, more recent studies have demonstrated paracrine effects of administered cells, including stimulation of angiogenesis and modulation of local inflammatory and immune responses in mouse lung disease models. Based on these studies and on safety and initial efficacy data from trials of adult stem cells in other diseases, groundbreaking clinical trials of cell-based therapy have been initiated for pulmonary hypertension and for chronic obstructive pulmonary disease. In parallel, the identity and role of endogenous lung progenitor cells in development and in repair from injury and potential contribution as lung cancer stem cells continue to be elucidated. Most recently, novel bioengineering approaches have been applied to develop functional lung tissue ex vivo. Advances in each of these areas will be described in this review with particular reference to animal models. PMID: 20801416 [PubMed - indexed for MEDLINE]
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Related Articles Mechanisms involved in lung cancer development in COPD. Int J Biochem Cell Biol. 2011 Jul;43(7):1030-44 Authors: Caramori G, Casolari P, Cavallesco GN, Giuffrè S, Adcock I, Papi A Abstract Lung cancer and chronic obstructive pulmonary disease (COPD) are leading causes of morbidity and mortality worldwide. They share a common environmental risk factor in cigarette smoke exposure and a genetic predisposition represented by the incidence of these diseases in only a fraction of smokers. COPD is also a major independent risk factor for lung carcinoma, among long-term smokers. Smokers with COPD also have a higher risk of developing a specific histological subtype of non-small cell lung cancer termed squamous cell carcinoma. For these reasons the focus of this review is on the potential pathogenic molecular links between tobacco smoking-related COPD and squamous cell carcinoma. We believe that we need to promote more studies on the molecular and cellular pathobiology of smokers with premalignant bronchial lesions of the squamous cell lung carcinoma compared with a control group of smokers with and without COPD to unravel the complex molecular interactions between COPD and early squamous cell lung carcinoma. These studies should also look at younger healthy smokers in combination with risk models of lung cancer and COPD. Overall these studies may allow the discovery of new molecular targets of the early carcinogenesis process that in the foreseeable future may render the early diagnosis and treatment, and may be even the prevention, of invasive squamous cell lung carcinoma a reality. PMID: 20951226 [PubMed - indexed for MEDLINE]
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Related Articles Pulmonary hypertension in COPD: pathophysiology and therapeutic targets. Curr Drug Targets. 2011 Apr;12(4):501-13 Authors: Zakynthinos E, Daniil Z, Papanikolaou J, Makris D Abstract The incidence of mild to moderate pulmonary hypertension (PH) is highly prevalent, reaching to 50% in advanced chronic obstructive pulmonary disease (COPD). However, a subpopulation (1-4% in most studies) with grim prognosis despite moderate airflow limitation, present with "out-of-proportion" severe PH, is arbitrarily defined by a mean PH ≥ 40 mmHg, at rest. The sequence of changes that lead to PH in COPD begins at early disease stages by the impairment of endothelial function, which is associated with impaired release of endothelium-derived vasodilating (nitric oxide, prostacyclin) and vasoconstrictive agents (endothelin-1) and imbalance among them. PH in COPD is caused by vasoconstriction and remodelling of pulmonary arteries, which is characterized by the intimal proliferation of poorly differentiated smooth muscle cells and the deposition of elastic and collagen fibres. Hypoxia, inflammation and toxic effects of cigarette smoke, independently or additively interacting, are confirmed factors leading to PH. To date, long-term supplemental oxygen remains the primary treatment in COPD patients with PH. The administration of new vasodilators (prostanoids, endothelin-1 receptor antagonists and phosphodiesterase-5 inhibitors) dedicated to idiopathic pulmonary arterial hypertension in the disproportionate subgroup of patients with "out-of-proportion" PH may be considered in the setting of clinical trials. The use of these drugs in COPD patients with PH < 40 mmHg may worsen gas exchange, and to date, has no proven benefit. Future treatments must target more directly pathogenetic mechanisms. Therefore, novel agents have been proposed and are under active investigation, including 5-HT receptor antagonists, Rho-kinase inhibitors, statins and stem cell therapy. PMID: 21194405 [PubMed - indexed for MEDLINE]
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Related Articles Is a regenerative approach viable for the treatment of COPD? Br J Pharmacol. 2011 May;163(1):106-15 Authors: Hind M, Maden M Abstract Degenerative lung diseases such as chronic obstructive pulmonary disease (COPD) are common with huge worldwide morbidity. Anti-inflammatory drug development strategies have proved disappointing and current treatment is aimed at symptomatic relief. Only lung transplantation with all its attendant difficulties offers hope of cure and the outlook for affected patients is bleak. Lung regeneration therapies aim to reverse the structural and functional deficits in COPD either by delivery of exogenous lung cells to replace lost tissue, delivery of exogenous stem cells to induce a local paracrine effect probably through an anti-inflammatory action or by the administration of small molecules to stimulate the endogenous regenerative ability of lung cells. In animal models of emphysema and disrupted alveolar development each of these strategies has shown some success but there are potential tumour-inducing dangers with a cellular approach. Small molecules such as all-trans retinoic acid have been successful in animal models although the mechanism is not completely understood. There are currently two Pharma-sponsored trials in progress concerning patients with COPD, one of a specific retinoic acid receptor gamma agonist and another using mesenchymal stem cells. PMID: 21265829 [PubMed - indexed for MEDLINE]
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Related Articles Unicentric study of cell therapy in chronic obstructive pulmonary disease/pulmonary emphysema. Int J Chron Obstruct Pulmon Dis. 2011;6:63-71 Authors: Ribeiro-Paes JT, Bilaqui A, Greco OT, Ruiz MA, Marcelino MY, Stessuk T, de Faria CA, Lago MR Abstract Within the chronic obstructive pulmonary disease (COPD) spectrum, lung emphysema presents, as a primarily histopathologic feature, the destruction of pulmonary parenchyma and, accordingly, an increase in the airflow obstruction distal to the terminal bronchiole. Notwithstanding the significant advances in prevention and treatment of symptoms, no effective or curative therapy has been accomplished. In this context, cellular therapy with stem cells (SCs) arises as a new therapeutic approach, with a wide application potential. The purpose of this study is to evaluate the safety of SCs infusion procedure in patients with advanced COPD (stage IV dyspnea). After selection, patients underwent clinical examination and received granulocyte colony-stimulating factor, immediately prior to the bone marrow harvest. The bone marrow mononuclear cells (BMMC) were isolated and infused into a peripheral vein. The 12-month follow-up showed a significant improvement in the quality of life, as well as a clinical stable condition, which suggest a change in the natural process of the disease. Therefore, the proposed methodology in this study for BMMC cell therapy in sufferers of advanced COPD was demonstrated to be free of significant adverse effects. Although a larger sample and a greater follow-up period are needed, it is possible to infer that BMMC cell therapy introduces an unprecedented change in the course or in the natural history of emphysema, inhibiting or slowing the progression of disease. This clinical trial was registered with ClinicalTrials.gov (NCT01110252) and was approved by the Brazilian National Committee of Ethics in Research (registration no. 14764, CONEP report 233/2009). PMID: 21311694 [PubMed - indexed for MEDLINE]
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Related Articles Impaired endothelial progenitor cell mobilization and colony-forming capacity in chronic obstructive pulmonary disease. Respirology. 2011 May;16(4):680-7 Authors: Takahashi T, Suzuki S, Kubo H, Yamaya M, Kurosawa S, Kato M Abstract BACKGROUND AND OBJECTIVE: Recent studies suggest that there is endothelial impairment in both the systemic and pulmonary circulations of patients with COPD. Endothelial progenitor cells (EPC) are mobilized into the circulation by physiological stressors such as surgery, and are thought to play a role in the repair of damaged endothelium. There has been a steady increase in the frequency of surgery among COPD patients, due to the incidence of complications and lung cancer; however, the mobilization of EPC during lung resection has not been examined. We evaluated whether the mobilization and proliferation of EPC are impaired in COPD patients. METHODS: The numbers of circulating EPC (CD34/KDR/AC133-positive mononuclear cells) were measured by flow cytometry, in COPD patients (n=30) and non-COPD patients (n=30) who were undergoing thoracic surgery. EPC colony-forming units (EPC-CFU) were also examined. RESULTS: In non-COPD patients, both circulating EPC and EPC-CFU were significantly increased 2h after the operation started, whereas in COPD patients there were no changes in circulating EPC or EPC-CFU, irrespective of the severity of COPD. Multiple linear regression analysis demonstrated that the presence of COPD was the only significant independent predictor of reduced mobilization of EPC during thoracic surgery. CONCLUSIONS: The number of circulating EPC and EPC-CFU was not increased during thoracic surgery in COPD patients. These results indicate that both the mobilization and proliferative capacity of EPC are severely impaired in COPD patients. PMID: 21355963 [PubMed - indexed for MEDLINE]
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Related Articles Mesenchymal stem cells restore lung function by recruiting resident and nonresident proteins. Cell Transplant. 2011;20(10):1561-74 Authors: Jungebluth P, Luedde M, Ferrer E, Luedde T, Vucur M, Peinado VI, Go T, Schreiber C, von Richthofen M, Bader A, Haag J, Darsow KH, Bartel SJ, Lange HA, Furlani D, Steinhoff G, Macchiarini P Abstract Because human lungs are unlikely to repair or regenerate beyond the cellular level, cell therapy has not previously been considered for chronic irreversible obstructive lung diseases. To explore whether cell therapy can restore lung function, we administered allogenic intratracheal mesenchymal stem cells (MSCs) in the trachea of rats with chronic thromboembolic pulmonary hypertension (CTEPH), a disease characterized by single or recurrent pulmonary thromboembolic obliteration and progressive pulmonary vascular remodeling. MSCs were retrieved only in high pressure-exposed lungs recruited via a homing stromal derived factor-1α/CXCR4 pathway. After MSC administration, a marked and long-lasting improvement of all clinical parameters and a significant change of the proteome level were detected. Beside a variation of liver proteome, such as caspase-3, NF-κB, collagen1A1, and α-SMA, we also identified more than 300 resident and nonresident lung proteins [e.g., myosin light chain 3 (P16409) or mitochondrial ATP synthase subunit alpha (P15999)]. These results suggest that cell therapy restores lung function and the therapeutic effects of MSCs may be related to protein-based tissue reconstituting effects. PMID: 21396162 [PubMed - indexed for MEDLINE]
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Related Articles Diagnosis and treatment of pulmonary chronic GVHD: report from the consensus conference on clinical practice in chronic GVHD. Bone Marrow Transplant. 2011 Oct;46(10):1283-95 Authors: Hildebrandt GC, Fazekas T, Lawitschka A, Bertz H, Greinix H, Halter J, Pavletic SZ, Holler E, Wolff D Abstract This consensus statement established under the auspices of the German working group on BM and blood stem cell transplantation (DAG-KBT), the German Society of Hematology and Oncology (DGHO), the Austrian Stem Cell Transplant Working Group, the Swiss Blood Stem Cell Transplantation Group (SBST) and the German-Austrian Pediatric Working Group on SCT (Päd-Ag-KBT) summarizes current evidence for diagnosis, immunosuppressive and supportive therapy to provide practical guidelines for the care and treatment of patients with pulmonary manifestations of chronic GVHD (cGVHD). Pulmonary cGVHD can present with obstructive and/or restrictive changes. Disease severity ranges from subclinical pulmonary function test (PFT) impairment to respiratory insufficiency with bronchiolitis obliterans being the only pulmonary complication currently considered diagnostic of cGVHD. Early diagnosis may improve clinical outcome, and regular post-transplant follow-up PFTs are recommended. Diagnostic work-up includes high-resolution computed tomography, bronchoalveolar lavage and histology. Topical treatment is based on inhalative steroids plus beta-agonists. Early addition of azithromycin is suggested. Systemic first-line treatment consists of corticosteroids plus, if any, continuation of other immunosuppressive therapy. Second-line therapy and beyond includes extracorporeal photopheresis, mammalian target of rapamycin inhibitors, mycophenolate, etanercept, imatinib and TLI, but efficacy is limited. Clinical trials are urgently needed to improve understanding and treatment of this deleterious complication. PMID: 21441964 [PubMed - indexed for MEDLINE]
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Related Articles The COPD Pipeline IX. COPD. 2011 Apr;8(2):136-8 Authors: Gross NJ PMID: 21495841 [PubMed - indexed for MEDLINE]
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Related Articles Bone marrow cells repair cigarette smoke-induced emphysema in rats. Am J Physiol Lung Cell Mol Physiol. 2011 Sep;301(3):L255-66 Authors: Huh JW, Kim SY, Lee JH, Lee JS, Van Ta Q, Kim M, Oh YM, Lee YS, Lee SD Abstract The therapeutic potential of stem cells in chronic obstructive pulmonary disease is not well known although stem cell therapy is effective in models of other pulmonary diseases. We tested the capacities of bone marrow cells (BMCs), mesenchymal stem cells (MSCs), and conditioned media of MSCs (MSC-CM) to repair cigarette smoke-induced emphysema. Inbred female Lewis rats were exposed to cigarette smoke for 6 mo and then received BMCs, MSCs, or MSC-CM from male Lewis rats. For 2 mo after injection, the BMC treatment gradually alleviated the cigarette smoke-induced emphysema and restored the increased mean linear intercept. The BMC treatment significantly increased cell proliferation and the number of small pulmonary vessels, reduced apoptotic cell death, attenuated the mean pulmonary arterial pressure, and inhibited muscularization in small pulmonary vessels. However, only a few male donor cells were detected from 1 day to 1 mo after BMC administration. The MSCs and cell-free MSC-CM also induced the repair of emphysema and increased the number of small pulmonary vessels. Our data show that BMC, MSCs, and MSC-CM treatment repaired cigarette smoke-induced emphysema. The repair activity of these treatments is consistent with a paracrine effect rather than stem cell engraftment because most of the donor cells disappeared and because cell-free MSC-CM also induced the repair. PMID: 21622846 [PubMed - indexed for MEDLINE]
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Related Articles Mechanisms of cellular therapy in respiratory diseases. Intensive Care Med. 2011 Sep;37(9):1421-31 Authors: Abreu SC, Antunes MA, Pelosi P, Morales MM, Rocco PR Abstract PURPOSE: Stem cells present a variety of clinical implications in the lungs. According to their origin, these cells can be divided into embryonic and adult stem cells; however, due to the important ethical and safety limitations that are involved in the embryonic stem cell use, most studies have chosen to focus on adult stem cell therapy. This article aims to present and clarify the recent advances in the field of stem cell biology, as well as to highlight the effects of mesenchymal stem cell (MSC) therapy in the context of acute lung injury/acute respiratory distress syndrome and chronic disorders such as lung fibrosis and chronic obstructive pulmonary disease. METHODS: For this purpose, we performed a critical review of adult stem cell therapies, covering the main clinical and experimental studies published in Pubmed databases in the past 11 years. Different characteristics were extracted from these articles, such as: the experimental model, strain, cellular type and administration route used as well as the positive or negative effects obtained. RESULTS: There is evidence for beneficial effects of MSC on lung development, repair, and remodeling. The engraftment in the injured lung does not occur easily, but several studies report that paracrine factors can be effective in reducing inflammation and promoting tissue repair. MSC releases several growth factors and anti-inflammatory cytokines that regulate endothelial and epithelial permeability and reduce the severity of inflammation. CONCLUSION: A better understanding of the mechanisms that control cell division and differentiation, as well as of their paracrine effects, is required to enable the optimal use of bone marrow-derived stem cell therapy to treat human respiratory diseases. PMID: 21656291 [PubMed - indexed for MEDLINE]
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Related Articles Pharmacological modulation of chemokine receptor function. Br J Pharmacol. 2012 Mar;165(6):1617-43 Authors: Scholten DJ, Canals M, Maussang D, Roumen L, Smit MJ, Wijtmans M, de Graaf C, Vischer HF, Leurs R Abstract G protein-coupled chemokine receptors and their peptidergic ligands are interesting therapeutic targets due to their involvement in various immune-related diseases, including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, chronic obstructive pulmonary disease, HIV-1 infection and cancer. To tackle these diseases, a lot of effort has been focused on discovery and development of small-molecule chemokine receptor antagonists. This has been rewarded by the market approval of two novel chemokine receptor inhibitors, AMD3100 (CXCR4) and Maraviroc (CCR5) for stem cell mobilization and treatment of HIV-1 infection respectively. The recent GPCR crystal structures together with mutagenesis and pharmacological studies have aided in understanding how small-molecule ligands interact with chemokine receptors. Many of these ligands display behaviour deviating from simple competition and do not interact with the chemokine binding site, providing evidence for an allosteric mode of action. This review aims to give an overview of the evidence supporting modulation of this intriguing receptor family by a range of ligands, including small molecules, peptides and antibodies. Moreover, the computer-assisted modelling of chemokine receptor-ligand interactions is discussed in view of GPCR crystal structures. Finally, the implications of concepts such as functional selectivity and chemokine receptor dimerization are considered. PMID: 21699506 [PubMed - indexed for MEDLINE]
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Related Articles Bone marrow-derived stem cells and respiratory disease. Chest. 2011 Jul;140(1):205-11 Authors: Jones CP, Rankin SM Abstract Adult bone marrow contains a number of discrete populations of progenitor cells, including endothelial, mesenchymal, and epithelial progenitor cells and fibrocytes. In the context of a range of diseases, endothelial progenitor cells have been reported to promote angiogenesis, mesenchymal stem cells are potent immunosuppressors but can also contribute directly to tissue regeneration, and fibrocytes have been shown to induce tissue fibrosis. This article provides an overview of the basic biology of these different subsets of progenitor cells, reporting their distinct phenotypes and functional activities. The differences in their secretomes are highlighted, and the relative role of cellular differentiation vs paracrine effects of progenitor cells is considered. The article reviews the literature examining the contribution of progenitor cells to the pathogenesis of respiratory disease, and discusses recent studies using bone marrow progenitor cells as stem cell therapies in the context of pulmonary hypertension, COPD, and asthma. PMID: 21729891 [PubMed - indexed for MEDLINE]
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Related Articles Rationale and emerging approaches for targeting lung repair and regeneration in the treatment of chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2011 Aug;8(4):368-75 Authors: Rennard SI, Wachenfeldt Kv Abstract Lung repair and regeneration are appropriate therapeutic targets for the treatment of chronic obstructive pulmonary disease (COPD). Abnormal repair results if fibrosis of the airways is a major contributor to fixed airflow limitation in airway disease. Inadequate repair in the face of tissue injury can contribute to the development of emphysema. With respect to the latter, acute exposure to cigarette smoke can impair repair responses of several cell types in the lung. Fibroblasts cultured from the lungs of patients with emphysema have persistent defects in repair that include modulation of extracellular matrix as well as production of growth factors that modulate other lung parenchymal cells. Some of the deficient repair functions appear to result from insensitivity to TGF-β and overproduction of prostaglandin E. Pharmacologic interventions targeting these pathways have the potential to at least partially reverse the abnormal repair. Alternate strategies that could modulate lung repair and regeneration could target resident or circulating stem/progenitor cells or potentially involve transplantation of new stem cells. Therapy directed at lung repair has the potential to restore lost lung function. In contrast to therapy designed to slow the progression of COPD, it may be much easier and less expensive to demonstrate efficacy for a therapy that restores lung function. PMID: 21816994 [PubMed - indexed for MEDLINE]
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Related Articles Successful allogeneic hematopoietic stem cell transplantation for chronic granulomatous disease with inflammatory complications and severe infection. Int J Hematol. 2011 Nov;94(5):479-82 Authors: Kato K, Kojima Y, Kobayashi C, Mitsui K, Nakajima-Yamaguchi R, Kudo K, Yanai T, Yoshimi A, Nakao T, Morio T, Kasahara M, Koike K, Tsuchida M Abstract We report two patients with chronic granulomatous disease (CGD). The first patient presented with granulomatous colitis and pulmonary aspergillosis, and the second patient with liver abscess and restrictive pulmonary disorder. Both patients underwent allogeneic hematopoietic stem cell transplantation, the first from an HLA-matched sibling donor, and the second from an HLA-matched unrelated donor, after preconditioning with fludarabine, anti-thymocyte globulin, cyclophosphamide, and total-body irradiation of 3 Gy. The engraftment was prompt and the regimen-related toxicity was mild. The patients are able to return to their daily lives with full donor chimerism, although the second patient underwent a living-related-donor orthotopic liver transplantation from his mother for chronic liver graft-versus-host disease. The conditioning regimen we used was feasible and applicable to patients with CGD accompanied by inflammatory disease and severe infection. PMID: 22015491 [PubMed - indexed for MEDLINE]
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Related Articles [Regenerative approach for COPD]. Nihon Rinsho. 2011 Oct;69(10):1869-72 Authors: Kubo H Abstract No treatment to cure of chronic obstructive pulmonary disease (COPD) is available. Regenerative medicine is one of promising areas for this intractable disease. Several reagents and growth factors are known to promote lung regeneration in small animal models. However, regenerative medicines for human lungs are not achieved yet. Recent advances in stem cell biology and tissue engineering have expanded our understanding of lung endogenous stem cells, and this new knowledge provides us with new ideas for future regenerative therapy for lung diseases. Although lungs are the most challenging organ for regenerative medicine, our cumulative knowledge of lung regeneration and of endogenous progenitor cells makes clear the possibilities for regenerative approach to COPD. PMID: 22073587 [PubMed - indexed for MEDLINE]
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Related Articles Human endothelial progenitor cells isolated from COPD patients are dysfunctional. Mol Cell Biochem. 2012 Apr;363(1-2):53-63 Authors: Liu X, Xie C Abstract Cardiovascular disease is the leading cause of morbidity and mortality in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). More than 44% of these patients present with generalized atherosclerosis at autopsy. It is accepted that endothelial progenitor cells (EPCs) participate in the repair of dysfunctional endothelium and thus protects against atherosclerosis. However, whether COPD affects the repairing capacity of EPCs is unknown. Therefore, the objective of this study was to determine whether and how EPCs are involved in the vascular repair process in patients with COPD. In our study, EPCs from 25 COPD and 16 control patients were isolated by Ficoll density-gradient centrifugation and identified using fluorescence activated cell sorting. Transwell Migratory Assay was performed to determine the number of EPC colony-forming units and the adherent capacity late-EPCs to human umbilical vein endothelial cells. Following arterial damage in NOD/SCID mice, the number of EPCs incorporated at the injured vascular site was determined using a fluorescence microscope. We found that the number of EPC clusters and cell migration, as well as the expression of CXCR4, was significantly decreased in patients with COPD. Additionally, the number of late-EPCs adherent to HUVEC tubules was significantly reduced, and fewer VEGFR2(+)-staining cells were incorporated into the injured site in COPD patients. Our study demonstrates that EPC capacity of repair was affected in COPD patients, which may contribute to altered vascular endothelium in this patient population. PMID: 22139347 [PubMed - indexed for MEDLINE]
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Related Articles In this issue. Clin Pharmacol Ther. 2012 Jan;91(1):1 Authors: PMID: 22179621 [PubMed - indexed for MEDLINE]
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Related Articles [Role of stem cells in the pathogenesis of chronic obstructive pulmonary disease and of pulmonary emphysema]. Recenti Prog Med. 2012 Jan;103(1):31-40 Authors: Caramori G, Casolari P, Garofano E, Mazzoni F, Marchi I, Contoli M, Papi A Abstract There are only few human translational studies performed in the area of stem cell research in patients with chronic obstructive pulmonary disease (COPD) and/or pulmonary emphysema. Before progress to clinical trials with stem cells we believe that more human translational studies are necessaries, otherwise the clinical rationale would be solely based on limited in vitro and animal studies. In the future, stem cell therapy could be a treatment for this disease. Currently, stem cell therapy is still to be considered as an area of active research, lacking a strong rationale for performing clinical trials in COPD. Although stem cells would be likely to represent a heterogeneous population of cells, the different cell subsets and their importance in the pathogenesis of the different clinical phenotypes need to be fully characterised before progressing to clinical trials. Moreover, the potential side effects of the stem cell therapy are often underestimated. We should not ignore that some of the most deadly neoplasms are arising from stem cells. PMID: 22322626 [PubMed - indexed for MEDLINE]
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Related Articles Increased activation of fibrocytes in patients with chronic obstructive asthma through an epidermal growth factor receptor-dependent pathway. J Allergy Clin Immunol. 2012 May;129(5):1367-76 Authors: Wang CH, Huang CD, Lin HC, Huang TT, Lee KY, Lo YL, Lin SM, Chung KF, Kuo HP Abstract BACKGROUND: Fibrocytes are circulating progenitor cells that are increased in asthmatic patients with chronic obstructive asthma (COA) and rapid decrease in lung function. Fibrocytes from patients with COA have a greater capacity for proliferation and differentiation. OBJECTIVE: We investigated whether epidermal growth factor receptor (EGFR) activation mediated the proliferation of fibrocytes in patients with COA and whether oxidative stress was involved in this activation. METHODS: Circulating fibrocytes from nonadherent non-T-cell mononuclear cell fractions from healthy subjects, asthmatic patients with normal pulmonary function, and patients with COA were determined by using flow cytometric coexpression of collagen I, CD45, and CD34 or EGFR or a disintegrin and metalloprotease domain 17 and placed in culture. RESULTS: Expression of EGFR was increased in fibrocytes from patients with COA compared with that seen in patients with NPF. AG1478 and gefitinib, inhibitors of EGFR tyrosine kinase, reduced fibrocyte proliferation and myofibroblast transformation. Increased expression of EGFR and fibrocyte proliferation and transformation were induced by hydrogen peroxide, and these effects were inhibited by N-acetylcysteine. CONCLUSIONS: Enhanced fibrocyte proliferation and transformation found in patients with COA might be mediated through an oxidant-sensitive EGFR-dependent pathway. PMID: 22325070 [PubMed - indexed for MEDLINE]
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Related Articles [Effects of secretary leukocyte protease inhibitor-transfected bone marrow mesenchymal stem cells on airway inflammation and mucus secretion in chronic obstructive pulmonary disease]. Zhonghua Yi Xue Za Zhi. 2011 Dec 27;91(48):3438-41 Authors: Jiang DP, Li Q, P Kolosov V, M Perelman J, Zhou XD Abstract OBJECTIVE: To explore the effects of secretary leukocyte protease inhibitor (SLPI)-transfected bone marrow mesenchymal stem cells (BMSCs) transplantation on airway inflammation and mucus secretion in chronic obstructive pulmonary disease (COPD) rats. METHODS: Sixty rats were equally and randomly divided into negative control, COPD model, BMSCs and SLPI-transfected BMSCs groups. The COPD rat model was established in all rats with the exception of the negative control rats by smoking and intratracheal instillation of lipopolysaccharide (LPS). BMSCs with or without transfection of plasmid containing SLPI gene were delivered through caudal vein of rats at 30 days post-induction. The expression of SLPI was examined with Western blot. The levels of interleukin (IL)-8 and tumor necrosis factor (TNF)-α were detected by enzyme-linked immunosorbent assay (ELISA). Goblet cell hyperplasia of lung pathological section was observed on. RESULTS: Compared with the negative control group, the expression of SLPI increased significantly after the administration of SLPI-transfected BMSCs (0.79 ± 0.06 vs 0.24 ± 0.02, P < 0.05). The levels of IL-8 and TNF-α in BMSCs and SLPI-transfected BMSCs group were lower than those in the COPD model group. Compared with the negative control group, the administration of SLPI-transfected BMSCs resulted in a further decrease in IL-8 and TNF-α in bronchoalveolar lavage fluid [(17.6 ± 1.7) vs (36.6 ± 4.0) ng/L, P < 0.05]. SLPI-transfected BMSCs transplantation also significantly attenuated goblet cell hyperplasia in rats (P < 0.05). CONCLUSION: There is a potential role for cell-based SLPI gene therapy in the treatment of COPD. PMID: 22333260 [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 The influence of cardiovascular risk factors on bone marrow mesenchymal stromal cell fitness. Cytotherapy. 2012 Jul;14(6):670-8 Authors: Neef K, Choi YH, Weichel A, Rahmanian PB, Liakopoulos OJ, Stamm C, Choi CY, Jacobshagen C, Wittwer T, Wahlers T Abstract BACKGROUND AIMS: In the past, cell transplantation strategies for the treatment of heart failure have shown promising results in experimental and clinical studies. Bone marrow (BM)-derived stem cells represent the most frequently used cell population. Within this heterogeneous cell population, mesenchymal stromal cells (MSC) have been identified to induce therapeutic effects, mainly through paracrine mechanisms. Because of their low frequency in native tissues, in vitro cell culture expansion is mandatory prior to transplantation. We sought to identify patient-specific cardiovascular risk factors influencing the proliferative potential of MSC. METHODS: BM aspirates from 51 patients undergoing elective cardiac surgery were analyzed for MSC frequency and cell culture expansion potential. Fibroblastic colony-forming units (CFU-F) were quantified for culture conditions applying autologous (AS) or fetal bovine serum (FBS) and different basic media. Univariate and multivariate analyzes were performed in order to determine the impact of patient-specific factors on CFU-F numbers. RESULTS: Expanded MSC showed a specific immune phenotype and displayed adipogenic, chondrogeneic and osteogeneic differentiation potential. CFU-F numbers did not differ under AS or FBS supplementation. Elevated numbers of mononuclear cells, diabetes mellitus, steroid treatment, chronic obstructive pulmonary disease, renal failure, high euroSCORE and impaired left ventricular function were significant determinants for higher CFU-F numbers. CONCLUSIONS: The impact of specific cardiovascular risk factors on MSC fitness could be determined. These results may help to establish patient profiling in order to identify patients suitable for autologous MSC transplantation, and might lead to the identification of disease-related mechanisms of stem cell activation. PMID: 22404082 [PubMed - indexed for MEDLINE]
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Related Articles Regenerative pulmonary medicine: potential and promise, pitfalls and challenges. Eur J Clin Invest. 2012 Aug;42(8):900-13 Authors: Anversa P, Perrella MA, Kourembanas S, Choi AM, Loscalzo J Abstract BACKGROUND: Chronic lung diseases contribute significantly to the morbidity and mortality of the population. There are few effective treatments for many chronic lung diseases, and even fewer therapies that can arrest or reverse the progress of the disease. DESIGN: In this review, we present the current state of regenerative therapies for the treatment of chronic lung diseases. We focus on endothelial progenitor cells, mesenchymal stem cells, and endogenous lung stem/progenitor cells; summarize the work to date in models of lung diseases for each of these therapies; and consider their potential benefits and risks as viable therapies for patients with lung diseases. CONCLUSIONS: Cell-based regenerative therapies for lung diseases offer great promise, with preclinical studies suggesting that the next decade should provide the evidence necessary for their ultimate application to our therapeutic armamentarium. PMID: 22435680 [PubMed - indexed for MEDLINE]
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Related Articles Inflammatory and satellite cells in the quadriceps of patients with COPD and response to resistance training. Chest. 2012 Nov;142(5):1134-42 Authors: Menon MK, Houchen L, Singh SJ, Morgan MD, Bradding P, Steiner MC Abstract BACKGROUND: Quadriceps dysfunction in COPD may be mediated by inflammatory mechanisms or impaired satellite cell function. Resistance training is of proven efficacy in these patients, but data on muscle inflammatory and satellite cell response to resistance exercise in COPD are lacking.We aimed to examine the inflammatory and satellite cell profile of the quadriceps in patients with COPD and healthy control subjects at rest and after acute and chronic resistance exercise. METHODS: Seventeen patients with COPD and 10 healthy control subjects underwent 8 weeks ofbilateral lower-limb, high-intensity resistance training, thrice weekly, on an isokinetic dynamometer.Quadriceps muscle biopsy specimens from the dominant thigh were obtained at baseline,24 h following the fi rst exercise bout, and after 8 weeks 24 h after the last exercise bout. Glycolmethacrylate-embedded muscle biopsy specimens were analyzed using immunohistochemistry to identify neutrophils, macrophages, and satellite cells. RESULTS: Neutrophils were significantly elevated in the quadriceps of patients with COPD at baseline compared with healthy control subjects ( P 5 .03). Inflammatory cells were increased significantly at 24 h in both groups but were similar to baseline values at week 8, with no difference detectable between healthy control subjects and patients with COPD. Satellite cell numbers were comparable between patients and control subjects at baseline, tended to increase at 24 h, and remained elevated at week 8. CONCLUSIONS: Inflammatory cells are elevated in the resting quadriceps of patients with COPD. Acute resistance exercise leads to an inflammatory myositis, which is attenuated with regular training. Satellite cells in patients and control subjects are comparable and are increased in response to exercise. TRIAL REGISTRY: ISRCTN Register ; No.: ISRCTN22764439; URL: www.controlled-trials.com. PMID: 22459782 [PubMed - indexed for MEDLINE]
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Related Articles Mesenchymal stem cells. Thorax. 2012 Jun;67(6):565-6 Authors: Rankin S Abstract Mesenchymal Stem cells (MSCs) are stromal cells that can be readily harvested from adult bone marrow and adipose tissue, but also umbilical cords. With respect to respiratory disease, the therapeutic potential of these cells lies in their paracrine effects which underlie their ability to enhance tissue regeneration and modulate immune responses. MSCs have been shown to be effective in a range of murine models of respiratory disease, and there are currently five clinical trials involving the administration of MSCs for respiratory diseases, including COPD and emphysema. This paper summarises the features of MSCs. PMID: 22555276 [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 The COPD Pipeline XVII. COPD. 2012 Aug;9(4):432-4 Authors: Gross N PMID: 22734623 [PubMed - indexed for MEDLINE]
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Related Articles Cell therapy with adipose tissue-derived stem/stromal cells for elastase-induced pulmonary emphysema in rats. Regen Med. 2012 Jul;7(4):503-12 Authors: Furuya N, Takenaga M, Ohta Y, Tokura Y, Hamaguchi A, Sakamaki A, Kida H, Handa H, Nishine H, Mineshita M, Miyazawa T Abstract AIMS: The purpose of this study was to elucidate the mechanism underlying the effects of adipose tissue-derived stem/stromal cell (ASC) transplantation on porcine pancreatic elastase-induced emphysema. MATERIALS & METHODS: ASCs (2.5 × 10(6)) were transplanted into pancreatic elastase (250 U/kg)-treated rats, after which gas exchange and growth factor/cytokine levels in lung tissue were determined. RESULTS: ASC transplantation restored pulmonary function (arterial oxygen tension and alveolar-arterial oxygen tension difference) almost to that of normal animals. Enlargement of the alveolar airspaces was inhibited. HGF and CINC-1 levels were significantly higher in the ASC group even at 2 weeks after transplantation. Sponge implantation with CINC-1 induced neovascular formation with increased HGF. In vitro secretion of HGF and CINC-1 from ASCs was promoted in the presence of IL-1β. CONCLUSION: Not only HGF, but also CINC-1, secreted from transplanted and viable ASCs presumably contributed to lung repair through angiogenesis. PMID: 22817624 [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 Bronchiolitis. Immunol Allergy Clin North Am. 2012 Nov;32(4):601-19 Authors: Garibaldi BT, Illei P, Danoff SK Abstract Bronchiolitis is a disease of the small airways accompanied by progressive and often irreversible airflow obstruction. Bronchiolitis can have several causes such as infection, toxic exposure, collagen vascular disease, post lung and stem cell transplant, and idiopathic etiology. Symptoms of cough and sputum production are often mistaken for chronic obstructive pulmonary disease or asthma, leading to a delay in diagnosis. Unfortunately, many types of bronchiolitis do not improve with therapy. Bronchiolitis following lung and stem cell transplant are the most common types seen in adults, and provide important insights into its pathogenesis. PMID: 23102068 [PubMed - indexed for MEDLINE]
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Related Articles Novel antiinflammatory therapies for COPD. Chest. 2012 Nov;142(5):1300-7 Authors: Gross NJ Abstract The biologic nature of COPD inflammation is not well understood and agents that inhibit inflammation in COPD are a major unmet need. However, a variety of agents that have the potential to be inhibitors of COPD inflammation are in various stages of development. Agents that have been approved for a non-COPD indication but that have potential for inhibiting COPD inflammation include the statins, some phosphodiesterase inhibitors, some long-acting β agonists, tiotropium bromide, the peroxisome proliferator-activated receptor-γ agonist rosiglitazone, and various monoclonal antibodies. New molecular entities that are being developed specifically as antiinflammatory agents for COPD include a variety of chemokine receptor antagonists, inhibitors of matrix metalloproteinases, inhibitors of p38 mitogen-activated protein kinases, and stem cells. Some other novel agents that are in preclinical or early clinical stages are mentioned. PMID: 23131938 [PubMed - indexed for MEDLINE]
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Related Articles Newer therapies for chronic obstructive pulmona disease. J Assoc Physicians India. 2012 Feb;60 Suppl:8-13 Authors: Kodgule R, Vaidya A, Salvi S PMID: 23155806 [PubMed - indexed for MEDLINE]
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Related Articles Therapeutic potential of growth factors in pulmonary emphysematous condition. Lung. 2013 Apr;191(2):147-63 Authors: Muyal JP, Muyal V, Kotnala S, Kumar D, Bhardwaj H Abstract Pulmonary emphysema is a major manifestation of chronic obstructive pulmonary disease (COPD), which is characterized by progressive destruction of alveolar parenchyma with persistent inflammation of the small airways. Such destruction in the distal respiratory tract is irreversible and irreparable. All-trans-retinoic acid was suggested as a novel therapy for regeneration of lost alveoli in emphysema. However, profound discrepancies were evident between studies. At present, no effective therapeutic options are available that allow for the regeneration of lost alveoli in emphysematous human lungs. Recently, some reports on rodent's models have suggested the beneficial effects of various growth factors toward alveolar maintenance and repair processes. PMID: 23161370 [PubMed - indexed for MEDLINE]
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Related Articles A placebo-controlled, randomized trial of mesenchymal stem cells in COPD. Chest. 2013 Jun;143(6):1590-8 Authors: Weiss DJ, Casaburi R, Flannery R, LeRoux-Williams M, Tashkin DP Abstract BACKGROUND: COPD is a devastating disease affecting millions worldwide. As disease pathogenesis includes both chronic pulmonary and systemic inflammation, antiinflammatory effects of systemically administered mesenchymal stem cells (MSCs) may decrease inflammation, resulting in improved lung function and quality of life. The goal of this study was to assess safety and to perform an initial evaluation of the potential efficacy of systemic MSC administration to patients with moderate to severe COPD. METHODS: Sixty-two patients at six sites were randomized to double-blinded IV infusions of either allogeneic MSCs (Prochymal; Osiris Therapeutics Inc) or vehicle control. Patients received four monthly infusions (100 × 10⁶ cells/infusion) and were subsequently followed for 2 years after the first infusion. End points included comprehensive safety evaluation, pulmonary function testing (PFT), and quality-of-life indicators including questionnaires, 6MWT, and assessments of systemic inflammation. RESULTS: All study patients completed the full infusion protocol, and 74% completed the 2-year follow-up. There were no infusional toxicities and no deaths or serious adverse events deemed related to MSC administration. There were no significant differences in the overall number of adverse events, frequency of COPD exacerbations, or worsening of disease in patients treated with MSCs. There were no significant differences in PFTs or quality-of-life indicators; however, an early, significant decrease in levels of circulating C-reactive protein (CRP) was observed in patients treated with MSCs who had elevated CRP levels at study entry. CONCLUSIONS: Systemic MSC administration appears to be safe in patients with moderate to severe COPD and provides a basis for subsequent cell therapy investigations. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00683722; URL: www.clinicaltrials.gov. PMID: 23172272 [PubMed - indexed for MEDLINE]
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Related Articles Concise review: clinical prospects for treating chronic obstructive pulmonary disease with regenerative approaches. Stem Cells Transl Med. 2012 Aug;1(8):627-31 Authors: Kubo H Abstract Chronic obstructive pulmonary disease (COPD) is becoming a major cause of death worldwide. COPD is characterized by a progressive and not fully reversible airflow limitation caused by chronic small airway disease and lung parenchymal destruction. Clinically available drugs improve airflow obstruction and respiratory symptoms but cannot cure the disease. Slowing the progressive lung destruction or rebuilding the destroyed lung structure is a promising strategy to cure COPD. In contrast to small animal models, pharmacological lung regeneration is difficult in human COPD. Maturation, aging, and senescence in COPD lung cells, including endogenous stem cells, may affect the regenerative capacity following pharmacological therapy. The lung is a complex organ composed of more than 40 different cell types; therefore, detailed analyses, such as epigenetic modification analysis, in each specific cell type have not been performed in lungs with COPD. Recently, a method for the direct isolation of individual cell types from human lung has been developed, and fingerprints of each cell type in COPD lungs can be analyzed. Research using this technique combined with the recently discovered lung endogenous stem-progenitor populations will give a better understanding about the fate of COPD lung cells and provide a future for cell-based therapy to treat this intractable disease. PMID: 23197868 [PubMed - indexed for MEDLINE]
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Related Articles Bronchiolitis obliterans syndrome after allogeneic hematopoietic SCT: phenotypes and prognosis. Bone Marrow Transplant. 2013 Jun;48(6):819-24 Authors: Bergeron A, Godet C, Chevret S, Lorillon G, Peffault de Latour R, de Revel T, Robin M, Ribaud P, Socié G, Tazi A Abstract Bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic SCT (HSCT) is recognized as a new-onset obstructive lung defect (OLD) in pulmonary function testing and is related to pulmonary chronic GVHD. Little is known about the different phenotypes of patients with BOS and their outcomes. We reviewed the data of all allogeneic HSCT recipients referred to our pulmonary department for a non-infectious bronchial disease between 1999 and 2010. We identified 103 patients (BOS (n=77), asthma (n=11) and chronic bronchitis (n=15)). In patients with BOS, we identified two functional phenotypes: a typical OLD, that is, forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio <0.7 (n=53), and an atypical OLD with a concomitant decrease in the FEV1 <80% and FVC <80% predicted with a normal total lung capacity (n=24). The typical OLD was characterized by more severe FEV1 and fewer centrilobular nodules on the computed tomography scan. The FEV1 was not significantly affected during the follow-up, regardless of the phenotype. In addition to acute and extensive chronic GVHD, only the occurrence of BOS soon after transplantation and the intentional treatment of BOS with steroids were associated with a poor survival. The determination of patient subgroups should be explored to improve the management of this condition. PMID: 23208317 [PubMed - indexed for MEDLINE]
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Related Articles Cell therapy with bone marrow mononuclear cells in elastase-induced pulmonary emphysema. Stem Cell Rev. 2013 Apr;9(2):210-8 Authors: Longhini-Dos-Santos N, Barbosa-de-Oliveira VA, Kozma RH, Faria CA, Stessuk T, Frei F, Ribeiro-Paes JT Abstract Emphysema is characterized by destruction of alveolar walls with loss of gas exchange surface and consequent progressive dyspnea. This study aimed to evaluate the efficiency of cell therapy with bone marrow mononuclear cells (BMMC) in an animal model of elastase-induced pulmonary emphysema. Emphysema was induced in C57Bl/J6 female mice by intranasal instillation of elastase. After 21 days, the mice received bone marrow mononuclear cells from EGFP male mice with C57Bl/J6 background. The groups were assessed by comparison and statistically significant differences (p < 0.05) were observed among the groups treated with BMMC and evaluated after 7, 14 and 21 days. Analysis of the mean linear intercept (Lm) values for the different groups allowed to observe that the group treated with BMMC and evaluated after 21 days showed the most significant result. The group that received no treatment showed a statistically significant difference when compared to other groups, except the group treated and evaluated after 21 days, evidencing the efficacy of cell therapy with BMMC in pulmonary emphysema. PMID: 23242964 [PubMed - indexed for MEDLINE]
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Related Articles Stem cell therapy in chronic obstructive pulmonary disease. Seeking the Prometheus effect. Curr Drug Targets. 2013 Feb;14(2):246-52 Authors: Tzouvelekis A, Laurent G, Bouros D Abstract Chronic obstructive pulmonary disease is characterized by dramatic alterations in lung architecture associated to an exaggerated inflammatory process, alveolar epithelial cell apoptosis, endothelial dysfunction and extracellular matrix destruction due to a protease and anti-protease imbalance. In addition a significant inflammatory spillover into systemic circulation has been suggested to be responsible for a wide range of fatal comorbidities. In view of the current disappointing status of available pharmaceutical agents, there is an urgent need for alternative more effective therapeutic approaches that will fulfill the unmet need of modulating both local and systemic inflammation and at the same time accelerate alveolar epithelial and endothelial turnover intervening into disease natural course and not only relieving patient's symptoms. Regenerative medicine based on stem cells properties represents one promising option with several fruitful therapeutic applications in patients with COPD. 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 administrated stem cells within the COPD lung as well as the mechanisms regulating activation of resident progenitor cells. The above evidence coupled with the rather disappointing results emerging from the first stem cell clinical trials in COPD patients underline the need for careful study design by setting realistic goals to assess efficacy such as biomarkers that reflect clinically inconspicuous alterations of the disease molecular phenotype before rigid conclusions can be safely drawn. PMID: 23256721 [PubMed - indexed for MEDLINE]
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Related Articles Successful Treatment of Gastric Relapse in Multiple Myeloma with Bortezomib after Autologous Hematopoietic Stem Cell Transplantation (autoHSCT). Mediterr J Hematol Infect Dis. 2013;5(1):e2013006 Authors: Sivgin S, Baldane S, Kaynar L, Kurnaz F, Baskol M, Kula M, Eroglu C, Deniz K, Eser B, Unal A, Cetin M Abstract We report a case of 59-year-old Turkish man with history of mitral valve replacement (MVR) and chronic obstructive pulmonary disease (COPD) who was diagnosed with stage IIIA IgG lambda multiple myeloma (MM) in 1997. He underwent autologous hematopoietic stem cell transplantation after a conditioning regimen with melphalan 200mg per body area (m(2)) in February 2006. On February 2011, he was admitted to the emergency service of university hospital with complaints of hematemesis and melena. Pathological evaluation of gastric biopsy, obtained from a lesion of small gastric curvature, showed the gastric mucosa infiltrated by neoplastic plasma cells, monoclonal lambda light chain positive. The patient was considered as having local gastric relapsed disease and was treated with 2 cycles of bortezomib. He achieved an excellent local response after 2 cycles of bortezomib, cyclophosphamide and prednisone (BEP) regimen, with healing of gastric ulcer and no recurrence of the hematemesis or melena. PMID: 23350019 [PubMed]
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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 Using Cell-Based Strategies to Break the Link between Bronchopulmonary Dysplasia and the Development of Chronic Lung Disease in Later Life. Pulm Med. 2013;2013:874161 Authors: O'Reilly M, Thébaud B Abstract Bronchopulmonary dysplasia (BPD) is the chronic lung disease of prematurity that affects very preterm infants. Although advances in perinatal care have changed the course of lung injury and enabled the survival of infants born as early as 23-24 weeks of gestation, BPD still remains a common complication of extreme prematurity, and there is no specific treatment for it. Furthermore, children, adolescents, and adults who were born very preterm and developed BPD have an increased risk of persistent lung dysfunction, including early-onset emphysema. Therefore, it is possible that early-life pulmonary insults, such as extreme prematurity and BPD, may increase the risk of COPD later in life, especially if exposed to secondary challenges such as respiratory infections and/or smoking. Recent advances in our understanding of stem/progenitor cells and their potential to repair damaged organs offer the possibility of cell-based treatments for neonatal and adult lung injuries. This paper summarizes the long-term pulmonary outcomes of preterm birth and BPD and discusses the recent advances of cell-based therapies for lung diseases, with a particular focus on BPD and COPD. PMID: 23401768 [PubMed]
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Related Articles The role of the β2 adrenergic receptor on endothelial progenitor cells dysfunction of proliferation and migration in chronic obstructive pulmonary disease patients. Expert Opin Ther Targets. 2013 May;17(5):485-500 Authors: Liu X, Tan W, Liu Y, Lin G, Xie C Abstract BACKGROUND: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD), with > 44% of these patients presenting with generalized atherosclerosis at autopsy. It is accepted that endothelial progenitor cells (EPCs) participate in the repair of dysfunctional endothelium, thereby, protecting against atherosclerosis. The β2 adrenergic receptor (β2AR) expressed on mononuclear cells in peripheral blood and CD34(+) cells in bone has been shown to regulate T-cell traffic and proliferation. At present, there have been few systematic studies evaluating β2AR expression on EPCs in the peripheral blood of COPD patients and its role in EPCs migration and proliferation. Therefore, the objective of this study was to determine the role of β2ARs in EPCs function and, if this role is altered, in the COPD population. METHODS: EPCs from 25 COPD and 16 control patients were isolated by Ficoll density-gradient centrifugation and identified using fluorescence-activated cell sorting. β2AR expression on EPCs was determined by western blotting and real-time PCR. The transwell migration assay was performed to determine the migration capacity of EPCs treated with a β2AR agonist, antagonist and β2AR monoclonal antibody. EPCs proliferation was assayed throughout the cell cycle. Following arterial damage in NOD/SCID mice, the number of EPCs treated with siRNA-β2AR incorporated at the injured vascular site was determined by fluorescence microscopy. RESULTS: Data showed a significant increase in the total number of β2ARs in addition to an increased expression on early EPCs in COPD patients. COPD EPCs treated with β2AR antagonist (ICI 118551) increased migration to SDF-1α when compared to treatment with the β2AR agonist, norepinephrine. These changes were directly correlated to increase CXCR4 on EPCs. The proliferation of early EPCs treated with β2AR antagonist was improved and was correlated to an intercellular decrease in reactive oxygen species. CONCLUSION: Changes in β2AR in COPD patients alter EPCs migration and proliferation, contributing to altered EPC repair capacity in this patient population. PMID: 23448263 [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 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 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 Increased levels of CD34+ cells are associated in patients with abdominal aortic aneurysms compared with patients with peripheral vascular disease. J Surg Res. 2013 Sep;184(1):638-43 Authors: Van Spyk EN, Chun KC, Samadzadeh KM, Peters JH, Lee ES Abstract BACKGROUND: Circulating progenitor cells are integral to vascular health and effectively predict vascular reactivity. CD34 is a known marker of circulating progenitor cells. Few studies have examined the role of CD34+ cells in abdominal aortic aneurysm (AAA) disease and peripheral vascular disease (PVD). The aim of this study was to compare the percentage of CD34+ cells between patients with AAA versus PVD. MATERIALS AND METHODS: We collected peripheral whole blood from AAA or PVD patients. The blood was stained with fluorescently labeled antibodies against CD34 or isotype controls. We collected data using a flow cytometer and analyzed them. We also recorded risk factors such as hypertension, diabetes, total cholesterol, serum white blood cells, serum creatinine, body mass index, blood pressure, statin use, current smoking status, coronary artery disease, cerebral vascular accident, and chronic obstructive pulmonary disease. RESULTS: We enrolled 24 patients in this study (AAA, n = 12; PVD, n = 12). The AAA patients had a greater percentage of CD34+ cells compared with PVD patients. (r = 0.84; P = 0.016). There were no significant risk factors differences between AAA and PVD patients. CONCLUSIONS: Based on CD34+ cell counts, AAA is a less severe vascular disease than PVD. Whether CD34+ cells can serve as a biomarker for risk stratification or a potential therapy warrants further study. PMID: 23680469 [PubMed - indexed for MEDLINE]
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Related Articles Cell therapy for lung disease: a step forward. Chest. 2013 Jun;143(6):1525-7 Authors: Gotts JE, Matthay MA PMID: 23732575 [PubMed - indexed for MEDLINE]
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Related Articles Alpha-1 antitrypsin deficiency: new developments in augmentation and other therapies. BioDrugs. 2013 Dec;27(6):547-58 Authors: Turner AM Abstract Alpha 1 antitrypsin deficiency (AATD) is a rare cause of chronic obstructive pulmonary disease. The lung disease is thought to be caused primarily by a lack of effective protection against the harmful effects of neutrophil elastase due to the low AAT levels in the lung. Patients may also develop liver disease due to polymerisation of AAT within hepatocytes. Consequently there has been much research over the years into AAT augmentation therapy in patients with lung disease, initially intravenously, and more recently in inhaled forms. This review article will discuss the role of augmentation therapy in AATD and the current status of recombinant AAT. The potential for other therapeutic strategies, such as blocking polymer formation, enhancing autophagy, gene therapy and stem cell-based treatment, will also be discussed more briefly. PMID: 23771682 [PubMed - in process]
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Related Articles Dysfunction of endothelial progenitor cells from smokers and chronic obstructive pulmonary disease patients due to increased DNA damage and senescence. Stem Cells. 2013 Dec;31(12):2813-26 Authors: Paschalaki KE, Starke RD, Hu Y, Mercado N, Margariti A, Gorgoulis VG, Randi AM, Barnes PJ Abstract Cardiovascular disease (CVD) is a major cause of death in smokers, particularly in those with chronic obstructive pulmonary disease (COPD). Circulating endothelial progenitor cells (EPC) are required for endothelial homeostasis, and their dysfunction contributes to CVD. To investigate EPC dysfunction in smokers, we isolated and expanded blood outgrowth endothelial cells (BOEC) from peripheral blood samples from healthy nonsmokers, healthy smokers, and COPD patients. BOEC from smokers and COPD patients showed increased DNA double-strand breaks and senescence compared to nonsmokers. Senescence negatively correlated with the expression and activity of sirtuin-1 (SIRT1), a protein deacetylase that protects against DNA damage and cellular senescence. Inhibition of DNA damage response by silencing of ataxia telangiectasia mutated (ATM) kinase resulted in upregulation of SIRT1 expression and decreased senescence. Treatment of BOEC from COPD patients with the SIRT1 activator resveratrol or an ATM inhibitor (KU-55933) also rescued the senescent phenotype. Using an in vivo mouse model of angiogenesis, we demonstrated that senescent BOEC from COPD patients are dysfunctional, displaying impaired angiogenic ability and increased apoptosis compared to cells from healthy nonsmokers. Therefore, this study identifies epigenetic regulation of DNA damage and senescence as pathogenetic mechanisms linked to endothelial progenitors' dysfunction in smokers and COPD patients. These defects may contribute to vascular disease and cardiovascular events in smokers and could therefore constitute therapeutic targets for intervention. PMID: 23897750 [PubMed - in process]
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Related Articles Concise review: current status of stem cells and regenerative medicine in lung biology and diseases. Stem Cells. 2014 Jan;32(1):16-25 Authors: Weiss DJ Abstract Lung diseases remain a significant and devastating cause of morbidity and mortality worldwide. In contrast to many other major diseases, lung diseases notably chronic obstructive pulmonary diseases (COPDs), including both asthma and emphysema, are increasing in prevalence and COPD is expected to become the third leading cause of disease mortality worldwide by 2020. New therapeutic options are desperately needed. A rapidly growing number of investigations of stem cells and cell therapies in lung biology and diseases as well as in ex vivo lung bioengineering have offered exciting new avenues for advancing knowledge of lung biology as well as providing novel potential therapeutic approaches for lung diseases. These initial observations have led to a growing exploration of endothelial progenitor cells and mesenchymal stem (stromal) cells in clinical trials of pulmonary hypertension and COPD with other clinical investigations planned. Ex vivo bioengineering of the trachea, larynx, diaphragm, and the lung itself with both biosynthetic constructs as well as decellularized tissues have been used to explore engineering both airway and vascular systems of the lung. Lung is thus a ripe organ for a variety of cell therapy and regenerative medicine approaches. Current state-of-the-art progress for each of the above areas will be presented as will discussion of current considerations for cell therapy-based clinical trials in lung diseases. PMID: 23959715 [PubMed - in process]
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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 - in process]
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Related Articles Targeting interleukin-6 in inflammatory autoimmune diseases and cancers. Pharmacol Ther. 2014 Feb;141(2):125-39 Authors: Yao X, Huang J, Zhong H, Shen N, Faggioni R, Fung M, Yao Y Abstract Interleukin-6 (IL-6) is a pleiotropic cytokine with significant functions in the regulation of the immune system. As a potent pro-inflammatory cytokine, IL-6 plays a pivotal role in host defense against pathogens and acute stress. However, increased or deregulated expression of IL-6 significantly contributes to the pathogenesis of various human diseases. Numerous preclinical and clinical studies have revealed the pathological roles of the IL-6 pathway in inflammation, autoimmunity, and cancer. Based on the rich body of studies on biological activities of IL-6 and its pathological roles, therapeutic strategies targeting the IL-6 pathway are in development for cancers, inflammatory and autoimmune diseases. Several anti-IL-6/IL-6 receptor monoclonal antibodies developed for targeted therapy have demonstrated promising results in both preclinical studies and clinical trials. Tocilizumab, an anti-IL-6 receptor antibody, is effective in the treatment of various autoimmune and inflammatory conditions notably rheumatoid arthritis. It is the only IL-6 pathway targeting agent approved by the regulatory agencies for clinical use. Siltuximab, an anti-IL-6 antibody, has been shown to have potential benefits treating various human cancers either as a single agent or in combination with other chemotherapy drugs. Several other anti-IL-6-based therapies are also under clinical development for various diseases. IL-6 antagonism has been shown to be a potential therapy for these disorders refractory to conventional drugs. New strategies, such as combination of IL-6 blockade with inhibition of other signaling pathways, may further improve IL-6-targeted immunotherapy of human diseases. PMID: 24076269 [PubMed - in process]
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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 A protocol proposition of cell therapy for the treatment of Chronic Obstructive Pulmonary Disease. Rev Port Pneumol. 2014 March - April;20(2):84-91 Authors: Ribeiro-Paes JT, Stessuk T, Marcelino M, Faria C, Marinelli T, Ribeiro-Paes MJ Abstract The main feature of pulmonary emphysema is airflow obstruction resulting from the destruction of the alveolar walls distal to the terminal bronchioles. Existing clinical approaches have improved and extended the quality of life of emphysema patients. However, no treatment currently exists that can change the disease course and cure the patient. The different therapeutic approaches that are available aim to increase survival and/or enhance the quality of life of emphysema patients. In this context, cell therapy is a promising therapeutic approach with great potential for degenerative pulmonary diseases. In this protocol proposition, all patients will be submitted to laboratory tests, such as evaluation of heart and lung function and routine examinations. Stem cells will be harvested by means of 10 punctures on each anterior iliac crest, collecting a total volume of 200mL bone marrow. After preparation, separation, counting and labeling (optional) of the mononuclear cells, the patients will receive an intravenous infusion from the pool of Bone Marrow Mononuclear Cells (BMMC). This article proposes a rational and safe clinical cellular therapy protocol which has the potential for developing new projects and can serve as a methodological reference for formulating clinical application protocols related to the use of cellular therapy in COPD. This study protocol was submitted and approved by the Brazilian National Committee of Ethics in Research (CONEP - Brazil) registration number 14764. It is also registered in ClinicalTrials.gov (NCT01110252). PMID: 24287082 [PubMed - as supplied by publisher]
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Related Articles Screening and identification of six serum microRNAs as novel potential combination biomarkers for pulmonary tuberculosis diagnosis. PLoS One. 2013;8(12):e81076 Authors: Zhang X, Guo J, Fan S, Li Y, Wei L, Yang X, Jiang T, Chen Z, Wang C, Liu J, Ping Z, Xu D, Wang J, Li Z, Qiu Y, Li JC Abstract BACKGROUND: It is very difficult to prevent pulmonary tuberculosis (TB) due to the lack of specific and diagnostic markers, which could lead to a high incidence of pulmonary TB. We screened the differentially expressed serum microRNAs (miRNAs) as potential biomarkers for the diagnosis of pulmonary TB. METHODS: In this study, serum miRNAs were screened using the Solexa sequencing method as the potential biomarkers for the diagnosis of pulmonary TB. The stem-loop quantitative reverse-transcription polymerase chain reaction (qRT-PCR) assay was used to verify differentially expressed serum miRNAs. The receiver operating characteristic (ROC) curve and logistic regression model were used to analyze the sensitivity and specificity of the single miRNA and a combination of miRNAs for diagnosis, respectively. Using the predicted target genes, we constructed the regulatory networks of miRNAs and genes that were related to pulmonary TB. RESULTS: The Solexa sequencing data showed that 91 serum miRNAs were differentially expressed in pulmonary TB patients, compared to healthy controls. Following qRT-PCR confirmation, six serum miRNAs (hsa-miR-378, hsa-miR-483-5p, hsa-miR-22, hsa-miR-29c, hsa-miR-101 and hsa-miR-320b) showed significant difference among pulmonary TB patients, healthy controls (P<0.001) and differential diagnosis groups (including patients with pneumonia, lung cancer and chronic obstructive pulmonary disease) (P<0.05). The logistic regression analysis of a combination of six serum miRNAs revealed that the sensitivity and the specificity of TB diagnosis were 95.0% and 91.8% respectively. The miRNAs-gene regulatory networks revealed that several miRNAs may regulate some target genes involved in immune pathways and participate in the pathogenesis of pulmonary TB. CONCLUSION: Our study suggests that a combination of six serum miRNAs have great potential to serve as non-invasive biomarkers of pulmonary TB. PMID: 24349033 [PubMed - in process]
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Related Articles Association between Anemia and COPD in Iranian Population. Int J Hematol Oncol Stem Cell Res. 2013;7(2):6-10 Authors: Zavarreh RH, Zahmatkesh MM, Vakili M, Shahriari-Ahmadi A, Zohal MA, Arabi M, Mahmoudian A, Gheisuri A, Kian A, Fahimi A Abstract BACKGROUND AND AIM: Chronic obstructive pulmonary disease (COPD) is one of the major causes of morbidity and mortality in adults. Anemia is known as comorbidity in many chronic diseases that can increase morbidity and mortality of COPD. Recent studies have shown that anemia may be more prevalent than expected in COPD patients and can increase disabilities of COPD. In this study we have evaluated the correlation between anemia and the severity of COPD in patients referred to teaching hospitals of the Tehran University of Medical Sciences (TUMS), Tehran, Iran. MATERIALS AND METHODS: In this cross-sectional study the severity of COPD in 760 patients with dyspnea who referred to teaching hospitals of Tehran University of Medical Sciences and 96 stable COPD patients were categorize using a GOLD criteria from mild to moderate, severe and very severe. Anemia was determined as hemoglobin <13 g/dL in men and <12 g/dL in women, respectively. Demographic characteristics, spirometry parameters and laboratory findings were compared between anemic and non-anemic groups using Student t-test and regression tests (SPSS v.18 software). RESULTS: The Mean age of patients was 65 ± 13.07 years (59.4% male). Overall prevalence of anemia was 27% and there was no correlation between severity of COPD and anemia. Anemic patients were significantly older than non-anemic patients (71.1 ± 8.5 years vs. 65.4± 12.8 years; p = 0.030). RBC count of anemic patients were significantly lower than non-anemic group (4.3 ± 0.5 vs. 5.02± 0.8 ×106/µL; p < 0.001). Erythropoietin levels in anemic group was significantly higher than non-anemic group (16.33±2.43 vs. 10.22 ± 2.67 mu/ml; p < 0.001) and there was a significant inverse correlation of hemoglobin vs erythropoietin (r= -0.8). CONCLUSION: There was a high prevalence of anemia in COPD patients. Anemia can increase disabilities of COPD. Thus, treatment of anemia may improve quality of life in these patients. Further comprehensive studies are needed for determination of exact prevalence of anemia and its physiologic effects in COPD. PMID: 24505521 [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 - 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 Advanced Sclerosis of The Chest Wall Skin Secondary to Chronic Graft-versus-Host Disease: A Case With Severe Restrictive Lung Defect. J Pediatr Hematol Oncol. 2014 Feb 26; Authors: Odek C, Kendirli T, Ileri T, Yaman A, Fatih Çakmakli H, Ince E, Ince E, Ertem M Abstract Pulmonary chronic graft-versus-host disease (cGvHD) is one of the most common causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (aHSCT). Herein, we describe a patient with severe restrictive lung defect secondary to cGvHD. A 21-year-old male patient was admitted to our pediatric intensive care unit (PICU) with pneumonia and respiratory distress. He had a history of aHSCT for chronic myelogeneous leukemia at the age of 17 years. Six months after undergoing aHSCT, he had developed cGvHD involving skin, mouth, eye, lung, liver, and gastrointestinal tract. At the time of PICU admission he had respiratory distress and required ventilation support. Thorax high-resolution computed tomography was consistent with bronchiolitis obliterans. Although bronchiolitis obliterans is an obstructive lung defect, a restrictive pattern became prominent in the clinical course because of the sclerotic chest wall skin. The activity of cGvHD kept increasing despite the therapy and we lost the patient because of severe respiratory distress and massive hemoptysis secondary to bronchiectasis. In conclusion, pulmonary cGvHD can present with restrictive changes related with the advanced sclerosis of the chest wall skin. Performing a fasciotomy or a scar revision for the rigid chest wall in selected patients may improve the patients ventilation. PMID: 24577553 [PubMed - as supplied by publisher]
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Related Articles Lung carcinogenesis from chronic obstructive pulmonary disease: characteristics of lung cancer from COPD and contribution of signal transducers and lung stem cells in the inflammatory microenvironment. Gen Thorac Cardiovasc Surg. 2014 Mar 14; Authors: Sekine Y, Hata A, Koh E, Hiroshima K Abstract Chronic obstructive pulmonary disease (COPD) and lung cancer are closely related. The annual incidence of lung cancer arising from COPD has been reported to be 0.8-1.7 %. Treatment of lung cancer from COPD is very difficult due to low cardiopulmonary function, rapid tumor growth, and resistance to molecularly targeted therapies. Chronic inflammation caused by toxic gases can induce COPD and lung cancer. Carcinogenesis in the inflammatory microenvironment occurs during cycles of tissue injury and repair. Cellular damage can induce induction of necrotic cell death and loss of tissue integrity. Quiescent normal stem cells or differentiated progenitor cells are introduced to repair injured tissues. However, inflammatory mediators may promote the growth of bronchioalveolar stem cells, and activation of NF-κB and signal transducer and activator of transcription 3 (STAT3) play crucial roles in the development of lung cancer from COPD. Many of the protumorgenic effects of NF-κB and STAT3 activation in immune cells are mediated through paracrine signaling. NF-κB and STAT3 also contribute to epithelial-mesenchymal transition. To improve lung cancer treatment outcomes, lung cancer from COPD must be overcome. In this article, we review the characteristics of lung cancer from COPD and the mechanisms of carcinogenesis in the inflammatory microenvironment. We also propose the necessity of identifying the mechanisms underlying progression of COPD to lung cancer, and comment on the clinical implications with respect to lung cancer prevention, screening, and therapy. PMID: 24627306 [PubMed - as supplied by publisher]
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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 Expanding the Pool of Stem Cell Therapy for Lung Growth and Repair. Circulation. 2014 Apr 7; Authors: Kourembanas S Abstract The lung's regenerative capacity resides within long-lived stem cells that can divide, self-renew, and differentiate to repair injured tissue or cell loss and maintain normal homeostasis. The ability to enhance endogenous stem cell capacity to regenerate lung tissue is the key to the treatment of a multitude of debilitating lung diseases such as bronchopulmonary dysplasia (BPD), idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, pulmonary arterial hypertension (PAH), and other acute and chronic ailments of the lung. The challenge lies in identifying the progenitors of a tissue and, in the case of the lung, understanding the complex interactions lung progenitors have with the unique environment of an air-liquid interphase, proximal and distal airways, the intricate vascular tree, and the innate immune response. Indeed, many different lung stem/progenitor cells have been described, and their identity and role in lung regeneration continue to be debated. PMID: 24710032 [PubMed - as supplied by publisher]
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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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