Inhibition of myocardin-related transcription factor/serum response factor signaling decreases lung fibrosis and promotes mesenchymal cell apoptosis

American Journal of Pathology

Volumn 185, Issue 4, 2015, Pages 969-986

  Sisson, Thomas H ^a   Ajayi, Iyabode O ^a   Subbotina, Natalya ^a   Dodi, Amos E ^a   Rodansky, Eva S ^a   Chibucos, Lauren N ^a   Kim, Kevin K ^a   Keshamouni, Venkateshwar G ^a   White, Eric S ^a   Zhou, Yong ^c   Higgins, Peter D R ^a   Larsen, Scott D ^b   Neubig, Richard R ^d   Horowitz, Jeffrey C ^a  

^a UNIVERSITY OF MICHIGAN MEDICAL SCHOOL   (United States)

^b UNIVERSITY OF MICHIGAN   (United States)

^c University of Alabama at Birmingham   (United States)

^d MICHIGAN STATE UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BLEOMYCIN; CASPASE 3; CASPASE 7; COLLAGEN; FIBRONECTIN; INHIBITOR OF APOPTOSIS PROTEIN; MYOCARDIN RELATED TRANSCRIPTION FACTOR; PLASMINOGEN ACTIVATOR INHIBITOR 1; SERUM RESPONSE FACTOR; SURVIVIN; TRANSCRIPTION FACTOR; TRANSFORMING GROWTH FACTOR BETA1; UNCLASSIFIED DRUG; X LINKED INHIBITOR OF APOPTOSIS; FAS ANTIGEN; FAS PROTEIN, HUMAN; MKL1 PROTEIN, HUMAN; MKL1 PROTEIN, MOUSE; N-(4-CHLOROPHENYL)-1-((3-(FURAN-2-YL)PHENYL)CARBONYL)PIPERIDINE-3-CARBOXAMIDE; NIPECOTIC ACID DERIVATIVE; TRANSACTIVATOR PROTEIN;

ACUTE LUNG INJURY; ADULT; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; APOPTOSIS; ARTICLE; CELL DIFFERENTIATION; CELL SURVIVAL; COLLAGEN SYNTHESIS; COMPARATIVE STUDY; CONTROLLED STUDY; ENZYME ACTIVATION; ENZYME LINKED IMMUNOSORBENT ASSAY; EXTRACELLULAR MATRIX; FETUS; HUMAN; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; LUNG FIBROBLAST; LUNG FIBROSIS; LUNG LAVAGE; MESENCHYME CELL; MOUSE; MYOFIBROBLAST; NICK END LABELING; NONHUMAN; PHENOTYPE; POLYACRYLAMIDE GEL ELECTROPHORESIS; PRIORITY JOURNAL; SIGNAL TRANSDUCTION; UPREGULATION; WEIGHT REDUCTION; WESTERN BLOTTING; ANIMAL; C57BL MOUSE; CELL NUCLEUS; CELL PROTECTION; DRUG EFFECTS; FIBROSIS; INFLAMMATION; LUNG; LUNG ALVEOLUS CELL; MESODERM; METABOLISM; PATHOLOGY; PIG; PROTEIN TRANSPORT;

ADULT; ANIMALS; ANTIGENS, CD95; APOPTOSIS; CELL DIFFERENTIATION; CELL NUCLEUS; CYTOPROTECTION; FIBRONECTINS; FIBROSIS; HUMANS; INFLAMMATION; LUNG; MESODERM; MICE, INBRED C57BL; MYOFIBROBLASTS; NIPECOTIC ACIDS; PLASMINOGEN ACTIVATOR INHIBITOR 1; PNEUMOCYTES; PROTEIN TRANSPORT; SERUM RESPONSE FACTOR; SIGNAL TRANSDUCTION; SUS SCROFA; TRANS-ACTIVATORS; TRANSFORMING GROWTH FACTOR BETA1; X-LINKED INHIBITOR OF APOPTOSIS PROTEIN;

EID: 84925293244     PISSN: 00029440     EISSN: 15252191     Source Type: Journal    
DOI: 10.1016/j.ajpath.2014.12.005     Document Type: Article

References (69)

1. G. Raghu, S.Y. Chen, W.S. Yeh, B. Maroni, Q. Li, Y.C. Lee, and H.R. Collard Idiopathic pulmonary fibrosis in US Medicare beneficiaries aged 65 years and older: incidence, prevalence, and survival, 2001-11 [erratum in: Lancet Respir Med 2014;2:e12] Lancet Respir Med 2 2014 566 572
2. G. Raghu, H.R. Collard, J.J. Egan, F.J. Martinez, J. Behr, K.K. Brown, T.V. Colby, J.F. Cordier, K.R. Flaherty, J.A. Lasky, D.A. Lynch, J.H. Ryu, J.J. Swigris, A.U. Wells, J. Ancochea, D. Bouros, C. Carvalho, U. Costabel, M. Ebina, D.M. Hansell, T. Johkoh, D.S. Kim, T.E. King Jr., Y. Kondoh, J. Myers, N.L. Müller, A.G. Nicholson, L. Richeldi, M. Selman, R.F. Dudden, B.S. Griss, S.L. Protzko, and H.J. Schünemann ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis: An official Ats/Ers/Jrs/Alat statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management Am J Respir Crit Care Med 183 2011 788 824
3. V.J. Thannickal, C.A. Henke, J.C. Horowitz, P.W. Noble, J. Roman, P.J. Sime, Y. Zhou, R.G. Wells, E.S. White, and D.J. Tschumperlin Matrix biology of idiopathic pulmonary fibrosis: a workshop report of the National Heart, Lung, and Blood Institute Am J Pathol 184 2014 1643 1651
4. B. Hinz, S.H. Phan, V.J. Thannickal, M. Prunotto, A. Desmoulière, J. Varga, O. De Wever, M. Mareel, and G. Gabbiani Recent developments in myofibroblast biology: paradigms for connective tissue remodeling Am J Pathol 180 2012 1340 1355
5. L. Follonier, S. Schaub, J.J. Meister, and B. Hinz Myofibroblast communication is controlled by intercellular mechanical coupling J Cell Sci 121 2008 3305 3316
6. B. Hinz, G. Celetta, J.J. Tomasek, G. Gabbiani, and C. Chaponnier Alpha-smooth muscle actin expression upregulates fibroblast contractile activity Mol Biol Cell 12 2001 2730 2741
7. J.J. Tomasek, G. Gabbiani, B. Hinz, C. Chaponnier, and R.A. Brown Myofibroblasts and mechano-regulation of connective tissue remodelling Nat Rev Mol Cell Biol 3 2002 349 363
8. P.J. Wipff, D.B. Rifkin, J.J. Meister, and B. Hinz Myofibroblast contraction activates latent TGF-beta1 from the extracellular matrix J Cell Biol 179 2007 1311 1323
9. P.S. Tsou, A.J. Haak, D. Khanna, and R.R. Neubig Cellular mechanisms of tissue fibrosis. 8. Current and future drug targets in fibrosis: focus on rho GTPase-regulated gene transcription Am J Physiol Cell Physiol 307 2014 C2 C13
10. F. Liu, J.D. Mih, B.S. Shea, A.T. Kho, A.S. Sharif, A.M. Tager, and D.J. Tschumperlin Feedback amplification of fibrosis through matrix stiffening and COX-2 suppression J Cell Biol 190 2010 693 706
11. N. Sandbo, C. Ngam, E. Torr, S. Kregel, J. Kach, and N. Dulin Control of myofibroblast differentiation by microtubule dynamics through a regulated localization of mDia2 J Biol Chem 288 2013 15466 15473
12. J.J. Tomasek, M.B. Vaughan, B.P. Kropp, G. Gabbiani, M.D. Martin, C.J. Haaksma, and B. Hinz Contraction of myofibroblasts in granulation tissue is dependent on rho/rho kinase/myosin light chain phosphatase activity Wound Repair Regen 14 2006 313 320
13. Y. Zhou, X. Huang, L. Hecker, D. Kurundkar, A. Kurundkar, H. Liu, T.H. Jin, L. Desai, K. Bernard, and V.J. Thannickal Inhibition of mechanosensitive signaling in myofibroblasts ameliorates experimental pulmonary fibrosis J Clin Invest 123 2013 1096 1108
14. N. Sandbo, and N. Dulin Actin cytoskeleton in myofibroblast differentiation: ultrastructure defining form and driving function Transl Res 158 2011 181 196
15. N. Sandbo, A. Lau, J. Kach, C. Ngam, D. Yau, and N.O. Dulin Delayed stress fiber formation mediates pulmonary myofibroblast differentiation in response to TGF-beta Am J Physiol Lung Cell Mol Physiol 301 2011 L656 L666
16. L.A. Johnson, E.S. Rodansky, A.J. Haak, S.D. Larsen, R.R. Neubig, and P.D. Higgins Novel Rho/MRTF/SRF inhibitors block matrix-stiffness and TGF-beta-induced fibrogenesis in human colonic myofibroblasts Inflamm Bowel Dis 20 2014 154 165
17. E.M. Small The actin-MRTF-SRF gene regulatory axis and myofibroblast differentiation J Cardiovasc Transl Res 5 2012 794 804
18. M.A. Scharenberg, B.E. Pippenger, R. Sack, D. Zingg, J. Ferralli, S. Schenk, I. Martin, and R. Chiquet-Ehrismann TGF-beta-induced differentiation into myofibroblasts involves specific regulation of two MKL1 isoforms J Cell Sci 127 2014 1079 1091
19. X. Huang, N. Yang, V.F. Fiore, T.H. Barker, Y. Sun, S.W. Morris, Q. Ding, V.J. Thannickal, and Y. Zhou Matrix stiffness-induced myofibroblast differentiation is mediated by intrinsic mechanotransduction Am J Respir Cell Mol Biol 47 2012 340 348
20. A.J. Haak, P.S. Tsou, M.A. Amin, J.H. Ruth, P. Campbell, D.A. Fox, D. Khanna, S.D. Larsen, and R.R. Neubig Targeting the myofibroblast genetic switch: inhibitors of myocardin-related transcription factor/serum response factor-regulated gene transcription prevent fibrosis in a murine model of skin injury J Pharmacol Exp Ther 349 2014 480 486
21. J.L. Bell, A.J. Haak, S.M. Wade, P.D. Kirchhoff, R.R. Neubig, and S.D. Larsen Optimization of novel nipecotic bis(amide) inhibitors of the Rho/MKL1/SRF transcriptional pathway as potential anti-metastasis agents Bioorg Med Chem Lett 23 2013 3826 3832
22. C.R. Evelyn, S.M. Wade, Q. Wang, M. Wu, J.A. Iñiguez-Lluhí, S.D. Merajver, and R.R. Neubig CCG-1423: a small-molecule inhibitor of RhoA transcriptional signaling Mol Cancer Ther 6 2007 2249 2260
23. K. Hayashi, B. Watanabe, Y. Nakagawa, S. Minami, and T. Morita RPEL proteins are the molecular targets for CCG-1423, an inhibitor of Rho signaling PLoS One 9 2014 e89016
24. J.C. Horowitz, I.O. Ajayi, P. Kulasekaran, D.S. Rogers, J.B. White, S.K. Townsend, E.S. White, R.S. Nho, P.D. Higgins, S.K. Huang, and T.H. Sisson Survivin expression induced by endothelin-1 promotes myofibroblast resistance to apoptosis Int J Biochem Cell Biol 44 2012 158 169
25. L.A. Johnson, E.S. Rodansky, K.L. Sauder, J.C. Horowitz, J.D. Mih, D.J. Tschumperlin, and P.D. Higgins Matrix stiffness corresponding to strictured bowel induces a fibrogenic response in human colonic fibroblasts Inflamm Bowel Dis 19 2013 891 903
26. J.J. Osterholzer, P.J. Christensen, V. Lama, J.C. Horowitz, N. Hattori, N. Subbotina, A. Cunningham, Y. Lin, B.J. Murdock, R.E. Morey, M.A. Olszewski, D.A. Lawrence, R.H. Simon, and T.H. Sisson PAI-1 promotes the accumulation of exudate macrophages and worsens pulmonary fibrosis following type II alveolar epithelial cell injury J Pathol 228 2012 170 180
27. J. Yang, M. Velikoff, E. Canalis, J.C. Horowitz, and K.K. Kim Activated alveolar epithelial cells initiate fibrosis through autocrine and paracrine secretion of connective tissue growth factor Am J Physiol Lung Cell Mol Physiol 306 2014 L786 L796
28. T.H. Sisson, M. Mendez, K. Choi, N. Subbotina, A. Courey, A. Cunningham, A. Dave, J.F. Engelhardt, X. Liu, E.S. White, V.J. Thannickal, B.B. Moore, P.J. Christensen, and R.H. Simon Targeted injury of type II alveolar epithelial cells induces pulmonary fibrosis Am J Respir Crit Care Med 181 2010 254 263
29. A.K. Reka, H. Kurapati, V.R. Narala, G. Bommer, J. Chen, T.J. Standiford, and V.G. Keshamouni Peroxisome proliferator-activated receptor-gamma activation inhibits tumor metastasis by antagonizing Smad3-mediated epithelial-mesenchymal transition Mol Cancer Ther 9 2010 3221 3232
30. A.J. Courey, J.C. Horowitz, K.K. Kim, T.J. Koh, M.L. Novak, N. Subbotina, M. Warnock, B. Xue, A.K. Cunningham, Y. Lin, M.P. Goldklang, R.H. Simon, D.A. Lawrence, and T.H. Sisson The vitronectin-binding function of PAI-1 exacerbates lung fibrosis in mice Blood 118 2011 2313 2321
31. L.R. Penke, S.K. Huang, E.S. White, and M. Peters-Golden Prostaglandin E2 inhibits alpha-smooth muscle actin transcription during myofibroblast differentiation via distinct mechanisms of modulation of serum response factor and myocardin-related transcription factor-A J Biol Chem 289 2014 17151 17162
32. I.I. Singer, D.W. Kawka, D.M. Kazazis, and R.A. Clark In vivo co-distribution of fibronectin and actin fibers in granulation tissue: immunofluorescence and electron microscope studies of the fibronexus at the myofibroblast surface J Cell Biol 98 1984 2091 2106
33. L. Hecker, N.J. Logsdon, D. Kurundkar, A. Kurundkar, K. Bernard, T. Hock, E. Meldrum, Y.Y. Sanders, and V.J. Thannickal Reversal of persistent fibrosis in aging by targeting Nox4-Nrf2 redox imbalance Sci Transl Med 6 2014 231ra47
34. L. Hecker, R. Vittal, T. Jones, R. Jagirdar, T.R. Luckhardt, J.C. Horowitz, S. Pennathur, F.J. Martinez, and V.J. Thannickal NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury Nat Med 15 2009 1077 1081
35. R. Vittal, J.C. Horowitz, B.B. Moore, H. Zhang, F.J. Martinez, G.B. Toews, T.J. Standiford, and V.J. Thannickal Modulation of prosurvival signaling in fibroblasts by a protein kinase inhibitor protects against fibrotic tissue injury Am J Pathol 166 2005 367 375
36. I.O. Ajayi, T.H. Sisson, P.D. Higgins, A.J. Booth, R.L. Sagana, S.K. Huang, E.S. White, J.E. King, B.B. Moore, and J.C. Horowitz X-linked inhibitor of apoptosis regulates lung fibroblast resistance to Fas-mediated apoptosis Am J Respir Cell Mol Biol 49 2013 86 95
37. T.S. Blackwell, A.M. Tager, Z. Borok, B.B. Moore, D.A. Schwartz, and K.J. Anstrom Future directions in idiopathic pulmonary fibrosis research. An NHLBI workshop report Am J Respir Crit Care Med 189 2014 214 222
38. J.C. Horowitz, D.Y. Lee, M. Waghray, V.G. Keshamouni, P.E. Thomas, H. Zhang, Z. Cui, and V.J. Thannickal Activation of the pro-survival phosphatidylinositol 3-kinase/AKT pathway by transforming growth factor-beta1 in mesenchymal cells is mediated by p38 MAPK-dependent induction of an autocrine growth factor J Biol Chem 279 2004 1359 1367
39. J.C. Horowitz, D.S. Rogers, V. Sharma, R. Vittal, E.S. White, Z. Cui, and V.J. Thannickal Combinatorial activation of FAK and AKT by transforming growth factor-beta1 confers an anoikis-resistant phenotype to myofibroblasts Cell Signal 19 2007 761 771
40. J.C. Horowitz, D.S. Rogers, R.H. Simon, T.H. Sisson, and V.J. Thannickal Plasminogen activation induced pericellular fibronectin proteolysis promotes fibroblast apoptosis Am J Respir Cell Mol Biol 38 2008 78 87
41. T.H. Sisson, T.M. Maher, I.O. Ajayi, J.E. King, P.D. Higgins, A.J. Booth, R.L. Sagana, S.K. Huang, E.S. White, B.B. Moore, and J.C. Horowitz Increased survivin expression contributes to apoptosis-resistance in IPF fibroblasts Adv Biosci Biotechnol 3 2012 657 664
42. D.J. Elzi, M. Song, K. Hakala, S.T. Weintraub, and Y. Shiio Wnt antagonist SFRP1 functions as a secreted mediator of senescence Mol Cell Biol 32 2012 4388 4399
43. J. Li, J.M. Lee, and J.A. Johnson Microarray analysis reveals an antioxidant responsive element-driven gene set involved in conferring protection from an oxidative stress-induced apoptosis in IMR-32 cells J Biol Chem 277 2002 388 394
44. S.H. Phan Biology of fibroblasts and myofibroblasts Proc Am Thorac Soc 5 2008 334 337
45. V.J. Thannickal, and J.C. Horowitz Evolving concepts of apoptosis in idiopathic pulmonary fibrosis Proc Am Thorac Soc 3 2006 350 356
46. G. Serini, M.L. Bochaton-Piallat, P. Ropraz, A. Geinoz, L. Borsi, L. Zardi, and G. Gabbiani The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growth factor-beta1 J Cell Biol 142 1998 873 881
47. V.J. Thannickal, and J. Roman Challenges in translating preclinical studies to effective drug therapies in idiopathic pulmonary fibrosis Am J Respir Crit Care Med 181 2010 532 533
48. J. Kach, N. Sandbo, J. La, D. Denner, E.B. Reed, O. Akimova, S. Koltsova, S.N. Orlov, and N.O. Dulin Antifibrotic effects of noscapine through activation of prostaglandin E2 receptors and protein kinase A J Biol Chem 289 2014 7505 7513
49. E.M. Small, J.E. Thatcher, L.B. Sutherland, H. Kinoshita, R.D. Gerard, J.A. Richardson, J.M. Dimaio, H. Sadek, K. Kuwahara, and E.N. Olson Myocardin-related transcription factor-a controls myofibroblast activation and fibrosis in response to myocardial infarction Circ Res 107 2010 294 304
50. H. Xu, X. Wu, H. Qin, W. Tian, J. Chen, L. Sun, M. Fang, and Y. Xu Myocardin-related transcription factor A epigenetically regulates renal fibrosis in diabetic nephropathy J Am Soc Nephrol 2014 2014, [Epub ahead of print] doi: 10.1681/ASN.2014070678
51. S.K. Huang, A.M. Scruggs, J. Donaghy, J.C. Horowitz, Z. Zaslona, S. Przybranowski, E.S. White, and M. Peters-Golden Histone modifications are responsible for decreased Fas expression and apoptosis resistance in fibrotic lung fibroblasts Cell Death Dis 4 2013 e621
52. M.W. Wynes, B.L. Edelman, A.G. Kostyk, M.G. Edwards, C. Coldren, S.D. Groshong, G.P. Cosgrove, E.F. Redente, A. Bamberg, K.K. Brown, N. Reisdorph, R.C. Keith, S.K. Frankel, and D.W. Riches Increased cell surface Fas expression is necessary and sufficient to sensitize lung fibroblasts to Fas ligation-induced apoptosis: implications for fibroblast accumulation in idiopathic pulmonary fibrosis J Immunol 187 2011 527 537
53. Q. Ding, G.Q. Cai, M. Hu, Y. Yang, A. Zheng, Q. Tang, C.L. Gladson, H. Hayasaka, H. Wu, Z. You, B.D. Southern, L.M. Grove, S.O. Rahaman, H. Fang, and M.A. Olman FAK-related nonkinase is a multifunctional negative regulator of pulmonary fibrosis Am J Pathol 182 2013 1572 1584
54. H.R. Kang, C.G. Lee, R.J. Homer, and J.A. Elias Semaphorin 7A plays a critical role in TGF-beta1-induced pulmonary fibrosis J Exp Med 204 2007 1083 1093
55. K. Kinoshita, Y. Aono, M. Azuma, J. Kishi, A. Takezaki, M. Kishi, H. Makino, H. Okazaki, H. Uehara, K. Izumi, S. Sone, and Y. Nishioka Antifibrotic effects of focal adhesion kinase inhibitor in bleomycin-induced pulmonary fibrosis in mice Am J Respir Cell Mol Biol 49 2013 536 543
56. D. Lagares, O. Busnadiego, R.A. García-Fernández, M. Kapoor, S. Liu, D.E. Carter, D. Abraham, X. Shi-Wen, P. Carreira, B.A. Fontaine, B.S. Shea, A.M. Tager, A. Leask, S. Lamas, and F. Rodríguez-Pascual Inhibition of focal adhesion kinase prevents experimental lung fibrosis and myofibroblast formation Arthritis Rheum 64 2012 1653 1664
57. D. Lagares, O. Busnadiego, R.A. García-Fernández, S. Lamas, and F. Rodríguez-Pascual Adenoviral gene transfer of endothelin-1 in the lung induces pulmonary fibrosis through the activation of focal adhesion kinase Am J Respir Cell Mol Biol 47 2012 834 842
58. T.D. Le Cras, T.R. Korfhagen, C. Davidson, S. Schmidt, M. Fenchel, M. Ikegami, J.A. Whitsett, and W.D. Hardie Inhibition of PI3K by PX-866 prevents transforming growth factor-alpha-induced pulmonary fibrosis Am J Pathol 176 2010 679 686
59. S.K. Huang, E.S. White, S.H. Wettlaufer, H. Grifka, C.M. Hogaboam, V.J. Thannickal, J.C. Horowitz, and M. Peters-Golden Prostaglandin E(2) induces fibroblast apoptosis by modulating multiple survival pathways FASEB J 23 2009 4317 4326
60. T.M. Maher, I.C. Evans, S.E. Bottoms, P.F. Mercer, A.J. Thorley, A.G. Nicholson, G.J. Laurent, T.D. Tetley, R.C. Chambers, and R.J. McAnulty Diminished prostaglandin E2 contributes to the apoptosis paradox in idiopathic pulmonary fibrosis Am J Respir Crit Care Med 182 2010 73 82
61. M. Gyrd-Hansen, and P. Meier IAPs: from caspase inhibitors to modulators of NF-kappaB, inflammation and cancer Nat Rev Cancer 10 2010 561 574
62. T.H. Sisson, and R.H. Simon The plasminogen activation system in lung disease Curr Drug Targets 8 2007 1016 1029
63. W. Chang, K. Wei, S.S. Jacobs, D. Upadhyay, D. Weill, and G.D. Rosen SPARC suppresses apoptosis of idiopathic pulmonary fibrosis fibroblasts through constitutive activation of beta-catenin J Biol Chem 285 2010 8196 8206
64. Y.P. Zhang, W.L. Wang, J. Liu, W.B. Li, L.L. Bai, Y.D. Yuan, and S.X. Song Plasminogen activator inhibitor-1 promotes the proliferation and inhibits the apoptosis of pulmonary fibroblasts by Ca(2+) signaling Thromb Res 131 2013 64 71
65. N. Sakai, J. Chun, J.S. Duffield, T. Wada, A.D. Luster, and A.M. Tager LPA1-induced cytoskeleton reorganization drives fibrosis through CTGF-dependent fibroblast proliferation FASEB J 27 2013 1830 1846
66. J.E. Kolodsick, M. Peters-Golden, J. Larios, G.B. Toews, V.J. Thannickal, and B.B. Moore Prostaglandin E2 inhibits fibroblast to myofibroblast transition via E. Prostanoid receptor 2 signaling and cyclic adenosine monophosphate elevation Am J Respir Cell Mol Biol 29 2003 537 544
67. T.A. Wynn Cellular and molecular mechanisms of fibrosis J Pathol 214 2008 199 210
68. T.E. King Jr., W.Z. Bradford, S. Castro-Bernardini, E.A. Fagan, I. Glaspole, M.K. Glassberg, E. Gorina, P.M. Hopkins, D. Kardatzke, L. Lancaster, D.J. Lederer, S.D. Nathan, C.A. Pereira, S.A. Sahn, R. Sussman, J.J. Swigris, P.W. Noble ASCEND Study Group A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis N Engl J Med 370 2014 2083 2092
69. L. Richeldi, R.M. du Bois, G. Raghu, A. Azuma, K.K. Brown, U. Costabel, V. Cottin, K.R. Flaherty, D.M. Hansell, Y. Inoue, D.S. Kim, M. Kolb, A.G. Nicholson, P.W. Noble, M. Selman, H. Taniguchi, M. Brun, F. Le Maulf, M. Girard, S. Stowasser, R. Schlenker-Herceg, B. Disse, H.R. Collard INPULSIS Trial Investigators Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis N Engl J Med 370 2014 2071 2082