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Mechanisms of fibrosis: therapeutic translation for fibrotic disease

Abstract

Fibrosis is a pathological feature of most chronic inflammatory diseases. Fibrosis, or scarring, is defined by the accumulation of excess extracellular matrix components. If highly progressive, the fibrotic process eventually leads to organ malfunction and death. Fibrosis affects nearly every tissue in the body. Here we discuss how key components of the innate and adaptive immune response contribute to the pathogenesis of fibrosis. We also describe how cell-intrinsic changes in important structural cells can perpetuate the fibrotic response by regulating the differentiation, recruitment, proliferation and activation of extracellular matrix–producing myofibroblasts. Finally, we highlight some of the key mechanisms and pathways of fibrosis that are being targeted as potential therapies for a variety of important human diseases.

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Figure 1: Overview of wound repair and fibrosis.
Figure 2: Innate immune cells in fibrosis.
Figure 3: Adaptive immune pathways in fibrosis.
Figure 4: EMT in fibrosis.

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References

  1. Bataller, R. & Brenner, D.A. Liver fibrosis. J. Clin. Invest. 115, 209–218 (2005).

    Article  CAS  Google Scholar 

  2. Wynn, T.A. Integrating mechanisms of pulmonary fibrosis. J. Exp. Med. 208, 1339–1350 (2011).

    CAS  Google Scholar 

  3. Wynn, T.A. Cellular and molecular mechanisms of fibrosis. J. Pathol. 214, 199–210 (2008).

    Article  CAS  Google Scholar 

  4. Gabbiani, G. The myofibroblast in wound healing and fibrocontractive diseases. J. Pathol. 200, 500–503 (2003).

    CAS  Google Scholar 

  5. Kalluri, R. & Zeisberg, M. Fibroblasts in cancer. Nat. Rev. Cancer 6, 392–401 (2006).

    Article  CAS  Google Scholar 

  6. Fujii, T. et al. Mouse model of carbon tetrachloride–induced liver fibrosis: histopathological changes and expression of CD133 and epidermal growth factor. BMC Gastroenterol. 10, 79 (2010).

    Google Scholar 

  7. Chen, J. & Stubbe, J. Bleomycins: towards better therapeutics. Nat. Rev. Cancer 5, 102–112 (2005).

    CAS  Google Scholar 

  8. Esmon, C.T. The interactions between inflammation and coagulation. Br. J. Haematol. 131, 417–430 (2005).

    CAS  Google Scholar 

  9. Barrientos, S., Stojadinovic, O., Golinko, M.S., Brem, H. & Tomic-Canic, M. Growth factors and cytokines in wound healing. Wound Repair Regen. 16, 585–601 (2008).

    Google Scholar 

  10. Chambers, R.C. Procoagulant signalling mechanisms in lung inflammation and fibrosis: novel opportunities for pharmacological intervention? Br. J. Pharmacol. 153, S367–S378 (2008).

    CAS  Google Scholar 

  11. Scotton, C.J. et al. Increased local expression of coagulation factor X contributes to the fibrotic response in human and murine lung injury. J. Clin. Invest. 119, 2550–2563 (2009).

    CAS  Google Scholar 

  12. Coughlin, S.R. Thrombin signalling and protease-activated receptors. Nature 407, 258–264 (2000).

    CAS  Google Scholar 

  13. Fiorucci, S. et al. PAR1 antagonism protects against experimental liver fibrosis. Role of proteinase receptors in stellate cell activation. Hepatology 39, 365–375 (2004).

    CAS  Google Scholar 

  14. Anstee, Q.M. et al. Coagulation status modulates murine hepatic fibrogenesis: implications for the development of novel therapies. J. Thromb. Haemost. 6, 1336–1343 (2008).

    CAS  Google Scholar 

  15. Wanless, I.R. et al. Hepatic and portal vein thrombosis in cirrhosis: possible role in development of parenchymal extinction and portal hypertension. Hepatology 21, 1238–1247 (1995).

    CAS  Google Scholar 

  16. Li, Y. et al. Severe lung fibrosis requires an invasive fibroblast phenotype regulated by hyaluronan and CD44. J. Exp. Med. 208, 1459–1471 (2011).

    CAS  Google Scholar 

  17. Duffield, J.S. et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J. Clin. Invest. 115, 56–65 (2005).

    CAS  Google Scholar 

  18. Pardo, A. et al. Increase of lung neutrophils in hypersensitivity pneumonitis is associated with lung fibrosis. Am. J. Respir. Crit. Care Med. 161, 1698–1704 (2000).

    CAS  Google Scholar 

  19. Connolly, M.K. et al. In liver fibrosis, dendritic cells govern hepatic inflammation in mice via TNF-α. J. Clin. Invest. 119, 3213–3225 (2009).

    CAS  Google Scholar 

  20. Zhang, Y., Lee, T.C., Guillemin, B., Yu, M.C. & Rom, W.N. Enhanced IL-1β and tumor necrosis factor-α release and messenger RNA expression in macrophages from idiopathic pulmonary fibrosis or after asbestos exposure. J. Immunol. 150, 4188–4196 (1993).

    CAS  Google Scholar 

  21. Miyazaki, Y. et al. Expression of a tumor necrosis factor-α transgene in murine lung causes lymphocytic and fibrosing alveolitis. A mouse model of progressive pulmonary fibrosis. J. Clin. Invest. 96, 250–259 (1995).

    CAS  Google Scholar 

  22. Kolb, M., Margetts, P.J., Anthony, D.C., Pitossi, F. & Gauldie, J. Transient expression of IL-1β induces acute lung injury and chronic repair leading to pulmonary fibrosis. J. Clin. Invest. 107, 1529–1536 (2001).

    CAS  Google Scholar 

  23. Piguet, P.F., Collart, M.A., Grau, G.E., Sappino, A.P. & Vassalli, P. Requirement of tumour necrosis factor for development of silica-induced pulmonary fibrosis. Nature 344, 245–247 (1990).

    CAS  Google Scholar 

  24. Piguet, P.F., Collart, M.A., Grau, G.E., Kapanci, Y. & Vassalli, P. Tumor necrosis factor/cachectin plays a key role in bleomycin-induced pneumopathy and fibrosis. J. Exp. Med. 170, 655–663 (1989).

    CAS  Google Scholar 

  25. Piguet, P.F., Ribaux, C., Karpuz, V., Grau, G.E. & Kapanci, Y. Expression and localization of tumor necrosis factor-α and its mRNA in idiopathic pulmonary fibrosis. Am. J. Pathol. 143, 651–655 (1993).

    CAS  Google Scholar 

  26. Bahcecioglu, I.H. et al. Hepatoprotective effect of infliximab, an anti–TNF-α agent, on carbon tetrachloride–induced hepatic fibrosis. Inflammation 31, 215–221 (2008).

    CAS  Google Scholar 

  27. Nawroth, I. et al. Intraperitoneal administration of chitosan/DsiRNA nanoparticles targeting TNF-α prevents radiation-induced fibrosis. Radiother. Oncol. 97, 143–148 (2010).

    CAS  Google Scholar 

  28. Tomita, K. et al. Tumour necrosis factor-α signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice. Gut 55, 415–424 (2006).

    CAS  Google Scholar 

  29. Raghu, G. et al. Treatment of idiopathic pulmonary fibrosis with etanercept: an exploratory, placebo-controlled trial. Am. J. Respir. Crit. Care Med. 178, 948–955 (2008).

    CAS  Google Scholar 

  30. Gasse, P. et al. IL-1R1/MyD88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in mice. J. Clin. Invest. 117, 3786–3799 (2007).

    CAS  Google Scholar 

  31. Bujak, M. & Frangogiannis, N.G. The role of IL-1 in the pathogenesis of heart disease. Arch. Immunol. Ther. Exp. (Warsz.) 57, 165–176 (2009).

    CAS  Google Scholar 

  32. Jones, L.K. et al. IL-1RI deficiency ameliorates early experimental renal interstitial fibrosis. Nephrol. Dial. Transplant. 24, 3024–3032 (2009).

    CAS  Google Scholar 

  33. Kamari, Y. et al. Lack of interleukin-1α or interleukin-1β inhibits transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice. J. Hepatol. 55, 1086–1094 (2011).

    CAS  Google Scholar 

  34. Fan, J.M. et al. Interleukin-1 induces tubular epithelial-myofibroblast transdifferentiation through a transforming growth factor-β1–dependent mechanism in vitro. Am. J. Kidney Dis. 37, 820–831 (2001).

    CAS  Google Scholar 

  35. Diaz, J.A. et al. Critical role for IL-6 in hypertrophy and fibrosis in chronic cardiac allograft rejection. Am. J. Transplant. 9, 1773–1783 (2009).

    CAS  Google Scholar 

  36. Natsume, M. et al. Attenuated liver fibrosis and depressed serum albumin levels in carbon tetrachloride–treated IL-6–deficient mice. J. Leukoc. Biol. 66, 601–608 (1999).

    CAS  Google Scholar 

  37. Verrecchia, F. & Mauviel, A. Transforming growth factor-β and fibrosis. World J. Gastroenterol. 13, 3056–3062 (2007).

    CAS  Google Scholar 

  38. Kitani, A. et al. Transforming growth factor (TGF)-β1–producing regulatory T cells induce Smad-mediated interleukin-10 secretion that facilitates coordinated immunoregulatory activity and amelioration of TGF-β1–mediated fibrosis. J. Exp. Med. 198, 1179–1188 (2003).

    CAS  Google Scholar 

  39. Wynn, T.A. & Barron, L. Macrophages: master regulators of inflammation and fibrosis. Semin. Liver Dis. 30, 245–257 (2010).

    CAS  Google Scholar 

  40. Gordon, S. & Taylor, P.R. Monocyte and macrophage heterogeneity. Nat. Rev. Immunol. 5, 953–964 (2005).

    CAS  Google Scholar 

  41. Hesse, M. et al. Differential regulation of nitric oxide synthase-2 and arginase-1 by type 1/type 2 cytokines in vivo: granulomatous pathology is shaped by the pattern of l-arginine metabolism. J. Immunol. 167, 6533–6544 (2001).

    CAS  Google Scholar 

  42. Song, E. et al. Influence of alternatively and classically activated macrophages on fibrogenic activities of human fibroblasts. Cell. Immunol. 204, 19–28 (2000).

    CAS  Google Scholar 

  43. Sun, L. et al. New concepts of IL-10–induced lung fibrosis: fibrocyte recruitment and M2 activation in a CCL2/CCR2 axis. Am. J. Physiol. Lung Cell Mol. Physiol. 300, L341–L353 (2011).

    CAS  Google Scholar 

  44. Herbert, D.R. et al. Alternative macrophage activation is essential for survival during schistosomiasis and downmodulates T helper 1 responses and immunopathology. Immunity 20, 623–635 (2004).

    CAS  Google Scholar 

  45. Pesce, J.T. et al. Arginase-1–expressing macrophages suppress TH2 cytokine-driven inflammation and fibrosis. PLoS Pathog. 5, e1000371 (2009).

    Google Scholar 

  46. Murray, P.J. & Wynn, T.A. Protective and pathogenic functions of macrophage subsets. Nat. Rev. Immunol. 11, 723–737 (2011).

    CAS  Google Scholar 

  47. Ricote, M., Li, A.C., Willson, T.M., Kelly, C.J. & Glass, C.K. The peroxisome proliferator–activated receptor-γ is a negative regulator of macrophage activation. Nature 391, 79–82 (1998).

    CAS  Google Scholar 

  48. Odegaard, J.I. et al. Macrophage-specific PPAR-γ controls alternative activation and improves insulin resistance. Nature 447, 1116–1120 (2007).

    CAS  Google Scholar 

  49. Kulkarni, A.A. et al. PPAR-γ ligands repress TGF-β–induced myofibroblast differentiation by targeting the PI3K/Akt pathway: implications for therapy of fibrosis. PLoS ONE 6, e15909 (2011).

    CAS  Google Scholar 

  50. Iglarz, M. et al. Peroxisome proliferator–activated receptor-α and receptor-γ activators prevent cardiac fibrosis in mineralocorticoid-dependent hypertension. Hypertension 42, 737–743 (2003).

    CAS  Google Scholar 

  51. Yang, L., Stimpson, S.A., Chen, L., Wallace Harrington, W. & Rockey, D.C. Effectiveness of the PPAR-γ agonist, GW570, in liver fibrosis. Inflamm. Res. 59, 1061–1071 (2010).

    CAS  Google Scholar 

  52. Kawai, T. et al. PPAR-γ agonist attenuates renal interstitial fibrosis and inflammation through reduction of TGF-β. Lab. Invest. 89, 47–58 (2009).

    CAS  Google Scholar 

  53. Aoki, Y. et al. Pioglitazone, a peroxisome proliferator–activated receptor-γ ligand, suppresses bleomycin-induced acute lung injury and fibrosis. Respiration 77, 311–319 (2009).

    CAS  Google Scholar 

  54. Levick, S.P. et al. Cardiac mast cells mediate left ventricular fibrosis in the hypertensive rat heart. Hypertension 53, 1041–1047 (2009).

    CAS  Google Scholar 

  55. Reiman, R.M. et al. Interleukin-5 (IL-5) augments the progression of liver fibrosis by regulating IL-13 activity. Infect. Immun. 74, 1471–1479 (2006).

    CAS  Google Scholar 

  56. Minshall, E.M. et al. Eosinophil-associated TGF-β1 mRNA expression and airways fibrosis in bronchial asthma. Am. J. Respir. Cell Mol. Biol. 17, 326–333 (1997).

    CAS  Google Scholar 

  57. Humbles, A.A. et al. A critical role for eosinophils in allergic airways remodeling. Science 305, 1776–1779 (2004).

    CAS  Google Scholar 

  58. Levi-Schaffer, F. et al. Human eosinophils regulate human lung- and skin-derived fibroblast properties in vitro: a role for transforming growth factor-β (TGF-β). Proc. Natl. Acad. Sci. USA 96, 9660–9665 (1999).

    CAS  Google Scholar 

  59. Peterson, M.W., Monick, M. & Hunninghake, G.W. Prognostic role of eosinophils in pulmonary fibrosis. Chest 92, 51–56 (1987).

    CAS  Google Scholar 

  60. Gilbert, H.S. Myelofibrosis revisited: characterization and classification of myelofibrosis in the setting of myeloproliferative disease. Prog. Clin. Biol. Res. 154, 3–17 (1984).

    CAS  Google Scholar 

  61. Wilson, M.S. et al. Bleomycin and IL-1β–mediated pulmonary fibrosis is IL-17A dependent. J. Exp. Med. 207, 535–552 (2010).

    CAS  Google Scholar 

  62. Faust, S.M. et al. Role of T cell TGF-β signaling and IL-17 in allograft acceptance and fibrosis associated with chronic rejection. J. Immunol. 183, 7297–7306 (2009).

    CAS  Google Scholar 

  63. Fan, L. et al. Neutralizing IL-17 prevents obliterative bronchiolitis in murine orthotopic lung transplantation. Am. J. Transplant. 11, 911–922 (2011).

    CAS  Google Scholar 

  64. Feng, W. et al. IL-17 induces myocardial fibrosis and enhances RANKL/OPG and MMP/TIMP signaling in isoproterenol-induced heart failure. Exp. Mol. Pathol. 87, 212–218 (2009).

    CAS  Google Scholar 

  65. Wang, L., Chen, S.J. & Xu, K.S. IL-17 expression is correlated with hepatitis B–related liver diseases and fibrosis. Int. J. Mol. Med. 27, 385–392 (2011).

    CAS  Google Scholar 

  66. Laan, M. et al. Neutrophil recruitment by human IL-17 via CXC chemokine release in the airways. J. Immunol. 162, 2347–2352 (1999).

    CAS  Google Scholar 

  67. Zhu, F. et al. IL-17 induces apoptosis of vascular endothelial cells—a potential mechanism for human acute coronary syndrome. Clin. Immunol. 141, 152–160 (2011).

    CAS  Google Scholar 

  68. Kinder, B.W. et al. Baseline BAL neutrophilia predicts early mortality in idiopathic pulmonary fibrosis. Chest 133, 226–232 (2008).

    CAS  Google Scholar 

  69. Gasse, P. et al. IL-1 and IL-23 mediate early IL-17A production in pulmonary inflammation leading to late fibrosis. PLoS ONE 6, e23185 (2011).

    CAS  Google Scholar 

  70. Cortez, D.M. et al. IL-17 stimulates MMP-1 expression in primary human cardiac fibroblasts via p38 MAPK- and ERK1/2-dependent C/EBP-β, NF-κB and AP-1 activation. Am. J. Physiol. Heart Circ. Physiol. 293, H3356–H3365 (2007).

    CAS  Google Scholar 

  71. Wynn, T.A. et al. An IL-12–based vaccination method for preventing fibrosis induced by schistosome infection. Nature 376, 594–596 (1995).

    CAS  Google Scholar 

  72. Wynn, T.A. Fibrotic disease and the TH1/TH2 paradigm. Nat. Rev. Immunol. 4, 583–594 (2004).

    CAS  Google Scholar 

  73. Ong, C., Wong, C., Roberts, C.R., Teh, H.S. & Jirik, F.R. Anti–IL-4 treatment prevents dermal collagen deposition in the tight-skin mouse model of scleroderma. Eur. J. Immunol. 28, 2619–2629 (1998).

    CAS  Google Scholar 

  74. Chiaramonte, M.G., Donaldson, D.D., Cheever, A.W. & Wynn, T.A. An IL-13 inhibitor blocks the development of hepatic fibrosis during a T helper type 2–dominated inflammatory response. J. Clin. Invest. 104, 777–785 (1999).

    CAS  Google Scholar 

  75. Yang, G. et al. Anti–IL-13 monoclonal antibody inhibits airway hyper-responsiveness, inflammation and airway remodeling. Cytokine 28, 224–232 (2004).

    CAS  Google Scholar 

  76. Murray, L.A. et al. Hyper-responsiveness of IPF/UIP fibroblasts: interplay between TGF-β1, IL-13 and CCL2. Int. J. Biochem. Cell Biol. 40, 2174–2182 (2008).

    CAS  Google Scholar 

  77. Kolodsick, J.E. et al. Protection from fluorescein isothiocyanate–induced fibrosis in IL-13–deficient, but not IL-4–deficient, mice results from impaired collagen synthesis by fibroblasts. J. Immunol. 172, 4068–4076 (2004).

    CAS  Google Scholar 

  78. Fuschiotti, P. Role of IL-13 in systemic sclerosis. Cytokine 56, 544–549 (2011).

    CAS  Google Scholar 

  79. Oh, M.H. et al. IL-13 induces skin fibrosis in atopic dermatitis by thymic stromal lymphopoietin. J. Immunol. 186, 7232–7242 (2011).

    CAS  Google Scholar 

  80. Han, G., Zhang, H., Xie, C.H. & Zhou, Y.F. TH2-like immune response in radiation-induced lung fibrosis. Oncol. Rep. 26, 383–388 (2011).

    CAS  Google Scholar 

  81. Heller, F., Fuss, I.J., Nieuwenhuis, E.E., Blumberg, R.S. & Strober, W. Oxazolone colitis, a TH2 colitis model resembling ulcerative colitis, is mediated by IL-13–producing NKT cells. Immunity 17, 629–638 (2002).

    CAS  Google Scholar 

  82. Weng, H.L. et al. The etiology of liver damage imparts cytokines transforming growth factor-β1 or interleukin-13 as driving forces in fibrogenesis. Hepatology 50, 230–243 (2009).

    CAS  Google Scholar 

  83. Shimamura, T. et al. Novel role of IL-13 in fibrosis induced by nonalcoholic steatohepatitis and its amelioration by IL-13R–directed cytotoxin in a rat model. J. Immunol. 181, 4656–4665 (2008).

    CAS  Google Scholar 

  84. Lee, C.G. et al. Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor-β1. J. Exp. Med. 194, 809–822 (2001).

    CAS  Google Scholar 

  85. Liu, Y. et al. IL-13 induces connective tissue growth factor in rat hepatic stellate cells via TGF-β–independent Smad signaling. J. Immunol. 187, 2814–2823 (2011).

    CAS  Google Scholar 

  86. Kaviratne, M. et al. IL-13 activates a mechanism of tissue fibrosis that is completely TGF-β independent. J. Immunol. 173, 4020–4029 (2004).

    CAS  Google Scholar 

  87. Kuperman, D.A. et al. Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma. Nat. Med. 8, 885–889 (2002).

    CAS  Google Scholar 

  88. Lee, J.H. et al. Interleukin-13 induces dramatically different transcriptional programs in three human airway cell types. Am. J. Respir. Cell Mol. Biol. 25, 474–485 (2001).

    CAS  Google Scholar 

  89. Wilson, M.S. et al. Colitis and intestinal inflammation in IL10−/− mice results from IL-13Rα2–mediated attenuation of IL-13 activity. Gastroenterology 140, 254–264 e2 (2011).

    CAS  Google Scholar 

  90. Ramalingam, T.R. et al. Unique functions of the type II interleukin-4 receptor identified in mice lacking the interleukin-13 receptor-α1 chain. Nat. Immunol. 9, 25–33 (2008).

    CAS  Google Scholar 

  91. Chiaramonte, M.G. et al. Regulation and function of the interleukin-13 receptor-α2 during a T helper cell type 2–dominant immune response. J. Exp. Med. 197, 687–701 (2003).

    CAS  Google Scholar 

  92. Mentink-Kane, M.M. et al. Accelerated and progressive and lethal liver fibrosis in mice that lack interleukin (IL)-10, IL-12p40, and IL-13Rα2. Gastroenterology 141, 2200–2209 (2011).

    CAS  Google Scholar 

  93. Mentink-Kane, M.M. & Wynn, T.A. Opposing roles for IL-13 and IL-13 receptor-α2 in health and disease. Immunol. Rev. 202, 191–202 (2004).

    CAS  Google Scholar 

  94. Baroni, G.S. et al. Interferon-γ decreases hepatic stellate cell activation and extracellular matrix deposition in rat liver fibrosis. Hepatology 23, 1189–1199 (1996).

    CAS  Google Scholar 

  95. Giri, S.N., Hyde, D.M. & Marafino, B.J. Jr. Ameliorating effect of murine interferon-γ on bleomycin-induced lung collagen fibrosis in mice. Biochem. Med. Metab. Biol. 36, 194–197 (1986).

    CAS  Google Scholar 

  96. Oldroyd, S.D., Thomas, G.L., Gabbiani, G. & El Nahas, A.M. Interferon-γ inhibits experimental renal fibrosis. Kidney Int. 56, 2116–2127 (1999).

    CAS  Google Scholar 

  97. Kim, J.H. et al. Natural killer T (NKT) cells attenuate bleomycin-induced pulmonary fibrosis by producing interferon-γ. Am. J. Pathol. 167, 1231–1241 (2005).

    CAS  Google Scholar 

  98. Jeong, W.I., Park, O. & Gao, B. Abrogation of the antifibrotic effects of natural killer cells/interferon-γ contributes to alcohol acceleration of liver fibrosis. Gastroenterology 134, 248–258 (2008).

    CAS  Google Scholar 

  99. Ulloa, L., Doody, J. & Massague, J. Inhibition of transforming growth factor-β/SMAD signalling by the interferon-γ/STAT pathway. Nature 397, 710–713 (1999).

    CAS  Google Scholar 

  100. Gurujeyalakshmi, G. & Giri, S.N. Molecular mechanisms of antifibrotic effect of interferon-γ in bleomycin mouse model of lung fibrosis: downregulation of TGF-β and procollagen I and III gene expression. Exp. Lung Res. 21, 791–808 (1995).

    CAS  Google Scholar 

  101. Shao, D.D., Suresh, R., Vakil, V., Gomer, R.H. & Pilling, D. Pivotal advance: TH1 cytokines inhibit, and TH2 cytokines promote fibrocyte differentiation. J. Leukoc. Biol. 83, 1323–1333 (2008).

    CAS  Google Scholar 

  102. Keane, M.P., Belperio, J.A., Burdick, M.D. & Strieter, R.M. IL-12 attenuates bleomycin-induced pulmonary fibrosis. Am. J. Physiol. Lung Cell Mol. Physiol. 281, L92–L97 (2001).

    CAS  Google Scholar 

  103. King, T.E. Jr. et al. Effect of interferon-γ-1b on survival in patients with idiopathic pulmonary fibrosis (INSPIRE): a multicentre, randomised, placebo-controlled trial. Lancet 374, 222–228 (2009).

    CAS  Google Scholar 

  104. Kotsianidis, I. et al. Global impairment of CD4+CD25+FOXP3+ regulatory T cells in idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 179, 1121–1130 (2009).

    CAS  Google Scholar 

  105. Vetrone, S.A. et al. Osteopontin promotes fibrosis in dystrophic mouse muscle by modulating immune cell subsets and intramuscular TGF-β. J. Clin. Invest. 119, 1583–1594 (2009).

    CAS  Google Scholar 

  106. Kanellakis, P., Dinh, T.N., Agrotis, A. & Bobik, A. CD4+CD25+Foxp3+ regulatory T cells suppress cardiac fibrosis in the hypertensive heart. J. Hypertens. 29, 1820–1828 (2011).

    CAS  Google Scholar 

  107. Zhang, J.L. et al. CD3 mAb treatment ameliorated the severity of the cGVHD-induced lupus nephritis in mice by upregulation of Foxp3+ regulatory T cells in the target tissue: kidney. Transpl. Immunol. 24, 17–25 (2010).

    Google Scholar 

  108. Claassen, M.A., de Knegt, R.J., Tilanus, H.W., Janssen, H.L. & Boonstra, A. Abundant numbers of regulatory T cells localize to the liver of chronic hepatitis C–infected patients and limit the extent of fibrosis. J. Hepatol. 52, 315–321 (2010).

    CAS  Google Scholar 

  109. Estes, J.D. et al. Simian immunodeficiency virus-induced lymphatic tissue fibrosis is mediated by transforming growth factor-β1–positive regulatory T cells and begins in early infection. J. Infect. Dis. 195, 551–561 (2007).

    CAS  Google Scholar 

  110. Liu, F. et al. CD4+CD25+Foxp3+ regulatory T cells depletion may attenuate the development of silica-induced lung fibrosis in mice. PLoS ONE 5, e15404 (2010).

    Google Scholar 

  111. Baarsma, H.A. et al. Activation of Wnt/β-catenin signaling in pulmonary fibroblasts by TGF-β is increased in chronic obstructive pulmonary disease. PLoS ONE 6, e25450 (2011).

    CAS  Google Scholar 

  112. Wei, J. et al. Canonical Wnt signaling induces skin fibrosis and subcutaneous lipoatrophy: a novel mouse model for scleroderma? Arthritis Rheum. 63, 1707–1717 (2011).

    CAS  Google Scholar 

  113. Surendran, K., Schiavi, S. & Hruska, K.A. Wnt-dependent β-catenin signaling is activated after unilateral ureteral obstruction, and recombinant secreted frizzled-related protein 4 alters the progression of renal fibrosis. J. Am. Soc. Nephrol. 16, 2373–2384 (2005).

    CAS  Google Scholar 

  114. Wang, D., Dai, C., Li, Y. & Liu, Y. Canonical Wnt/β-catenin signaling mediates transforming growth factor-β1–driven podocyte injury and proteinuria. Kidney Int. 80, 1159–1169 (2011).

    CAS  Google Scholar 

  115. Jiang, F., Parsons, C.J. & Stefanovic, B. Gene-expression profile of quiescent and activated rat hepatic stellate cells implicates Wnt signaling pathway in activation. J. Hepatol. 45, 401–409 (2006).

    CAS  Google Scholar 

  116. Königshoff, M. et al. WNT1-inducible signaling protein-1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis. J. Clin. Invest. 119, 772–787 (2009).

    Google Scholar 

  117. Hinz, B., Celetta, G., Tomasek, J.J., Gabbiani, G. & Chaponnier, C. α-smooth muscle actin expression upregulates fibroblast contractile activity. Mol. Biol. Cell 12, 2730–2741 (2001).

    CAS  Google Scholar 

  118. Heise, R.L., Stober, V., Cheluvaraju, C., Hollingsworth, J.W. & Garantziotis, S. Mechanical stretch induces epithelial-mesenchymal transition in alveolar epithelia via hyaluronan activation of innate immunity. J. Biol. Chem. 286, 17435–17444 (2011).

    CAS  Google Scholar 

  119. Chen, J.H., Chen, W.L., Sider, K.L., Yip, C.Y. & Simmons, C.A. β-catenin mediates mechanically regulated, transforming growth factor-β1–induced myofibroblast differentiation of aortic valve interstitial cells. Arterioscler. Thromb. Vasc. Biol. 31, 590–597 (2011).

    CAS  Google Scholar 

  120. Balestrini, J.L., Chaudhry, S., Sarrazy, V., Koehler, A. & Hinz, B. The mechanical memory of lung myofibroblasts. Integr. Biol. 4, 410–421 (2012).

    CAS  Google Scholar 

  121. Hinz, B. Tissue stiffness, latent TGF-β1 activation, and mechanical signal transduction: implications for the pathogenesis and treatment of fibrosis. Curr. Rheumatol. Rep. 11, 120–126 (2009).

    CAS  Google Scholar 

  122. Bechtel, W. et al. Methylation determines fibroblast activation and fibrogenesis in the kidney. Nat. Med. 16, 544–550 (2010).

    CAS  Google Scholar 

  123. Coward, W.R., Watts, K., Feghali-Bostwick, C.A., Jenkins, G. & Pang, L. Repression of IP-10 by interactions between histone deacetylation and hypermethylation in idiopathic pulmonary fibrosis. Mol. Cell Biol. 30, 2874–2886 (2010).

    CAS  Google Scholar 

  124. Sanders, Y.Y. et al. Thy-1 promoter hypermethylation: a novel epigenetic pathogenic mechanism in pulmonary fibrosis. Am. J. Respir. Cell Mol. Biol. 39, 610–618 (2008).

    CAS  Google Scholar 

  125. Malhi, H. & Gores, G.J. Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease. Semin. Liver Dis. 28, 360–369 (2008).

    CAS  Google Scholar 

  126. Korfei, M. et al. Epithelial endoplasmic reticulum stress and apoptosis in sporadic idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 178, 838–846 (2008).

    CAS  Google Scholar 

  127. Lawson, W.E. et al. Endoplasmic reticulum stress in alveolar epithelial cells is prominent in IPF: association with altered surfactant protein processing and herpesvirus infection. Am. J. Physiol. Lung Cell Mol. Physiol. 294, L1119–L1126 (2008).

    CAS  Google Scholar 

  128. Calado, R.T. & Young, N.S. Telomere diseases. N. Engl. J. Med. 361, 2353–2365 (2009).

    CAS  Google Scholar 

  129. Tsakiri, K.D. et al. Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc. Natl. Acad. Sci. USA 104, 7552–7557 (2007).

    CAS  Google Scholar 

  130. Cronkhite, J.T. et al. Telomere shortening in familial and sporadic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 178, 729–737 (2008).

    CAS  Google Scholar 

  131. Alder, J.K. et al. Short telomeres are a risk factor for idiopathic pulmonary fibrosis. Proc. Natl. Acad. Sci. USA 105, 13051–13056 (2008).

    CAS  Google Scholar 

  132. Armanios, M.Y. et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N. Engl. J. Med. 356, 1317–1326 (2007).

    CAS  Google Scholar 

  133. Lee, J. et al. Lung alveolar integrity is compromised by telomere shortening in telomerase-null mice. Am. J. Physiol. Lung Cell Mol. Physiol. 296, L57–L70 (2009).

    CAS  Google Scholar 

  134. Liu, T. et al. Telomerase regulation of myofibroblast differentiation. Am. J. Respir. Cell Mol. Biol. 34, 625–633 (2006).

    CAS  Google Scholar 

  135. Li, H., Xu, D., Li, J., Berndt, M.C. & Liu, J.P. Transforming growth factor-β suppresses human telomerase reverse transcriptase (hTERT) by Smad3 interactions with c-Myc and the hTERT gene. J. Biol. Chem. 281, 25588–25600 (2006).

    CAS  Google Scholar 

  136. Proctor, C.J. & Kirkwood, T.B. Modelling telomere shortening and the role of oxidative stress. Mech. Ageing Dev. 123, 351–363 (2002).

    CAS  Google Scholar 

  137. Liu, T. et al. Telomerase activity is required for bleomycin-induced pulmonary fibrosis in mice. J. Clin. Invest. 117, 3800–3809 (2007).

    CAS  Google Scholar 

  138. Liu, G. et al. miR-21 mediates fibrogenic activation of pulmonary fibroblasts and lung fibrosis. J. Exp. Med. 207, 1589–1597 (2010).

    CAS  Google Scholar 

  139. Thum, T. et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 456, 980–984 (2008).

    CAS  Google Scholar 

  140. Chan, J.A., Krichevsky, A.M. & Kosik, K.S. MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res. 65, 6029–6033 (2005).

    CAS  Google Scholar 

  141. Patrick, D.M. et al. Stress-dependent cardiac remodeling occurs in the absence of microRNA-21 in mice. J. Clin. Invest. 120, 3912–3916 (2010).

    CAS  Google Scholar 

  142. Chung, A.C., Huang, X.R., Meng, X. & Lan, H.Y. miR-192 mediates TGF-β/Smad3-driven renal fibrosis. J. Am. Soc. Nephrol. 21, 1317–1325 (2010).

    CAS  Google Scholar 

  143. Kato, M. et al. TGF-β activates Akt kinase through a microRNA-dependent amplifying circuit targeting PTEN. Nat. Cell Biol. 11, 881–889 (2009).

    CAS  Google Scholar 

  144. Maurer, B. et al. MicroRNA-29, a key regulator of collagen expression in systemic sclerosis. Arthritis Rheum. 62, 1733–1743 (2010).

    CAS  Google Scholar 

  145. Roderburg, C. et al. Micro-RNA profiling reveals a role for miR-29 in human and murine liver fibrosis. Hepatology 53, 209–218 (2011).

    CAS  Google Scholar 

  146. van Rooij, E. et al. Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis. Proc. Natl. Acad. Sci. USA 105, 13027–13032 (2008).

    CAS  Google Scholar 

  147. Ogawa, T. et al. Suppression of type I collagen production by microRNA-29b in cultured human stellate cells. Biochem. Biophys. Res. Commun. 391, 316–321 (2010).

    CAS  Google Scholar 

  148. Pandit, K.V. et al. Inhibition and role of let-7d in idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 182, 220–229 (2010).

    CAS  Google Scholar 

  149. Duisters, R.F. et al. miR-133 and miR-30 regulate connective tissue growth factor: implications for a role of microRNAs in myocardial matrix remodeling. Circ. Res. 104, 170–178 (2009).

    CAS  Google Scholar 

  150. Venugopal, S.K. et al. Liver fibrosis causes downregulation of miRNA-150 and miRNA-194 in hepatic stellate cells, and their overexpression causes decreased stellate cell activation. Am. J. Physiol. Gastrointest. Liver Physiol. 298, G101–G106 (2010).

    CAS  Google Scholar 

  151. Wang, B. et al. miR-200a Prevents renal fibrogenesis through repression of TGF-β2 expression. Diabetes 60, 280–287 (2011).

    CAS  Google Scholar 

  152. Richeldi, L. & du Bois, R.M. Pirfenidone in idiopathic pulmonary fibrosis: the CAPACITY program. Expert Rev. Respir. Med. 5, 473–481 (2011).

    CAS  Google Scholar 

  153. Nakanishi, H., Sugiura, T., Streisand, J.B., Lonning, S.M. & Roberts, J.D. Jr. TGF-β–neutralizing antibodies improve pulmonary alveologenesis and vasculogenesis in the injured newborn lung. Am. J. Physiol. Lung Cell Mol. Physiol. 293, L151–L161 (2007).

    CAS  Google Scholar 

  154. Munger, J.S. et al. The integrin αvβ6 binds and activates latent TGF-β1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 96, 319–328 (1999).

    CAS  Google Scholar 

  155. Hahm, K. et al. αvβ6 integrin regulates renal fibrosis and inflammation in Alport mouse. Am. J. Pathol. 170, 110–125 (2007).

    CAS  Google Scholar 

  156. Hemavathy, K. & Wang, J.C. Epigenetic modifications: new therapeutic targets in primary myelofibrosis. Curr. Stem Cell Res. Ther. 4, 281–286 (2009).

    CAS  Google Scholar 

  157. Tedstone, J.L., Richards, S.M., Garman, R.D. & Ruzek, M.C. Ultrasound imaging accurately detects skin thickening in a mouse scleroderma model. Ultrasound Med. Biol. 34, 1239–1247 (2008).

    Google Scholar 

  158. Kono, M. et al. Plasma CCN2 (connective tissue growth factor; CTGF) is a potential biomarker in idiopathic pulmonary fibrosis (IPF). Clin. Chim. Acta 412, 2211–2215 (2011).

    CAS  Google Scholar 

  159. Pradère, J.P. et al. LPA1 receptor activation promotes renal interstitial fibrosis. J. Am. Soc. Nephrol. 18, 3110–3118 (2007).

    Google Scholar 

  160. Tager, A.M. et al. The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak. Nat. Med. 14, 45–54 (2008).

    CAS  Google Scholar 

  161. Zeisberg, M. et al. BMP-7 counteracts TGF-β1–induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat. Med. 9, 964–968 (2003).

    CAS  Google Scholar 

  162. Sidharta, P.N., van Giersbergen, P.L., Halabi, A. & Dingemanse, J. Macitentan: entry-into-humans study with a new endothelin receptor antagonist. Eur. J. Clin. Pharmacol. 67, 977–984 (2011).

    CAS  Google Scholar 

  163. Barry-Hamilton, V. et al. Allosteric inhibition of lysyl oxidase–like-2 impedes the development of a pathologic microenvironment. Nat. Med. 16, 1009–1017 (2010).

    CAS  Google Scholar 

  164. Myllyharju, J. Prolyl 4-hydroxylases, key enzymes in the synthesis of collagens and regulation of the response to hypoxia, and their roles as treatment targets. Ann. Med. 40, 402–417 (2008).

    CAS  Google Scholar 

  165. Fineschi, S. et al. In vivo investigations on antifibrotic potential of proteasome inhibition in lung and skin fibrosis. Am. J. Respir. Cell Mol. Biol. 39, 458–465 (2008).

    CAS  Google Scholar 

  166. Anan, A. et al. Proteasome inhibition induces hepatic stellate cell apoptosis. Hepatology 43, 335–344 (2006).

    CAS  Google Scholar 

  167. Kralovics, R. et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N. Engl. J. Med. 352, 1779–1790 (2005).

    CAS  Google Scholar 

  168. Daniels, C.E. et al. Imatinib treatment for idiopathic pulmonary fibrosis: randomized placebo-controlled trial results. Am. J. Respir. Crit. Care Med. 181, 604–610 (2010).

    CAS  Google Scholar 

  169. Kay, J. & High, W.A. Imatinib mesylate treatment of nephrogenic systemic fibrosis. Arthritis Rheum. 58, 2543–2548 (2008).

    CAS  Google Scholar 

  170. Richeldi, L. et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N. Engl. J. Med. 365, 1079–1087 (2011).

    CAS  Google Scholar 

  171. Verstovsek, S. Therapeutic potential of Janus-activated kinase-2 inhibitors for the management of myelofibrosis. Clin. Cancer Res. 16, 1988–1996 (2010).

    CAS  Google Scholar 

  172. Pockros, P.J. et al. Final results of a double-blind, placebo-controlled trial of the antifibrotic efficacy of interferon-γ1b in chronic hepatitis C patients with advanced fibrosis or cirrhosis. Hepatology 45, 569–578 (2007).

    CAS  Google Scholar 

  173. Noble, P.W., Richeldi, L. & Kaminski, N. End of an ERA: lessons from negative clinical trials in idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 184, 4–5 (2011).

    Google Scholar 

  174. Park, S.W. et al. Interleukin-13 and its receptors in idiopathic interstitial pneumonia: clinical implications for lung function. J. Korean Med. Sci. 24, 614–620 (2009).

    CAS  Google Scholar 

  175. Corren, J. et al. Lebrikizumab treatment in adults with asthma. N. Engl. J. Med. 365, 1088–1098 (2011).

    CAS  Google Scholar 

  176. Kraft, M. Asthma phenotypes and interleukin-13—moving closer to personalized medicine. N. Engl. J. Med. 365, 1141–1144 (2011).

    CAS  Google Scholar 

  177. Ekert, J.E. et al. Chemokine (C-C motif) ligand-2 mediates direct and indirect fibrotic responses in human and murine cultured fibrocytes. Fibrogenesis Tissue Repair 4, 23 (2011).

    CAS  Google Scholar 

  178. Duffield, J.S. & Lupher, M.L. Jr. PRM-151 (recombinant human serum amyloid P/pentraxin 2) for the treatment of fibrosis. Drug News Perspect. 23, 305–315 (2010).

    CAS  Google Scholar 

  179. Castaño, A.P. et al. Serum amyloid P inhibits fibrosis through FcγR-dependent monocyte-macrophage regulation in vivo. Sci. Transl. Med. 1, 5ra13 (2009).

    Google Scholar 

  180. McKinsey, T.A. Therapeutic potential for HDAC inhibitors in the heart. Annu. Rev. Pharmacol. Toxicol. 52, 303–319 (2012).

    CAS  Google Scholar 

  181. Dart, M.L. et al. Interleukin-17–dependent autoimmunity to collagen type V in atherosclerosis. Circ. Res. 107, 1106–1116 (2010).

    CAS  Google Scholar 

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Acknowledgements

We would like to sincerely thank the past and present members of our laboratory for their guidance, comments and support. The Wynn laboratory is supported by the intramural research program of the US National Institutes of Health, National Institute of Allergy and Infectious Diseases and has benefited from cooperative research-and-development agreements with Pfizer, MedImmune, Amgen, Regeneron, Centocor and Genentech.

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Correspondence to Thomas A Wynn.

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T.A.W. holds patents on IL-13 as a target for fibrotic disease.

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Wynn, T., Ramalingam, T. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med 18, 1028–1040 (2012). https://doi.org/10.1038/nm.2807

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