33 results on '"Marchal-Somme J"'
Search Results
2. Altered Nrf2/Keap1-Bach1 equilibrium in pulmonary emphysema
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Goven, D., Boutten, A., Lecon-Malas, V., Marchal-Somme, J., Amara, N., Crestani, B., Fournier, M., Leseche, G., Soler, P., Boczkowski, J., and Bonay, M.
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Emphysema, Pulmonary -- Development and progression ,Emphysema, Pulmonary -- Research ,Oxidative stress -- Physiological aspects ,Oxidative stress -- Research ,Antioxidants -- Physiological aspects ,Antioxidants -- Research ,Health - Published
- 2008
3. Le FGF-9 inhibe la fibrose pleurale induite par un adénovirus chez la souris
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Justet, A., primary, Johannes, A., additional, Marchal-Somme, J., additional, Besnard, V., additional, Bonniaud, P., additional, Mailleux, A., additional, and Crestani, B., additional
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- 2015
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4. Le FGF9 contrôle le phénotype des fibroblastes pulmonaires humains au cours de la fibrose pulmonaire idiopathique
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Joannes, A., primary, Marchal-Somme, J., additional, Crestani, B., additional, and Mailleux, A., additional
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- 2015
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5. Rôle potentiel de human airway trypsin-like protease dans la fibrose pulmonaire idiopathique
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Menou, A., primary, Francois, C., additional, Carlier, N., additional, Bardou, O., additional, Marchal-Somme, J., additional, Crestani, B., additional, and Borensztajn, K., additional
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- 2015
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6. Le FGF-9 inhibe la fibrose pleurale viro-induite chez la souris
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Justet, A., primary, Joannes, A., additional, Marchal-Somme, J., additional, Besnard, V., additional, Bellaye, P.-S., additional, Bonniaud, P., additional, Mailleux, A., additional, and Crestani, B., additional
- Published
- 2015
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7. Spatial distribution and quantitative analysis of extracellular matrix remodelling in lung fibrosis using multiphoton microscopy
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Fabre, A., Ana-Maria Pena, Delphine Débarre, Marchal-Somme, J., Bruno Crestani, Jean-Louis Martin, Hénin, D., Emmanuel Beaurepaire, Marie-Claire Schanne-Klein, Laboratoire d'optique et biosciences (LOB), École polytechnique (X)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Lachapelle, Laure
- Abstract
International audience; The micro- and macro- organization of collagen during fibrotic processes is usually characterized by 2D assessment using histochemical stains on selected slides such as Masson's Trichrome or Sirius Red. However, these staining methods are limited to semi quantitative evaluation on restricted surfaces. Quantitative evaluation of collagen contents, such as Hydroxyproline or Sircol assays, performed on lung homogenates requires large amounts of tissue, are time consuming and do not give the spatial distribution of collagen. Non linear multimodal, multiphoton microscopy provides novel insights into collagen deposition in tissues. In this study, the micrometerscale three-dimensional spatial distribution of fi brosis was characterized in normal mouse lung (n=5) and in the murine model of bleomycininduced lung fi brosis (n=5) by second harmonic generation (SHG) of fi brillar collagen, using C56Bl/6 mice at day 14 post intra-tracheal instillation of bleomycin, 80 µg in 50 µl of 0.9 % sterile saline.
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- 2006
8. La petite protéine de choc thermique αB-crystallin a un rôle clé dans la fibrogenèse pulmonaire par son action sur la SMAD4
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Bellaye, P.-S., primary, Wettstein, G., additional, Burgy, O., additional, Besnard, V., additional, Joannes, A., additional, Colas, J., additional, Causse, S., additional, Marchal-Somme, J., additional, Crestani, B., additional, Garrido, C., additional, Camus, P., additional, and Bonniaud, P., additional
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- 2014
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9. Le FGF9 est exprimé dans le poumon au cours de la fibrose pulmonaire idiopathique et module l’activation des fibroblastes pulmonaires
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Joannes, A., primary, Marchal-Somme, J., additional, Crestani, B., additional, and Mailleux, A.-A., additional
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- 2014
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10. Un nouveau rôle potentiel de Human Airway Trypsin-like protease dans la fibrose pulmonaire
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Carlier, N., primary, Francois, C., additional, Bardou, O., additional, Marchal-Somme, J., additional, Crestani, B., additional, and Borensztajn, K., additional
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- 2014
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11. Alveolar fibroblasts in acute lung injury: biological behaviour and clinical relevance
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Quesnel, C., primary, Nardelli, L., additional, Piednoir, P., additional, Lecon, V., additional, Marchal-Somme, J., additional, Lasocki, S., additional, Bouadma, L., additional, Philip, I., additional, Soler, P., additional, Crestani, B., additional, and Dehoux, M., additional
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- 2009
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12. Periplakin: A New Antigenic Target in Idiopathic Pulmonary Fibrosis?.
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Taille, C, primary, Mignot, S, additional, Boursier, C, additional, Nicaise, P, additional, Champagnat, C, additional, Marchand-Adam, S, additional, Marchal-Somme, J, additional, Soler, P, additional, Aubier, M, additional, Chollet-Martin, S, additional, and Crestani, B, additional
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- 2009
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13. Effet du lavage broncho-alvéolaire sur la migration des fibroblastes pulmonaires humains dans les agressions alvéolaires aiguës : rôle du PDGF
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Piednoir, P., primary, Quesnel, C., additional, Nardelli, L., additional, Stervinou, L., additional, Leçon, V., additional, Marchal-Somme, J., additional, Mailleux, A., additional, Soler, P., additional, Crestani, B., additional, and Dehoux, M., additional
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- 2008
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14. Le pasireotide (SOM230) inhibe la synthèse de collagène 1 par les fibroblastes pulmonaires humains in vitro
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Prost, F., primary, Verrecchia, F., additional, Marchal-Somme, J., additional, Piednoir, P., additional, Dehoux, M., additional, Soler, P., additional, and Crestani, B., additional
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- 2008
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15. Modulation of bleomycin-induced lung fibrosis by serotonin receptor antagonists in mice
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Fabre, A., primary, Marchal-Somme, J., additional, Marchand-Adam, S., additional, Quesnel, C., additional, Borie, R., additional, Dehoux, M., additional, Ruffie, C., additional, Callebert, J., additional, Launay, J-M., additional, Henin, D., additional, Soler, P., additional, and Crestani, B., additional
- Published
- 2008
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16. Nonlinear microscopy of collagen fibers
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Strupler, M., primary, Pena, A.-M., additional, Hernest, M., additional, Tharaux, P.-L., additional, Fabre, A., additional, Marchal-Somme, J., additional, Crestani, B., additional, Débarre, D., additional, Martin, J.-L., additional, Beaurepaire, E., additional, and Schanne-Klein, M.-C., additional
- Published
- 2007
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17. 066 La microscopie multiphoton permet l’analyse du remodelage de la matrice extracellulaire dans la fibrose pulmonaire
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Fabre, A., primary, Pena, A.M., additional, Debarre, D., additional, Marchal-Somme, J., additional, Crestani, B., additional, Martin, J.L., additional, Henin, D., additional, Beaurepaire, E., additional, and Schanne-Klein, M.C., additional
- Published
- 2006
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18. Fgf9 Prevents Pleural Fibrosis Induced By Intra-Pleural Adenovirus Injection In Mice
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Justet, A., Joannes, A., Besnard, V., Marchal-Somme, J., Jaillet, M., Bonniaud, P., Sallenave, J-M, Mordant, P., Mal, H., Cazes, A., Borie, R., Arnaud Mailleux, Crestani, B., université de Bourgogne, LNC, Université Paris Diderot, Sorbonne Paris Cité, Paris, France, Université Paris Diderot - Paris 7 (UPD7), Université de Bourgogne (UB), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), APHP Service de Pneumologie B, Hôpital Bichat, Université Paris Diderot - Paris 7 ( UPD7 ), Université de Bourgogne ( UB ), Assistance Publique - Hôpitaux de Paris, and Assistance publique - Hôpitaux de Paris (AP-HP)
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Pleural Fibrosis ,[SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract ,[SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract ,[ SDV.MHEP.PSR ] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract ,ComputingMilieux_MISCELLANEOUS ,Antifibrotic effect - Abstract
International audience
19. Rôle potentiel de human airway trypsin-like proteasedans la fibrose pulmonaire idiopathique
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Menou, A., Francois, C., Carlier, N., Bardou, O., Marchal-Somme, J., Crestani, B., and Borensztajn, K.
- Abstract
La fibrose pulmonaire idiopathique (FPI) est une maladie grave d’évolution progressive, caractérisée par une destruction du parenchyme pulmonaire, une différenciation aberrante des fibroblastes en myofibroblastes et une synthèse dérégulée de matrice extracellulaire. Human airway trypsin-like protease(HAT) appartient à la famille des type II transmembrane serine proteases. Un de ses substrats connus est protease activated receptor-2(PAR-2), un récepteur qui joue un rôle important dans les mécanismes de fibrogenèse pulmonaire [1]. Dans cette étude, nous avons étudié le rôle de HAT dans la fibrogenèse pulmonaire.
- Published
- 2015
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20. 079 Caractérisation des cellules dendritiques dans la fibrose pulmonaire idiopathique
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Marchal-Sommé, J., Uzunhan, Y., Marchand-Adam, S., Valeyre, D., Crestani, B., and Soler, P.
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- 2006
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21. Antifibrotic role of αB-crystallin inhibition in pleural and subpleural fibrosis.
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Bellaye PS, Burgy O, Colas J, Fabre A, Marchal-Somme J, Crestani B, Kolb M, Camus P, Garrido C, and Bonniaud P
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- Animals, Cytoskeleton drug effects, Disease Models, Animal, Epithelial Cells drug effects, Humans, Idiopathic Pulmonary Fibrosis pathology, Mice, Mice, Knockout, Pleura metabolism, Signal Transduction drug effects, Transforming Growth Factor beta1 metabolism, Bleomycin pharmacology, Crystallins metabolism, Idiopathic Pulmonary Fibrosis drug therapy, Myofibroblasts drug effects, Pleura drug effects
- Abstract
Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by myofibroblast proliferation and extracellular-matrix accumulation. IPF typically starts in subpleural lung regions, and recent studies suggest that pleural mesothelial cells play a role in the onset of the disease. The transition of mesothelial cells into myofibroblasts (mesothelio-mesenchymal transition) is induced by the profibrotic cytokine, transforming growth factor (TGF)-β1, and is thought to play a role in the development and progression of IPF. The Mothers Against Decapentaplegic homolog (Smad)-dependent pathway is the main TGF-β1 pathway involved in fibrosis. αB-crystallin is constitutively expressed in the lungs, and is inducible by stress, acts as a chaperon, and is known to play a role in cell cytoskeleton architecture. We recently showed that the lack of αB-crystallin hampered TGF-β1 signaling by favoring Smad4 monoubiquitination and nuclear export. We demonstrate here, for the first time, that αB-crystallin is strongly overexpressed in the pleura of fibrotic lungs from patients with IPF and in rodent models of pleural/subpleural fibrosis. αB-crystallin-deficient mice are protected from pleural/subpleural fibrosis induced by the transient adenoviral-mediated overexpression of TGF-β1 or the intrapleural injection of bleomycin combined with carbon particles. We show that αB-crystallin inhibition hampers Smad4 nuclear localization in pleural mesothelial cells and the consequent characteristics of mesothelio-mesenchymal transition. αB-crystallin-deficient mesothelial cells fail to acquire the properties of myofibroblasts, thus limiting their migration in vivo and the progression of fibrosis in the lung parenchyma. In conclusion, our work demonstrates that αB-crystallin may be a key target for the development of specific drugs in the treatment of IPF.
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- 2015
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22. Increased expression of protease nexin-1 in fibroblasts during idiopathic pulmonary fibrosis regulates thrombin activity and fibronectin expression.
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François D, Venisse L, Marchal-Somme J, Jandrot-Perrus M, Crestani B, Arocas V, and Bouton MC
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- Case-Control Studies, Fibronectins metabolism, Humans, Thrombin metabolism, Transforming Growth Factor beta metabolism, Fibroblasts enzymology, Idiopathic Pulmonary Fibrosis enzymology, Lung enzymology, Serpin E2 metabolism
- Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic diffuse lung disease characterized by an accumulation of excess fibrous material in the lung. Protease nexin-1 (PN-1) is a tissue serpin produced by many cell types, including lung fibroblasts. PN-1 is capable of regulating proteases of both coagulation and fibrinolysis systems, by inhibiting, respectively, thrombin and plasminergic enzymes. PN-1 is thus a good candidate for regulating tissue remodeling occurring during IPF. We demonstrated a significant increase of PN-1 expression in lung tissue extracts, lung fibroblasts and bronchoalveolar lavage fluids of patients with IPF. The increase of PN-1 expression was reproduced after stimulation of control lung fibroblasts by transforming growth factor-β, a major pro-fibrotic cytokine involved in IPF. Another serpin, plasminogen activator inhibitor-1 (PAI-1) is also overexpressed in fibrotic fibroblasts. Unlike PAI-1, cell-bound PN-1 as well as secreted PN-1 from IPF and stimulated fibroblasts were shown to inhibit efficiently thrombin activity, indicating that both serpins should exhibit complementary roles in IPF pathogenesis, via their different preferential antiprotease activities. Moreover, we observed that overexpression of PN-1 induced by transfection of control fibroblasts led to increased fibronectin expression, whereas PN-1 silencing induced in fibrotic fibroblasts led to decreased fibronectin expression. Overexpression of PN-1 lacking either its antiprotease activity or its binding capacity to glycosaminoglycans had no effect on fibronectin expression. These novel findings suggest that modulation of PN-1 expression in lung fibroblasts may also have a role in the development of IPF by directly influencing the expression of extracellular matrix proteins. Our data provide new insights into the role of PN-1 in the poorly understood pathological processes involved in IPF and could therefore give rise to new therapeutic approaches.
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- 2014
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23. The small heat-shock protein αB-crystallin is essential for the nuclear localization of Smad4: impact on pulmonary fibrosis.
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Bellaye PS, Wettstein G, Burgy O, Besnard V, Joannes A, Colas J, Causse S, Marchal-Somme J, Fabre A, Crestani B, Kolb M, Gauldie J, Camus P, Garrido C, and Bonniaud P
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- Active Transport, Cell Nucleus, Animals, Bleomycin, Cell Nucleus pathology, Cells, Cultured, Collagen metabolism, Disease Models, Animal, Epithelial Cells metabolism, Female, Fibroblasts metabolism, Humans, Idiopathic Pulmonary Fibrosis chemically induced, Idiopathic Pulmonary Fibrosis genetics, Idiopathic Pulmonary Fibrosis pathology, Idiopathic Pulmonary Fibrosis prevention & control, Interleukin-1beta genetics, Interleukin-1beta metabolism, Lung pathology, Mice, Mice, 129 Strain, Mice, Knockout, RNA Interference, Rats, Sprague-Dawley, Transcription Factors metabolism, Transfection, Transforming Growth Factor beta1 genetics, Transforming Growth Factor beta1 metabolism, Ubiquitin-Protein Ligases metabolism, Ubiquitination, alpha-Crystallin B Chain genetics, Cell Nucleus metabolism, Idiopathic Pulmonary Fibrosis metabolism, Lung metabolism, Smad4 Protein metabolism, alpha-Crystallin B Chain metabolism
- Abstract
Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by the proliferation of myofibroblasts and the accumulation of extracellular matrix (ECM) in the lungs. TGF-β1 is the major profibrotic cytokine involved in IPF and is responsible for myofibroblast proliferation and differentiation and ECM synthesis. αB-crystallin is constitutively expressed in the lungs and is inducible by stress, acts as a chaperone and is known to play a role in cell cytoskeleton architecture homeostasis. The role of αB-crystallin in fibrogenesis remains unknown. The principal signalling pathway involved in this process is the Smad-dependent pathway. We demonstrate here that αB-crystallin is strongly expressed in fibrotic lung tissue from IPF patients and in vivo rodent models of pulmonary fibrosis. We also show that αB-crystallin-deficient mice are protected from bleomycin-induced fibrosis. Similar protection from fibrosis was observed in αB-crystallin KO mice after transient adenoviral-mediated over-expression of IL-1β or TGF-β1. We show in vitro in primary epithelial cells and fibroblasts that αB-crystallin increases the nuclear localization of Smad4, thereby enhancing the TGF-β1-Smad pathway and the consequent activation of TGF-β1 downstream genes. αB-crystallin over-expression disrupts Smad4 mono-ubiquitination by interacting with its E3-ubiquitin ligase, TIF1γ, thus limiting its nuclear export. Conversely, in the absence of αB-crystallin, TIF1γ can freely interact with Smad4. Consequently, Smad4 mono-ubiquitination and nuclear export are favoured and thus TGF-β1-Smad4 pro-fibrotic activity is inhibited. This study demonstrates that αB-crystallin may be a key target for the development of specific drugs in the treatment of IPF or other fibrotic diseases., (Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)
- Published
- 2014
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24. Inhibition of HSP27 blocks fibrosis development and EMT features by promoting Snail degradation.
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Wettstein G, Bellaye PS, Kolb M, Hammann A, Crestani B, Soler P, Marchal-Somme J, Hazoume A, Gauldie J, Gunther A, Micheau O, Gleave M, Camus P, Garrido C, and Bonniaud P
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- Animals, Cadherins metabolism, Cell Line, Epithelial Cells metabolism, Fibrosis metabolism, Humans, Oligonucleotides, Antisense pharmacology, Rats, Rats, Sprague-Dawley, Thionucleotides pharmacology, Transcription Factors metabolism, Epithelial-Mesenchymal Transition drug effects, HSP27 Heat-Shock Proteins antagonists & inhibitors, Snails metabolism, Transforming Growth Factor beta1 metabolism
- Abstract
Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by myofibroblast proliferation. Transition of epithelial/mesothelial cells into myofibroblasts [epithelial-to-mesenchymal transition (EMT)] occurs under the influence of transforming growth factor (TGF)-β1, with Snail being a major transcription factor. We study here the role of the heat-shock protein HSP27 in fibrogenesis and EMT. In vitro, we have up- and down-modulated HSP27 expression in mesothelial and epithelial cell lines and studied the expression of different EMT markers induced by TGF-β1. In vivo, we inhibited HSP27 with the antisense oligonucleotide OGX-427 (in phase II clinical trials as anticancer agent) in our rat subpleural/pulmonary fibrosis models. We demonstrate that HSP27 is strongly expressed during the fibrotic process in patients with IPF and in different in vivo models. We showed that HSP27 binds to and stabilizes Snail and consequently induces EMT. Conversely, HSP27 knockdown leads to Snail proteasomal degradation, thus inhibiting TGF-β1-induced EMT. Inhibition of HSP27 with OGX-427 efficiently blocks EMT and fibrosis development. Controls in vivo were an empty adenovirus that did not induce fibrosis and a control antisense oligonucleotide. The present work opens the possibility of a new therapeutic use for HSP27 inhibitors against IPF, for which there is no conclusively effective treatment.
- Published
- 2013
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25. Nuclear factor erythroid 2-related factor 2 nuclear translocation induces myofibroblastic dedifferentiation in idiopathic pulmonary fibrosis.
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Artaud-Macari E, Goven D, Brayer S, Hamimi A, Besnard V, Marchal-Somme J, Ali ZE, Crestani B, Kerdine-Römer S, Boutten A, and Bonay M
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- Active Transport, Cell Nucleus, Aldehydes metabolism, Animals, Becaplermin, Cells, Cultured, Collagen Type I metabolism, Epoxide Hydrolases metabolism, Gene Knockdown Techniques, Heme Oxygenase-1 metabolism, Humans, Idiopathic Pulmonary Fibrosis metabolism, Isothiocyanates, Lipid Peroxidation, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Myofibroblasts physiology, NAD(P)H Dehydrogenase (Quinone) metabolism, NF-E2-Related Factor 2 genetics, NF-E2-Related Factor 2 physiology, Oxidative Stress, Phenotype, Proto-Oncogene Proteins c-sis physiology, RNA, Small Interfering genetics, Sulfoxides, Thiocyanates pharmacology, Transforming Growth Factor beta physiology, Cell Dedifferentiation, Cell Nucleus metabolism, Idiopathic Pulmonary Fibrosis pathology, Myofibroblasts metabolism, NF-E2-Related Factor 2 metabolism
- Abstract
Aims: Oxidants have been implicated in the pathophysiology of idiopathic pulmonary fibrosis (IPF), especially in myofibroblastic differentiation. We aimed at testing the hypothesis that nuclear factor erythroid 2-related factor 2 (Nrf2), the main regulator of endogenous antioxidant enzymes, is involved in fibrogenesis via myofibroblastic differentiation. Fibroblasts were cultured from the lungs of eight controls and eight IPF patients. Oxidants-antioxidants balance, nuclear Nrf2 expression, and fibroblast phenotype (α-smooth muscle actin and collagen I expression, proliferation, migration, and contraction) were studied under basal conditions and after Nrf2 knockdown or activation by Nrf2 or Keap1 siRNA transfection. The effects of sulforaphane (SFN), an Nrf2 activator, on the fibroblast phenotype were tested under basal and pro-fibrosis conditions (transforming growth factor β [TGF-β])., Results: Decreased Nrf2 expression was associated with a myofibroblast phenotype in IPF compared with control fibroblasts. Nrf2 knockdown induced oxidative stress and myofibroblastic differentiation in control fibroblasts. Conversely, Nrf2 activation increased antioxidant defences and myofibroblastic dedifferentation in IPF fibroblasts. SFN treatment decreased oxidants, and induced Nrf2 expression, antioxidants, and myofibroblastic dedifferentiation in IPF fibroblasts. SFN inhibited TGF-β profibrotic deleterious effects in IPF and control fibroblasts and restored antioxidant defences. Nrf2 knockdown abolished SFN antifibrosis effects, suggesting that they were Nrf2 mediated., Innovation and Conclusion: Our findings confirm that decreased nuclear Nrf2 plays a role in myofibroblastic differentiation and that SFN induces human pulmonary fibroblast dedifferentiation in vitro via Nrf2 activation. Thus, Nrf2 could be a novel therapeutic target in IPF.
- Published
- 2013
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26. Detection of alveolar fibrocytes in idiopathic pulmonary fibrosis and systemic sclerosis.
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Borie R, Quesnel C, Phin S, Debray MP, Marchal-Somme J, Tiev K, Bonay M, Fabre A, Soler P, Dehoux M, and Crestani B
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- Aged, Aged, 80 and over, Bronchoalveolar Lavage, Cell Count, Female, Humans, Idiopathic Pulmonary Fibrosis therapy, Male, Middle Aged, Scleroderma, Systemic therapy, Time Factors, Fibroblasts pathology, Idiopathic Pulmonary Fibrosis pathology, Pulmonary Alveoli pathology, Scleroderma, Systemic pathology
- Abstract
Background: Fibrocytes are circulating precursors for fibroblasts. Blood fibrocytes are increased in patients with idiopathic pulmonary fibrosis (IPF). The aim of this study was to determine whether alveolar fibrocytes are detected in broncho-alveolar lavage (BAL), to identify their prognostic value, and their potential association with culture of fibroblasts from BAL., Methods: We quantified fibrocytes in BAL from 26 patients with IPF, 9 patients with Systemic Sclerosis(SSc)-interstitial lung disease (ILD), and 11 controls. BAL cells were cultured to isolate alveolar fibroblasts., Results: Fibrocytes were detected in BAL in 14/26 IPF (54%) and 5/9 SSc patients (55%), and never in controls. Fibrocytes were in median 2.5% [0.4-19.7] and 3.0% [2.7-3.7] of BAL cells in IPF and SSc-ILD patients respectively. In IPF patients, the number of alveolar fibrocytes was correlated with the number of alveolar macrophages and was associated with a less severe disease but not with a better outcome. Fibroblasts were cultured from BAL in 12/26 IPF (46%), 5/9 SSc-ILD (65%) and never in controls. The detection of BAL fibrocytes did not predict a positive culture of fibroblasts., Conclusion: Fibrocytes were detected in BAL fluid in about half of the patients with IPF and SSc-ILD. Their number was associated with less severe disease in IPF patients and did not associate with the capacity to grow fibroblasts from BAL fluid.
- Published
- 2013
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27. The hedgehog system machinery controls transforming growth factor-β-dependent myofibroblastic differentiation in humans: involvement in idiopathic pulmonary fibrosis.
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Cigna N, Farrokhi Moshai E, Brayer S, Marchal-Somme J, Wémeau-Stervinou L, Fabre A, Mal H, Lesèche G, Dehoux M, Soler P, Crestani B, and Mailleux AA
- Subjects
- Adult, Aged, Aged, 80 and over, Case-Control Studies, Cell Nucleus drug effects, Cell Nucleus metabolism, Cell Proliferation drug effects, Cilia drug effects, Cilia pathology, Female, Gene Expression Regulation drug effects, Hedgehog Proteins genetics, Humans, Idiopathic Pulmonary Fibrosis genetics, Immunohistochemistry, Lung drug effects, Lung metabolism, Lung pathology, Male, Middle Aged, Models, Biological, Myofibroblasts drug effects, Phenotype, RNA, Messenger genetics, RNA, Messenger metabolism, Signal Transduction drug effects, Signal Transduction genetics, Veratrum Alkaloids pharmacology, Cell Differentiation drug effects, Cell Differentiation genetics, Hedgehog Proteins metabolism, Idiopathic Pulmonary Fibrosis metabolism, Idiopathic Pulmonary Fibrosis pathology, Myofibroblasts metabolism, Myofibroblasts pathology, Transforming Growth Factor beta metabolism
- Abstract
Idiopathic pulmonary fibrosis (IPF) is a devastating disease of unknown cause. Key signaling developmental pathways are aberrantly expressed in IPF. The hedgehog pathway plays a key role during fetal lung development and may be involved in lung fibrogenesis. We determined the expression pattern of several Sonic hedgehog (SHH) pathway members in normal and IPF human lung biopsies and primary fibroblasts. The effect of hedgehog pathway inhibition was assayed by lung fibroblast proliferation and differentiation with and without transforming growth factor (TGF)-β1. We showed that the hedgehog pathway was reactivated in the IPF lung. Importantly, we deciphered the cross talk between the hedgehog and TGF-β pathway in human lung fibroblasts. TGF-β1 modulated the expression of key components of the hedgehog pathway independent of Smoothened, the obligatory signal transducer of the pathway. Smoothened was required for TGF-β1-induced myofibroblastic differentiation of control fibroblasts, but differentiation of IPF fibroblasts was partially resistant to Smoothened inhibition. Furthermore, functional hedgehog pathway machinery from the primary cilium, as well as GLI-dependent transcription in the nucleus, was required for the TGF-β1 effects on normal and IPF fibroblasts during myofibroblastic differentiation. These data identify the GLI transcription factors as potential therapeutic targets in lung fibrosis., (Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2012
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28. Alveolar fibroblasts in acute lung injury: biological behaviour and clinical relevance.
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Quesnel C, Nardelli L, Piednoir P, Leçon V, Marchal-Somme J, Lasocki S, Bouadma L, Philip I, Soler P, Crestani B, and Dehoux M
- Subjects
- Acute Lung Injury physiopathology, Adult, Aged, Biomarkers metabolism, Cell Division physiology, Cell Movement physiology, Cells, Cultured, Chemokine CCL2 metabolism, Collagen Type I metabolism, Female, Fetal Proteins metabolism, Fibroblasts metabolism, Humans, Interleukin-8 metabolism, Male, Middle Aged, Peptide Fragments, Procollagen, Respiratory Distress Syndrome physiopathology, Transforming Growth Factor beta1 metabolism, Acute Lung Injury pathology, Bronchoalveolar Lavage Fluid cytology, Fibroblasts pathology, Pulmonary Alveoli pathology, Respiratory Distress Syndrome pathology
- Abstract
Although fibroblasts are key cells in the lung repair/fibrosis process, their characteristics are poorly studied in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). The aims of our study were to: 1) determine the biological behaviour of alveolar fibroblasts during ALI; and 2) to evaluate the clinical relevance of positive alveolar fibroblast culture from patients with ALI/ARDS. Cells were cultured from bronchoalveolar lavage (BAL) obtained from 68 critically ill, ventilated patients: ALI n = 17; ARDS n = 31; and ventilated controls n = 20. Patients were followed for 28 days and clinical data was recorded. We studied proliferation, migration and collagen-1 synthesis capacities of fibroblasts. Cells expressing fibroblast markers were cultured from BAL obtained in six (35%) ALI patients and six (19%) ARDS patients, but never from ventilated controls. Alveolar fibroblasts exhibited a persistent activated phenotype with enhanced migratory and collagen-1 production capacities, with hyporesponsiveness to prostaglandin E(2) compared to normal lung fibroblasts (p< or =0.04). Positive fibroblast culture was associated with both an increased collagen-1 concentration and monocyte/macrophage percentage in BAL fluid (p< or =0.01), and with a reduced duration of mechanical ventilation (p<0.001). We conclude that activated alveolar fibroblasts can be cultured either in ALI or ARDS and that their presence might reflect the initiation of the organising phase of ALI.
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- 2010
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29. Imbalance in the pro-hepatocyte growth factor activation system in bleomycin-induced lung fibrosis in mice.
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Phin S, Marchand-Adam S, Fabre A, Marchal-Somme J, Bantsimba-Malanda C, Kataoka H, Soler P, and Crestani B
- Subjects
- Animals, Antibodies, Neutralizing immunology, Bronchoalveolar Lavage Fluid, Cell Line, Epithelial Cells metabolism, Gene Expression Regulation, Humans, Lung metabolism, Lung pathology, Membrane Glycoproteins genetics, Membrane Glycoproteins immunology, Membrane Glycoproteins metabolism, Mice, Mice, Inbred C57BL, Phosphorylation, Proteinase Inhibitory Proteins, Secretory, Proto-Oncogene Proteins c-met metabolism, Pulmonary Alveoli metabolism, Pulmonary Alveoli pathology, Pulmonary Fibrosis pathology, Serine Endopeptidases genetics, Serine Endopeptidases immunology, Serine Endopeptidases metabolism, Bleomycin, Hepatocyte Growth Factor metabolism, Protein Precursors metabolism, Pulmonary Fibrosis chemically induced, Pulmonary Fibrosis metabolism
- Abstract
Hepatocyte growth factor (HGF) is a growth factor for alveolar epithelial cells. Activation of pro-HGF to HGF is regulated by the HGF activator (HGFA), a serine protease, and a specific inhibitor (HGFA inhibitor-1, HAI-1). An imbalance in the HGFA/HAI-1 system might contribute to lung fibrosis. Pro-HGF activation capacity from bronchoalveolar lavage (BAL) fluid was evaluated 3, 7, and 14 days after the intratracheal bleomycin injection (Bleo) in mice with or without thrombin. BAL fluid from naïve mice was used as control. HGFA and HAI-1 mRNA were evaluated by QPCR in the whole lung or by Western blot in BAL fluid. BAL fluid from control mice and Bleo mice activated pro-HGF in vitro at a similar degree. Thrombin accelerated proHGF activation by Bleo BAL on Day 3 and Day 7, but not on Day 14, or in control BAL. Incubation of pro-HGF with BAL from Bleo Day 3 and Day 7 mice increased phosphorylation of HGFR on A549 cells. Thrombin-induced pro-HGF activation was inhibited by an anti-HGFA antibody and accelerated by an anti-HAI-1 antibody. Active HGFA was not detected in control BAL and was strongly induced in Bleo BAL. HGFA concentrations were higher on Day 3 and Day 7 than on Day 14. HAI-1 was detected at low levels in control BAL and increased strongly by Day 3 with stable concentrations until Day 14. By demonstrating an imbalance between HGFA and HAI-1 expression in BAL fluid, our results highlight a defective thrombin-dependent proHGF activation system at the fibrotic phase of bleomycin-induced pulmonary fibrosis.
- Published
- 2010
- Full Text
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30. Non-invasive molecular imaging of fibrosis using a collagen-targeted peptidomimetic of the platelet collagen receptor glycoprotein VI.
- Author
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Muzard J, Sarda-Mantel L, Loyau S, Meulemans A, Louedec L, Bantsimba-Malanda C, Hervatin F, Marchal-Somme J, Michel JB, Le Guludec D, Billiald P, and Jandrot-Perrus M
- Subjects
- Animals, Aorta metabolism, Blotting, Western, Fibrosis metabolism, In Vitro Techniques, Peptides chemical synthesis, Rats, Tail metabolism, Diagnostic Imaging methods, Fibrosis pathology, Peptides chemistry, Peptides metabolism, Platelet Membrane Glycoproteins chemistry, Radionuclide Imaging methods
- Abstract
Background: Fibrosis, which is characterized by the pathological accumulation of collagen, is recognized as an important feature of many chronic diseases, and as such, constitutes an enormous health burden. We need non-invasive specific methods for the early diagnosis and follow-up of fibrosis in various disorders. Collagen targeting molecules are therefore of interest for potential in vivo imaging of fibrosis. In this study, we developed a collagen-specific probe using a new approach that takes advantage of the inherent specificity of Glycoprotein VI (GPVI), the main platelet receptor for collagens I and III., Methodology/principal Findings: An anti-GPVI antibody that neutralizes collagen-binding was used to screen a bacterial random peptide library. A cyclic motif was identified, and the corresponding peptide (designated collagelin) was synthesized. Solid-phase binding assays and histochemical analysis showed that collagelin specifically bound to collagen (Kd 10(-7) M) in vitro, and labelled collagen fibers ex vivo on sections of rat aorta and rat tail. Collagelin is therefore a new specific probe for collagen. The suitability of collagelin as an in vivo probe was tested in a rat model of healed myocardial infarctions (MI). Injecting Tc-99m-labelled collagelin and scintigraphic imaging showed that uptake of the probe occurred in the cardiac area of rats with MI, but not in controls. Post mortem autoradiography and histological analysis of heart sections showed that the labeled areas coincided with fibrosis. Scintigraphic molecular imaging with collagelin provides high resolution, and good contrast between the fibrotic scars and healthy tissues. The capacity of collagelin to image fibrosis in vivo was confirmed in a mouse model of lung fibrosis., Conclusion/significance: Collagelin is a new collagen-targeting agent which may be useful for non-invasive detection of fibrosis in a broad spectrum of diseases.
- Published
- 2009
- Full Text
- View/download PDF
31. Regulation of hepatocyte growth factor secretion by fibroblasts in patients with acute lung injury.
- Author
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Quesnel C, Marchand-Adam S, Fabre A, Marchal-Somme J, Philip I, Lasocki S, Leçon V, Crestani B, and Dehoux M
- Subjects
- Antibodies pharmacology, Bronchoalveolar Lavage Fluid cytology, Cell Line, Cyclooxygenase 2 genetics, Cyclooxygenase 2 metabolism, Cyclooxygenase 2 Inhibitors pharmacology, Dinoprostone metabolism, Female, Fibroblast Growth Factor 7 genetics, Fibroblast Growth Factor 7 metabolism, Fibroblasts drug effects, Fibroblasts enzymology, Gene Expression Regulation drug effects, Hepatocyte Growth Factor genetics, Humans, Interleukin 1 Receptor Antagonist Protein metabolism, Interleukin-1beta metabolism, Male, Middle Aged, RNA, Messenger genetics, RNA, Messenger metabolism, Respiratory Distress Syndrome enzymology, Fibroblasts metabolism, Hepatocyte Growth Factor metabolism, Respiratory Distress Syndrome metabolism, Respiratory Distress Syndrome pathology
- Abstract
The mechanisms of pulmonary repair in acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are poorly known. Hepatocyte growth factor (HGF) and keratinocyte growth factor (KGF) are key factors involved in alveolar epithelial repair, present in the bronchoalveolar lavage fluid (BALF) from patients with ALI/ARDS. The role of BALF mediators in their production remains to be determined. We evaluated the overall effect of BALF from 52 patients (27 ventilated patients with ALI/ARDS, 10 ventilated patients without ALI, and 15 nonventilated control patients) on HGF and KGF synthesis by lung fibroblasts. Fibroblasts were cultured in the presence of BALF. HGF and KGF protein secretion was measured using ELISA, and mRNA expression was evaluated using quantitative real-time RT-PCR. Only BALF from ALI/ARDS patients upregulated both HGF and KGF mRNA expression and protein synthesis (+271 and +146% for HGF and KGF, respectively). BALF-induced HGF synthesis from ALI/ARDS patients was higher than that from ventilated patients without ALI (P < 0.05). HGF secretion was correlated with BALF IL-1beta levels (rho = 0.62, P < 0.001) and BALF IL-1beta/IL-1 receptor antagonist ratio (rho = 0.54, P < 0.007) in the ALI/ARDS group. An anti-IL-1beta antibody partially (>50%) inhibited the BALF-induced HGF and PGE(2) secretion, whereas NS-398, a specific cyclooxygenase-2 (COX-2) inhibitor, completely inhibited it. Anti-IL-1beta antibodies as well as NS-398 reversed the COX-2 upregulation induced by BALF. Therefore, IL-1beta is a main BALF mediator involved in HGF secretion, which is mediated through a PGE(2)/COX-2-dependent mechanism. BALF mediators may participate in vivo in the production of HGF and KGF by lung fibroblasts during ALI/ARDS.
- Published
- 2008
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32. Three-dimensional investigation and scoring of extracellular matrix remodeling during lung fibrosis using multiphoton microscopy.
- Author
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Pena AM, Fabre A, Débarre D, Marchal-Somme J, Crestani B, Martin JL, Beaurepaire E, and Schanne-Klein MC
- Subjects
- Animals, Bleomycin, Humans, Macrophages, Alveolar pathology, Male, Mice, Mice, Inbred C57BL, Pleura pathology, Pulmonary Fibrosis chemically induced, Collagen ultrastructure, Extracellular Matrix ultrastructure, Lung pathology, Microscopy, Fluorescence, Multiphoton methods, Pulmonary Fibrosis pathology
- Abstract
The organization of collagen during fibrotic processes is poorly characterized because of the lack of appropriate methodologies. Here we show that multimodal multiphoton microscopy provides novel insights into lung fibrosis. We characterize normal and fibrotic pulmonary tissue in the bleomycin model, and show that second-harmonic generation by fibrillar collagen reveals the micrometer-scale three-dimensional spatial distribution of the fibrosis. We find that combined two-photon excited fluorescence and second-harmonic imaging of unstained lung tissue allows separating the inflammatory and fibrotic steps in this pathology, underlining characteristic features of fibroblastic foci in human Idiopathic Pulmonary Fibrosis samples. Finally, we propose phenomenological scores of lung fibrosis and we show that they unambiguously sort out control and treated mice, with a better sensitivity and reproducibility in the subpleural region. These results should be readily generalized to other organs, as an accurate method to assess extracellular matrix remodeling during fibrosis.
- Published
- 2007
- Full Text
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33. HGF synthesis in human lung fibroblasts is regulated by oncostatin M.
- Author
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Cohen M, Marchand-Adam S, Lecon-Malas V, Marchal-Somme J, Boutten A, Durand G, Crestani B, and Dehoux M
- Subjects
- Cell Line, Cells, Cultured, Cycloheximide pharmacology, Hepatocyte Growth Factor genetics, Humans, Imidazoles pharmacology, Lung cytology, Oncostatin M, Protein Synthesis Inhibitors pharmacology, Pyridines pharmacology, RNA, Messenger genetics, Wound Healing, Cytokines pharmacology, Fibroblasts physiology, Hepatocyte Growth Factor biosynthesis, Lung physiology
- Abstract
Oncostatin M (OSM) is a IL-6 family cytokine locally produced in acute lung injury. Its profibrotic properties suggest a role in lung wound repair. Hepatocyte growth factor (HGF), produced by fibroblasts, is involved in pulmonary epithelial repair. We investigated the role of OSM in HGF synthesis by human lung fibroblasts. We showed that OSM upregulated HGF mRNA in MRC5 cells and in human lung fibroblasts, whereas IL-6 and leukemia inhibitory factor did not. OSM induced HGF secretion to a similar extent as IL-1beta in both a time- and dose-dependent manner. HGF was released in its cleaved mature form, and its secretion was completely inhibited in the presence of cycloheximide, indicating a de novo protein synthesis. OSM in combination with prostaglandin E(2), a powerful HGF inductor, led to an additive effect. OSM and indomethacin in combination further increased HGF secretion. This could be explained, at least in part, by a moderate upregulation of specific OSM receptor beta mRNA expression through cyclooxygenase inhibition. These results demonstrate that OSM-induced HGF synthesis did not involve a PGE(2) pathway. OSM-induced HGF secretion was inhibited by PD-98059 (a specific pharmacological inhibitor of ERK1/2), SB-203580 (a p38 MAPK inhibitor), and SP-600125 (a JNK inhibitor) by 70, 82, and 100%, respectively, whereas basal HGF secretion was only inhibited by SP-600125 by 30%. Our results demonstrate a specific upregulation of HGF synthesis by OSM, most likely through a MAPK pathway, and support the suggestion that OSM may participate in lung repair through HGF production.
- Published
- 2006
- Full Text
- View/download PDF
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