Mechanical aspects of lung fibrosis: A spotlight on the myofibroblast

Proceedings of the American Thoracic Society

Volumn 9, Issue 3, 2012, Pages 137-147

  Hinz, Boris ^a  

^a UNIVERSITY OF TORONTO   (Canada)

Author keywords

Contraction; Integrin; Matrix stiffness; Stress fiber; TGF 1 activation

Indexed keywords

ALPHA SMOOTH MUSCLE ACTIN; COLLAGEN; INTEGRIN; MATRIX PROTEIN; RELAXIN; THROMBIN; TRANSFORMING GROWTH FACTOR; TRANSFORMING GROWTH FACTOR BETA1;

CELL DIFFERENTIATION; CELL TRANSDIFFERENTIATION; CONFERENCE PAPER; EXTRACELLULAR MATRIX; HUMAN; LUNG FIBROSIS; LUNG FUNCTION; LUNG PARENCHYMA; MYOFIBROBLAST; NONHUMAN; SCAR; SMOOTH MUSCLE FIBER; STEM CELL; STRESS FIBER; TUMOR GROWTH; YOUNG MODULUS;

CELL DIFFERENTIATION; CELL PROLIFERATION; CICATRIX; EXTRACELLULAR MATRIX; FIBROBLASTS; HUMANS; INTEGRIN ALPHA CHAINS; MYOFIBROBLASTS; PULMONARY ALVEOLI; PULMONARY FIBROSIS; STRESS FIBERS; TRANSFORMING GROWTH FACTOR BETA1; WOUND HEALING;

EID: 84865822608     PISSN: 15463222     EISSN: 19435665     Source Type: Journal    
DOI: 10.1513/pats.201202-017AW     Document Type: Conference Paper

References (198)

1. Thannickal VJ, Lee DY, White ES, Cui Z, Larios JM, Chacon R, Horowitz JC, Day RM, Thomas PE. Myofibroblast differentiation by transforming growth factor-beta1 is dependent on cell adhesion and integrin signaling via focal adhesion kinase. J Biol Chem 2003;278:12384-12389.
2. Wynn TA. Integrating mechanisms of pulmonary fibrosis. J Exp Med 2011;208:1339-1350.
3. Araya J, Nishimura SL. Fibrogenic reactions in lung disease. Annu Rev Pathol 2010;5:77-98.
4. Phan SH. Biology of fibroblasts and myofibroblasts. Proc Am Thorac Soc 2008;5:334-337.
5. Hinz B, Celetta G, Tomasek JJ, Gabbiani G, Chaponnier C. Alpha-smooth muscle actin expression upregulates fibroblast contractile activity. Mol Biol Cell 2001;12:2730-2741.
6. Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol 2002;3:349-363.
7. Kapanci Y, Ribaux C, Chaponnier C, Gabbiani G. Cytoskeletal features of alveolar myofibroblasts and pericytes in normal human and rat lung. J Histochem Cytochem 1992;40:1955-1963.
8. Zhang HY, Gharaee-Kermani M, Zhang K, Karmiol S, Phan SH. Lung fibroblast alpha-smooth muscle actin expression and contractile phenotype in bleomycin-induced pulmonary fibrosis. Am J Pathol 1996;148:527-537.
9. Powell DW, Mifflin RC, Valentich JD, Crowe SE, Saada JI, West AB. Myofibroblasts. I. Paracrine cells important in health and disease. Am J Physiol 1999;277:C1-C9.
10. King TE Jr, Schwarz MI, Brown K, Tooze JA, Colby TV, Waldron JA Jr, Flint A, Thurlbeck W, Cherniack RM. Idiopathic pulmonary fibrosis: relationship between histopathologic features and mortality. Am J Respir Crit Care Med 2001;164:1025-1032.
11. Kis K, Liu X, Hagood JS. Myofibroblast differentiation and survival in fibrotic disease. Expert Rev Mol Med 2011;13:e27.
12. Hardie WD, Glasser SW, Hagood JS. Emerging concepts in the pathogenesis of lung fibrosis. American Journal of Pathology 2009;175:3-16.
13. Souders CA, Bowers SL, Baudino TA. Cardiac fibroblast: the Renaissance cell. Circ Res 2009;105:1164-1176.
14. Porter KE, Turner NA. Cardiac fibroblasts: at the heart of myocardial remodeling. Pharmacol Ther 2009;123:255-278.
15. Leask A. Potential therapeutic targets for cardiac fibrosis: TGFbeta, angiotensin, endothelin, CCN2, and PDGF, partners in fibroblast activation. Circ Res 2010;106:1675-1680.
16. Hinz B. Formation and function of the myofibroblast during tissue repair. J Invest Dermatol 2007;127:526-537.
17. Wong JK, Lui YH, Kapacee Z, Kadler KE, Ferguson MW, McGrouther DA. The cellular biology of flexor tendon adhesion formation: an old problem in a new paradigm. Am J Pathol 2009;175:1938-1951.
18. Kinner B, Gerstenfeld LC, Einhorn TA, Spector M. Expression of smooth muscle actin in connective tissue cells participating in fracture healing in a murine model. Bone 2002;30:738-745.
19. Spector M. Musculoskeletal connective tissue cells with muscle: expression of muscle actin in and contraction of fibroblasts, chondrocytes, and osteoblasts. Wound Repair Regen 2001;9:11-18.
20. Kulasekaran P, Scavone CA, Rogers DS, Arenberg DA, Thannickal VJ, Horowitz JC. Endothelin-1 and transforming growth factor-beta1 independently induce fibroblast resistance to apoptosis via AKT activation. Am J Respir Cell Mol Biol 2009;41:484-493.
21. de Andrade JA, Thannickal VJ. Innovative approaches to the therapy of fibrosis. Curr Opin Rheumatol 2009.
22. Douglass A, Wallace K, Parr R, Park J, Durward E, Broadbent I, Barelle C, Porter AJ, Wright MC. Antibody-targeted myofibroblast apoptosis reduces fibrosis during sustained liver injury. J Hepatol 2008;49:88-98.
23. Desmoulière A, Redard M, Darby I, Gabbiani G. Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. Am J Pathol 1995;146:56-66.
24. Wynes MW, Edelman BL, Kostyk AG, Edwards MG, Coldren C, Groshong SD, Cosgrove GP, Redente EF, Bamberg A, Brown KK, et al. 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 2011;187:527-537.
25. Wynn TA. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest 2007;117:524-529.
26. Goodwin A, Jenkins G. Role of integrin-mediated TGFbeta activation in the pathogenesis of pulmonary fibrosis. Biochem Soc Trans 2009;37:849-854.
27. Gharaee-Kermani M, Hu B, Phan SH, Gyetko MR. Recent advances in molecular targets and treatment of idiopathic pulmonary fibrosis: focus on TGFbeta signaling and the myofibroblast. Curr Med Chem 2009;16:1400-1417.
28. Junker JP, Kratz C, Tollback A, Kratz G. Mechanical tension stimulates the transdifferentiation of fibroblasts into myofibroblasts in human burn scars. Burns 2008.
29. Varga J, Abraham D. Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest 2007;117:557-567.
30. Asano Y. Future treatments in systemic sclerosis. Journal of Dermatology 2010;37:54-70.
31. Verjee LS, Midwood K, Davidson D, Essex D, Sandison A, Nanchahal J. Myofibroblast distribution in Dupuytren's cords: correlation with digital contracture. J Hand Surg Am 2009;34:1785-1794.
32. Desmoulière A. Hepatic stellate cells: the only cells involved in liver fibrogenesis? A dogma challenged. Gastroenterology 2007;132:2059-2062.
33. Iredale JP. Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ. J Clin Invest 2007;117:539-548.
34. Friedman SL. Evolving challenges in hepatic fibrosis. Nat Rev Gastroenterol Hepatol 2010;7:425-436.
35. Hewitson TD. Renal tubulointerstitial fibrosis: common but never simple. Am J Physiol Renal Physiol 2009;296:F1239-1244.
36. Grande MT, Lopez-Novoa JM. Fibroblast activation and myofibroblast generation in obstructive nephropathy. Nat Rev Nephrol 2009;5:319-328.
37. De Wever O, Demetter P, Mareel M, Bracke M. Stromal myofibroblasts are drivers of invasive cancer growth. Int J Cancer 2008;123:2229-2238.
38. Hinz B. The myofibroblast in connective tissue repair and regeneration. In: Ralphs CAJ, editor. Regenerative medicine and biomaterials for the repair of connective tissues. Cambridge, UK: Woodhead Publishing Ltd.; 2010. pp. 39-82.
39. Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat ML, Gabbiani G. The myofibroblast: one function, multiple origins. Am J Pathol 2007;170:1807-1816.
40. Rock JR, Hogan BL. Epithelial progenitor cells in lung development, maintenance, repair, and disease. Annu Rev Cell Dev Biol 2011;27:493-512.
41. Greenbaum LE, Wells RG. The role of stem cells in liver repair and fibrosis. Int J Biochem Cell Biol 2011;43:222-229.
42. Hoyles RK, Derrett-Smith EC, Khan K, Shiwen X, Howat SL, Wells AU, Abraham DJ, Denton CP. An essential role for resident fibroblasts in experimental lung fibrosis is defined by lineage-specific deletion of high-affinity type II transforming growth factor beta receptor. Am J Respir Crit Care Med 2010;183:249-261.
43. Inoue T, Okada H, Takenaka T, Watanabe Y, Suzuki H. A case report suggesting the occurrence of epithelial-mesenchymal transition in obstructive nephropathy. Clin Exp Nephrol 2009;13:385-388.
44. Quaggin SE, Kapus A. Scar wars: mapping the fate of epithelial- mesenchymal-myofibroblast transition. Kidney Int 2011;80:41-50.
45. Radisky DC, Kenny PA, Bissell MJ. Fibrosis and cancer: do myofibroblasts come also from epithelial cells via EMT? J Cell Biochem 2007;101:830-839.
46. Kasai H, Allen JT, Mason RM, Kamimura T, Zhang Z. TGF-beta1 induces human alveolar epithelial to mesenchymal cell transition (EMT). Respir Res 2005;6:56.
47. Kim KK, Kugler MC, Wolters PJ, Robillard L, Galvez MG, Brumwell AN, Sheppard D, Chapman HA. Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci U S A 2006;103:13180-13185.
48. Willis BC, Liebler JM, Luby-Phelps K, Nicholson AG, Crandall ED, du Bois RM, Borok Z. Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1: potential role in idiopathic pulmonary fibrosis. Am J Pathol 2005;166:1321-1332.
49. Selman M, Pardo A, Kaminski N. Idiopathic pulmonary fibrosis: aberrant recapitulation of developmental programs? PLoS Med 2008;5:e62.
50. Masszi A, Speight P, Charbonney E, Lodyga M, Nakano H, Szaszi K, Kapus A. Fate-determining mechanisms in epithelial-myofibroblast transition: major inhibitory role for SMAD3. J Cell Biol 2010;188:383-399.
51. Xu J, Lamouille S, Derynck R. TGF-beta-induced epithelial to mesenchymal transition. Cell Res 2009;19:156-172.
52. Barth K, Reh J, Sturrock A, Kasper M. Epithelial vs myofibroblast differentiation in immortal rat lung cell lines-modulating effects of bleomycin. Histochem Cell Biol 2005;124:453-464.
53. Rock JR, Barkauskas CE, Cronce MJ, Xue Y, Harris JR, Liang J, Noble PW, Hogan BL. Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition. Proc Natl Acad Sci U S A 2011;108:E1475-1483.
54. Humphreys BD, Lin SL, Kobayashi A, Hudson TE, Nowlin BT, Bonventre JV, Valerius MT, McMahon AP, Duffield JS. Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am J Pathol 2010;176:85-97.
55. Zeisberg M, Duffield JS. Resolved: EMT produces fibroblasts in the kidney. J Am Soc Nephrol 2010;21:1247-1253.
56. Popov Y, Schuppan D. Epithelial-to-mesenchymal transition in liver fibrosis: dead or alive? Gastroenterology 2010;139:722-725.
57. Herzog EL, Bucala R. Fibrocytes in health and disease. Exp Hematol 2010;38:548-556.
58. Abe R, Donnelly SC, Peng T, Bucala R, Metz CN. Peripheral blood fibrocytes: differentiation pathway and migration to wound sites. J Immunol 2001;166:7556-7562.
59. Phillips RJ, Burdick MD, Hong K, Lutz MA, Murray LA, Xue YY, Belperio JA, Keane MP, Strieter RM. Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. J Clin Invest 2004;114:438-446.
60. Hashimoto N, Jin H, Liu T, Chensue SW, Phan SH. Bone marrow-derived progenitor cells in pulmonary fibrosis. J Clin Invest 2004;113:243-252.
61. Brocker V, Langer F, Fellous TG, Mengel M, Brittan M, Bredt M, Milde S, Welte T, Eder M, Haverich A, et al. Fibroblasts of recipient origin contribute to bronchiolitis obliterans in human lung transplants. Am J Respir Crit Care Med 2006;173:1276-1282.
62. Andersson-Sjoland A, de Alba CG, Nihlberg K, Becerril C, Ramirez R, Pardo A, Westergren-Thorsson G, Selman M. Fibrocytes are a potential source of lung fibroblasts in idiopathic pulmonary fibrosis. Int J Biochem Cell Biol 2008;40:2129-2140.
63. Strieter RM. Pathogenesis and natural history of usual interstitial pneumonia: the whole story or the last chapter of a long novel. Chest 2005;128:526S-532S.
64. Kisseleva T, Uchinami H, Feirt N, Quintana-Bustamante O, Segovia JC, Schwabe RF, Brenner DA. Bone marrow-derived fibrocytes participate in pathogenesis of liver fibrosis. J Hepatol 2006;45:429-438.
65. Yokota T, Kawakami Y, Nagai Y, Ma JX, Tsai JY, Kincade PW, Sato S. Bone marrow lacks a transplantable progenitor for smooth muscle type alpha-actin-expressing cells. Stem Cells 2006;24:13-22.
66. Follonier Castella L, Gabbiani G, McCulloch CA, Hinz B. Regulation of myofibroblast activities: calcium pulls some strings behind the scene. Exp Cell Res 2010;316:2390-2401.
67. Hill-Eubanks DC, Werner ME, Heppner TJ, Nelson MT. Calcium signaling in smooth muscle. Cold Spring Harb Perspect Biol 2011;3: a004549.
68. Jude JA, Wylam ME, Walseth TF, Kannan MS. Calcium signaling in airway smooth muscle. Proc Am Thorac Soc 2008;5:15-22.
69. Katoh K, Kano Y, Amano M, Onishi H, Kaibuchi K, Fujiwara K. Rhokinase- mediated contraction of isolated stress fibers. J Cell Biol 2001;153:569-584.
70. Kimura K, Ito M, Amano M, Chihara K, Fukata Y, Nakafuku M, Yamamori B, Feng JH, Nakano T, Okawa K, et al. Regulation of myosin phosphatase by Rho and Rho-associated kinase (rho-kinase). Science 1996;273:245-248.
71. 2+ sensitivity of smooth muscle and nonmuscle myosin ii: modulated by G proteins, kinases, and myosin phosphatase. Physiol Rev 2003;83:1325-1358.
72. Loirand G, Guerin P, Pacaud P. Rho kinases in cardiovascular physiology and pathophysiology. Circ Res 2006;98:322-334.
73. Tomasek JJ, Vaughan MB, Kropp BP, Gabbiani G, Martin MD, Haaksma CJ, Hinz B. Contraction of myofibroblasts in granulation tissue is dependent on Rho/Rho kinase/myosin light chain phosphatase activity. Wound Repair Regen 2006;14:313-320.
74. Yee HF Jr, Melton AC, Tran BN. RhoA/Rho-associated kinase mediates fibroblast contractile force generation. Biochem Biophys Res Commun 2001;280:1340-1345.
75. 2+-independent contraction in rat embryo fibroblasts. Am J Physiol Cell Physiol 2004;286:C8-21.
76. Nobe H, Nobe K, Fazal F, De Lanerolle P, Paul RJ. Rho kinase mediates serum-induced contraction in fibroblast fibers independent of myosin LC20 phosphorylation. Am J Physiol Cell Physiol 2003;284:C599-606.
77. Parizi M, Howard EW, Tomasek JJ. Regulation of LPA-promoted myofibroblast contraction: role of Rho, myosin light chain kinase, and myosin light chain phosphatase. Exp Cell Res 2000;254:210-220.
78. Follonier Castella L, Buscemi L, Godbout C, Meister JJ, Hinz B. A new lock-step mechanism of matrix remodelling based on subcellular contractile events. J Cell Sci 2010;123:1751-1760.
79. Wipff PJ, Rifkin DB, Meister JJ, Hinz B. Myofibroblast contraction activates latent TGF-beta1 from the extracellular matrix. J Cell Biol 2007;179:1311-1323.
80. Levinson H, Moyer KE, Saggers GC, Ehrlich HP. Calmodulin-myosin light chain kinase inhibition changes fibroblast-populated collagen lattice contraction, cell migration, focal adhesion formation, and wound contraction. Wound Repair Regen 2004;12:505-511.
81. Gabbiani G, Ryan GB, Majno G. Presence of modified fibroblasts in granulation tissue and their possible role in wound contraction. Experientia 1971;27:549-550.
82. Hinz B, Gabbiani G, Chaponnier C. The NH2-terminal peptide of alpha-smooth muscle actin inhibits force generation by the myofibroblast in vitro and in vivo. J Cell Biol 2002;157:657-663.
83. Goto T, Yanaga F, Ohtsuki I. Studies on the endothelin-1-induced contraction of rat granulation tissue pouch mediated by myofibroblasts. Biochim Biophys Acta 1998;1405:55-66.
84. Majno G, Gabbiani G, Hirschel BJ, Ryan GB, Statkov PR. Contraction of granulation tissue in vitro: similarity to smooth muscle. Science 1971;173:548-550.
85. Gabbiani G, Hirschel BJ, Ryan GB, Statkov PR, Majno G. Granulation tissue as a contractile organ: a study of structure and function. J Exp Med 1972;135:719-734.
86. + currents regulate the resting membrane potential, proliferation, and contractile responses in ventricular fibroblasts and myofibroblasts. Am J Physiol Heart Circ Physiol 2005;288:H2931-2939.
87. 2+ exchanger in primary cardiac myofibroblast migration, contraction, and proliferation. J Cell Physiol 2007;213:540-551.
88. Kernochan LE, Tran BN, Tangkijvanich P, Melton AC, Tam SP, Yee HF Jr. Endothelin-1 stimulates human colonic myofibroblast contraction and migration. Gut 2002;50:65-70.
89. 2+ -dependent and -independent pathways are involved in rat hepatic stellate cell contraction and intrahepatic hyperresponsiveness to methoxamine. Am J Physiol Gastrointest Liver Physiol 2007;292: G556-564.
90. Kawada N, Tran-Thi TA, Klein H, Decker K. The contraction of hepatic stellate (Ito) cells stimulated with vasoactive substances: possible involvement of endothelin 1 and nitric oxide in the regulation of the sinusoidal tonus. Eur J Biochem 1993;213:815-823.
91. Pinzani M, Failli P, Ruocco C, Casini A, Milani S, Baldi E, Giotti A, Gentilini P. Fat-storing cells as liver-specific pericytes: spatial dynamics of agonist-stimulated intracellular calcium transients. J Clin Invest 1992;90:642-646.
92. Goffin JM, Pittet P, Csucs G, Lussi JW, Meister JJ, Hinz B. Focal adhesion size controls tension-dependent recruitment of alpha-smooth muscle actin to stress fibers. J Cell Biol 2006;172:259-268.
93. Adhikari AS, Chai J, Dunn AR. Mechanical load induces a 100-fold increase in the rate of collagen proteolysis by MMP-1. J Am Chem Soc 2011.
94. Flynn BP, Bhole AP, Saeidi N, Liles M, Dimarzio CA, Ruberti JW. Mechanical strain stabilizes reconstituted collagen fibrils against enzymatic degradation by mammalian collagenase matrix metalloproteinase 8 (MMP-8). PLoS One 2010;5:e12337.
95. Hinz B. The myofibroblast: paradigm for a mechanically active cell. J Biomech 2010;43:146-155.
96. Liu F, Mih JD, Shea BS, Kho AT, Sharif AS, Tager AM, Tschumperlin DJ. Feedback amplification of fibrosis through matrix stiffening and COX-2 suppression. J Cell Biol 2010;190:693-706.
97. Liu F, Tschumperlin DJ. Micro-mechanical characterization of lung tissue using atomic force microscopy. J Vis Exp 2011.
98. Dolhnikoff M, Mauad T, Ludwig MS. Extracellular matrix and oscillatory mechanics of rat lung parenchyma in bleomycin-induced fibrosis. Am J Respir Crit Care Med 1999;160:1750-1757.
99. Ebihara T, Venkatesan N, Tanaka R, Ludwig MS. Changes in extracellular matrix and tissue viscoelasticity in bleomycin-induced lung fibrosis: temporal aspects. Am J Respir Crit Care Med 2000;162:1569-1576.
100. Soucy PA, Werbin J, Heinz W, Hoh JH, Romer LH. Microelastic properties of lung cell-derived extracellular matrix. Acta Biomater 2011;7:96-105.
101. Janmey PA, Winer JP, Murray ME, Wen Q. The hard life of soft cells. Cell Motil Cytoskeleton 2009;66:597-605.
102. Buxboim A, Discher DE. Stem cells feel the difference. Nat Methods 2010;7:695-697.
103. Discher DE, Janmey P, Wang YL. Tissue cells feel and respond to the stiffness of their substrate. Science 2005;310:1139-1143.
104. Georges PC, Janmey PA. Cell type-specific response to growth on soft materials. J Appl Physiol 2005;98:1547-1553.
105. Engler AJ, Sen S, Sweeney HL, Discher DE. Matrix elasticity directs stem cell lineage specification. Cell 2006;126:677-689.
106. Wells RG. The role of matrix stiffness in regulating cell behavior. Hepatology 2008;47:1394-1400.
107. Tschumperlin DJ, Boudreault F, Liu F. Recent advances and new opportunities in lung mechanobiology. Journal of Biomechanics 2010; 43:99-107.
108. Arora PD, Narani N, McCulloch CA. The compliance of collagen gels regulates transforming growth factor-beta induction of alpha-smooth muscle actin in fibroblasts. Am J Pathol 1999;154:871-882.
109. Hinz B, Mastrangelo D, Iselin CE, Chaponnier C, Gabbiani G. Mechanical tension controls granulation tissue contractile activity and myofibroblast differentiation. Am J Pathol 2001;159:1009-1020.
110. Grinnell F, Petroll WM. Cell motility and mechanics in three-dimensional collagen matrices. Annu Rev Cell Dev Biol 2010;26: 335-361.
111. Wang J, Chen H, Seth A, McCulloch CA. Mechanical force regulation of myofibroblast differentiation in cardiac fibroblasts. Am J Physiol Heart Circ Physiol 2003;285:H1871-1881.
112. Cabrera-Benitez NE, Parotto M, Post M, Han B, Spieth PM, Cheng WE, Valladares F, Villar J, Liu M, Sato M, et al. Mechanical stress induces lung fibrosis by epithelial-mesenchymal transition. Crit Care Med 2012;40:510-517.
113. Wipff PJ, Hinz B. Integrins and the activation of latent transforming growth factor beta1 - an intimate relationship. Eur J Cell Biol 2008; 87:601-615.
114. Balestrini J, Chaudhry S, Sarrazy V, Koehler A, Hinz B. The mechanical memory of lung myofibroblasts. Integrative Biology 2012;4:410-421.
115. Trujillo G, Meneghin A, Flaherty KR, Sholl LM, Myers JL, Kazerooni EA, Gross BH, Oak SR, Coelho AL, Evanoff H, et al. TLR9 differentiates rapidly from slowly progressing forms of idiopathic pulmonary fibrosis. Sci Transl Med 2011;2:57ra82.
116. Georges PC, Hui JJ, Gombos Z, McCormick ME, Wang AY, Uemura M, Mick R, Janmey PA, Furth EE, Wells RG. Increased stiffness of the rat liver precedes matrix deposition: Implications for fibrosis. Am J Physiol Gastrointest Liver Physiol 2007;293:G1147-1154.
117. Barker HE, Chang J, Cox TR, Lang G, Bird D, Nicolau M, Evans HR, Gartland A, Erler JT. LOXL2-mediated matrix remodeling in metastasis and mammary gland involution. Cancer Res 2011;71:1561-1572.
118. van der Slot AJ, Zuurmond AM, van den Bogaerdt AJ, Ulrich MM, Middelkoop E, Boers W, Karel Ronday H, DeGroot J, Huizinga TW, Bank RA. Increased formation of pyridinoline cross-links due to higher telopeptide lysyl hydroxylase levels is a general fibrotic phenomenon. Matrix Biol 2004;23:251-257.
119. Selman M, Pardo A. Role of epithelial cells in idiopathic pulmonary fibrosis: From innocent targets to serial killers. Proc Am Thorac Soc 2006;3:364-372.
120. Zhao XH, Laschinger C, Arora P, Szaszi K, Kapus A, McCulloch CA. Force activates smooth muscle alpha-actin promoter activity through the rho signaling pathway. J Cell Sci 2007;120:1801-1809.
121. Shi M, Zhu J, Wang R, Chen X, Mi L, Walz T, Springer TA. Latent TGF-beta structure and activation. Nature 2011;474:343-349.
122. Buscemi L, Ramonet D, Klingberg F, Formey A, Smith-Clerc J, Meister JJ, Hinz B. The single-molecule mechanics of the latent TGF-beta1 complex. Curr Biol 2011;21:2046-2054.
123. Zhou Y, Hagood JS, Lu B, Merryman WD, Murphy-Ullrich JE. Thy-1- integrin alphavbeta5 interactions inhibit lung fibroblast contraction-induced latent TGF-beta1 activation and myofibroblast differentiation. J Biol Chem 2010.
124. Maeda T, Sakabe T, Sunaga A, Sakai K, Rivera AL, Keene DR, Sasaki T, Stavnezer E, Iannotti J, Schweitzer R, et al. Conversion of mechanical force into TGF-beta-mediated biochemical signals. Curr Biol 2011;21:933-941.
125. Ahamed J, Burg N, Yoshinaga K, Janczak CA, Rifkin DB, Coller BS. In vitro and in vivo evidence for shear-induced activation of latent transforming growth factor-beta1. Blood 2008;112:3650-3660.
126. Giacomini MM, Travis MA, Kudo M, Sheppard D. Epithelial cells utilize cortical actin/myosin to activate latent TGF-beta through integrin alpha(v)beta(6)-dependent physical force. Exp Cell Res 2012.
127. Gauldie J, Bonniaud P, Sime P, Ask K, Kolb M. TGF-beta, smad3 and the process of progressive fibrosis. Biochem Soc Trans 2007;35:661-664.
128. Sheppard D. Transforming growth factor beta: a central modulator of pulmonary and airway inflammation and fibrosis. Proc Am Thorac Soc 2006;3:413-417.
129. Ueda T, Niimi A, Matsumoto H, Takemura M, Yamaguchi M, Matsuoka H, Jinnai M, Chin K, Minakuchi M, Cheng L, et al. TGFbetab1 promoter polymorphism C-509t and pathophysiology of asthma. J Allergy Clin Immunol 2008;121:659-664.
130. Takizawa H, Tanaka M, Takami K, Ohtoshi T, Ito K, Satoh M, Okada Y, Yamasawa F, Nakahara K, Umeda A. Increased expression of transforming growth factor-beta1 in small airway epithelium from tobacco smokers and patients with chronic obstructive pulmonary disease (COPD). Am J Respir Crit Care Med 2001;163:1476-1483.
131. de Boer WI, van Schadewijk A, Sont JK, Sharma HS, Stolk J, Hiemstra PS, van Krieken JH. Transforming growth factor beta1 and recruitment of macrophages and mast cells in airways in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;158:1951-1957.
132. Khalil N, O'Connor RN, Unruh HW, Warren PW, Flanders KC, Kemp A, Bereznay OH, Greenberg AH. Increased production and immunohistochemical localization of transforming growth factor-beta in idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol 1991;5:155-162.
133. Xaubet A, Marin-Arguedas A, Lario S, Ancochea J, Morell F, Ruiz-Manzano J, Rodriguez-Becerra E, Rodriguez-Arias JM, Inigo P, Sanz S, et al. Transforming growth factor-beta1 gene polymorphisms are associated with disease progression in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2003;168:431-435.
134. Sime PJ, Xing Z, Graham FL, Csaky KG, Gauldie J. Adenovector-mediated gene transfer of active transforming growth factor-beta1 induces prolonged severe fibrosis in rat lung. J Clin Invest 1997;100:768-776.
135. Kenyon NJ, Ward RW, McGrew G, Last JA. TGF-beta1 causes airway fibrosis and increased collagen i and iii mRNA in mice. Thorax 2003; 58:772-777.
136. Giri SN, Hyde DM, Hollinger MA. Effect of antibody to transforming growth factor beta on bleomycin induced accumulation of lung collagen in mice. Thorax 1993;48:959-966.
137. Shi Y, Massague J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 2003;113:685-700.
138. Moustakas A, Heldin CH. The regulation of TGFbeta signal transduction. Development 2009;136:3699-3714.
139. Malmstrom J, Lindberg H, Lindberg C, Bratt C, Wieslander E, Delander EL, Sarnstrand B, Burns JS, Mose-Larsen P, Fey S, et al. Transforming growth factor-beta 1 specifically induce proteins involved in the myofibroblast contractile apparatus. Mol Cell Proteomics 2004;3:466-477.
140. Roy SG, Nozaki Y, Phan SH. Regulation of alpha-smooth muscle actin gene expression in myofibroblast differentiation from rat lung fibroblasts. Int J Biochem Cell Biol 2001;33:723-734.
141. Breen EC. Mechanical strain increases type I collagen expression in pulmonary fibroblasts in vitro. J Appl Physiol 2000;88:203-209.
142. Varga J, Pasche B. Transforming growth factor beta as a therapeutic target in systemic sclerosis. Nat Rev Rheumatol 2009;5:200-206.
143. Ikushima H, Miyazono K. TGFbeta signalling: a complex web in cancer progression. Nat Rev Cancer 2010;10:415-424.
144. Yang L, Pang Y, Moses HL. TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression. Trends Immunol 2010;31:220-227.
145. Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA. Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol 2006;24:99-146.
146. Wakefield LM, Stuelten C. Keeping order in the neighborhood: new roles for TGFbeta in maintaining epithelial homeostasis. Cancer Cell 2007;12:293-295.
147. ten Dijke P, Arthur HM. Extracellular control of TGFbeta signalling in vascular development and disease. Nat Rev Mol Cell Biol 2007;8:857-869.
148. Howell JE, McAnulty RJ. TGF-beta: its role in asthma and therapeutic potential. Curr Drug Targets 2006;7:547-565.
149. Meier K, Nanney LB. Emerging new drugs for scar reduction. Expert Opin Emerg Drugs 2006;11:39-47.
150. Nishimura SL. Integrin-mediated transforming growth factor-beta activation, a potential therapeutic target in fibrogenic disorders. Am J Pathol 2009;175:1362-1370.
151. Worthington JJ, Klementowicz JE, Travis MA. TGFbeta: a sleeping giant awoken by integrins. Trends Biochem Sci 2010;36:47-54.
152. Annes JP, Munger JS, Rifkin DB. Making sense of latent TGFbeta activation. J Cell Sci 2003;116:217-224.
153. Hyytiainen M, Penttinen C, Keski-Oja J. Latent TGF-beta binding proteins: extracellular matrix association and roles in TGF-beta activation. Crit Rev Clin Lab Sci 2004;41:233-264.
154. Ramirez F, Rifkin DB. Extracellular microfibrils: contextual platforms for TGFbeta and BMP signaling. Curr Opin Cell Biol 2009;21:616-622.
155. Hynes RO. The extracellular matrix: not just pretty fibrils. Science 2009;326:1216-1219.
156. Todorovic V, Rifkin DB. LTBPs, more than just an escort service. J Cell Biochem 2012;113:410-418.
157. Annes JP, Chen Y, Munger JS, Rifkin DB. Integrin {alpha}v{beta}6- mediated activation of latent TGF-{beta} requires the latent TGF-{beta} binding protein-1. J Cell Biol 2004;165:723-734.
158. Jenkins G. The role of proteases in transforming growth factor-beta activation. Int J Biochem Cell Biol 2008;40:1068-1078.
159. Sweetwyne MT, Murphy-Ullrich JE. Thrombospondin1 in tissue repair and fibrosis: TGF-beta-dependent and independent mechanisms. Matrix Biol 2012.
160. Crawford SE, Stellmach V, Murphy-Ullrich JE, Ribeiro SM, Lawler J, Hynes RO, Boivin GP, Bouck N. Thrombospondin-1 is a major activator of TGF-beta1 in vivo. Cell 1998;93:1159-1170.
161. Derynck R, Jarrett JA, Chen EY, Goeddel DV. The murine transforming growth factor-beta precursor. J Biol Chem 1986;261:4377-4379.
162. Lu M, Munger JS, Steadele M, Busald C, Tellier M, Schnapp LM. Integrin alpha8beta1 mediates adhesion to LAP-TGFbeta1. J Cell Sci 2002;115(Pt 23):4641-4648.
163. Munger JS, Harpel JG, Giancotti FG, Rifkin DB. Interactions between growth factors and integrins: latent forms of transforming growth factor-beta are ligands for the integrin alphavbeta1. Mol Biol Cell 1998;9:2627-2638.
164. Sheppard D. Integrin-mediated activation of latent transforming growth factor beta. Cancer Metastasis Rev 2005;24:395-402.
165. Ludbrook SB, Barry ST, Delves CJ, Horgan CM. The integrin alphavbeta3 is a receptor for the latency-associated peptides of transforming growth factors beta1 and beta3. Biochem J 2003;369:311-318.
166. Mu D, Cambier S, Fjellbirkeland L, Baron JL, Munger JS, Kawakatsu H, Sheppard D, Broaddus VC, Nishimura SL. The integrin alpha(v)beta8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-beta1. J Cell Biol 2002;157:493-507.
167. Schultz-Cherry S, Lawler J, Murphy-Ullrich JE. The type 1 repeats of thrombospondin 1 activate latent transforming growth factor-beta. J Biol Chem 1994;269:26783-26788.
168. McMahon GA, Dignam JD, Gentry LE. Structural characterization of the latent complex between transforming growth factor beta 1 and beta 1-latency-associated peptide. Biochem J 1996;313:343-351.
169. Young GD, Murphy-Ullrich JE. Molecular interactions that confer latency to transforming growth factor-beta. J Biol Chem 2004;279: 38032-38039.
170. Sha X, Yang L, Gentry LE. Identification and analysis of discrete functional domains in the pro region of pre-pro-transforming growth factor beta 1. J Cell Biol 1991;114:827-839.
171. Walton KL, Makanji Y, Chen J, Wilce MC, Chan KL, Robertson DM, Harrison CA. Two distinct regions of latency-associated peptide coordinate stability of the latent transforming growth factor-beta1 complex. J Biol Chem 2010;285:17029-17037.
172. Aluwihare P, Munger JS. What the lung has taught us about latent TGF-beta activation. Am J Respir Cell Mol Biol 2008;39:499-502.
173. Huang XZ, Wu JF, Cass D, Erle DJ, Corry D, Young SG, Farese RV Jr., Sheppard D. Inactivation of the integrin beta 6 subunit gene reveals a role of epithelial integrins in regulating inflammation in the lung and skin. J Cell Biol 1996;133:921-928.
174. Bader BL, Rayburn H, Crowley D, Hynes RO. Extensive vasculogenesis, angiogenesis, and organogenesis precede lethality in mice lacking all alpha v integrins. Cell 1998;95:507-519.
175. Zhu J, Motejlek K, Wang D, Zang K, Schmidt A, Reichardt LF. Beta8 integrins are required for vascular morphogenesis in mouse embryos. Development 2002;129:2891-2903.
176. Yang Z, Mu Z, Dabovic B, Jurukovski V, Yu D, Sung J, Xiong X, Munger JS. Absence of integrin-mediated TGF{beta}1 activation in vivo recapitulates the phenotype of tgf{beta}1-null mice. J Cell Biol 2007;176:787-793.
177. Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, Allen R, Sidman C, Proetzel G, Calvin D, et al. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 1992;359:693-699.
178. Munger JS, Huang X, Kawakatsu H, Griffiths MJ, Dalton SL, Wu J, Pittet JF, Kaminski N, Garat C, Matthay MA, et al. The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 1999;96:319-328.
179. Horan GS, Wood S, Ona V, Li DJ, Lukashev ME, Weinreb PH, Simon KJ, Hahm K, Allaire NE, Rinaldi NJ, et al. Partial inhibition of integrin alpha(v)beta6 prevents pulmonary fibrosis without exacerbating inflammation. Am J Respir Crit
180. Jenkins RG, Su X, Su G, Scotton CJ, Camerer E, Laurent GJ, Davis GE, Chambers RC, Matthay MA, Sheppard D. Ligation of protease-activated receptor 1 enhances alpha(v)beta6 integrin-dependent TGF-beta activation and promotes acute lung injury. J Clin Invest 2006;116:1606-1614.
181. Li M, Krishnaveni MS, Li C, Zhou B, Xing Y, Banfalvi A, Li A, Lombardi V, Akbari O, Borok Z, et al. Epithelium-specific deletion of TGF-beta receptor type ii protects mice from bleomycin-induced pulmonary fibrosis. J Clin Invest 2011;121:277-287.
182. Phan SH. The myofibroblast in pulmonary fibrosis. Chest 2002;122: 286S-289S.
183. Thannickal VJ, Toews GB, White ES, Lynch JP 3rd, Martinez FJ. Mechanisms of pulmonary fibrosis. Annu Rev Med 2004;55:395-417.
184. Scotton CJ, Krupiczojc MA, Konigshoff M, Mercer PF, Lee YC, Kaminski N, Morser J, Post JM, Maher TM, Nicholson AG, et al. Increased local expression of coagulation factor X contributes to the fibrotic response in human and murine lung injury. J Clin Invest 2009;119:2550-2563.
185. Tatler AL, John AE, Jolly L, Habgood A, Porte J, Brightling C, Knox AJ, Pang L, Sheppard D, Huang X, et al. Integrin alphavbeta5-mediated TGF-beta activation by airway smooth muscle cells in asthma. J Immunol 2011;187:6094-6107.
186. Sheppard D. Roles of alphav integrins in vascular biology and pulmonary pathology. Curr Opin Cell Biol 2004;16:552-557.
187. Huang X, Griffiths M, Wu J, Farese RV Jr, Sheppard D. Normal development, wound healing, and adenovirus susceptibility in beta5-deficient mice. Mol Cell Biol 2000;20:755-759.
188. Levine D, Rockey DC, Milner TA, Breuss JM, Fallon JT, Schnapp LM. Expression of the integrin alpha8beta1 during pulmonary and hepatic fibrosis. Am J Pathol 2000;156:1927-1935.
189. Bouzeghrane F, Mercure C, Reudelhuber TL, Thibault G. Alpha8beta1 integrin is upregulated in myofibroblasts of fibrotic and scarring myocardium. J Mol Cell Cardiol 2004;36:343-353.
190. Thibault G, Lacombe MJ, Schnapp LM, Lacasse A, Bouzeghrane F, Lapalme G. Upregulation of alpha(8)beta(1)-integrin in cardiac fibroblast by angiotensin ii and transforming growth factor-beta1. Am J Physiol Cell Physiol 2001;281:C1457-1467.
191. Scotton CJ, Chambers RC. Molecular targets in pulmonary fibrosis: the myofibroblast in focus. Chest 2007;132:1311-1321.
192. Huang X, Gai Y, Yang N, Lu B, Samuel CS, Thannickal VJ, Zhou Y. Relaxin regulates myofibroblast contractility and protects against lung fibrosis. Am J Pathol 2011;179:2751-2765.
193. Bond JE, Kokosis G, Ren L, Selim MA, Bergeron A, Levinson H. Wound contraction is attenuated by fasudil inhibition of Rho-associated kinase. Plast Reconstr Surg 2011;128:438e-450e.
194. Takeda Y, Nishikimi T, Akimoto K, Matsuoka H, Ishimitsu T. Beneficial effects of a combination of Rho-kinase inhibitor and ACE inhibitor on tubulointerstitial fibrosis induced by unilateral ureteral obstruction. Hypertens Res 2010;33:965-973.
195. Bogatkevich GS, Ludwicka-Bradley A, Silver RM. Dabigatran, a direct thrombin inhibitor, demonstrates antifibrotic effects on lung fibroblasts. Arthritis Rheum 2009;60:3455-3464.
196. Tucker GC. Inhibitors of integrins. Curr Opin Pharmacol 2002;2:394-402.
197. Weinreb PH, Simon KJ, Rayhorn P, Yang WJ, Leone DR, Dolinski BM, Pearse BR, Yokota Y, Kawakatsu H, Atakilit A, et al. Function-blocking integrin alphavbeta6 monoclonal antibodies: distinct ligand-mimetic and nonligand-mimetic classes. J Biol Chem 2004;279:17875-17887.
198. Hinz B, Gabbiani G. The role of myofibroblasts in Dupuytren's disease: fundamental aspects of contraction and therapeutic perspectives. In: Eaton C, Seegenschmiedt MH, Bayat A, Gabbiani G, Werker G, Wach W, editors. Dupuytren's disease and related hyperproliferative disorders: principles, research, and clinical perspectives. Springer Verlag; 2012.