Skip to main content Accessibility help
×
×
Home

Myofibroblast differentiation and survival in fibrotic disease

  • Kornelia Kis (a1), Xiaoqiu Liu (a1) and James S. Hagood (a1) (a2)

Abstract

During wound healing, contractile fibroblasts called myofibroblasts regulate the formation and contraction of granulation tissue; however, pathological and persistent myofibroblast activation, which occurs in hypertrophic scars or tissue fibrosis, results in a loss of function. Many reviews outline the cellular and molecular features of myofibroblasts and their roles in a variety of diseases. This review focuses on the origins of myofibroblasts and the factors that control their differentiation and prolonged survival in fibrotic tissues. Pulmonary fibrosis is used to illustrate many key points, but examples from other tissues and models are also included. Myofibroblasts originate mostly from tissue-resident fibroblasts, and also from epithelial and endothelial cells or other mesenchymal precursors. Their differentiation is influenced by cytokines, growth factors, extracellular matrix composition and stiffness, and cell surface molecules such as proteoglycans and THY1, among other factors. Many of these effects are modulated by cell contraction. Myofibroblasts resist programmed cell death, which promotes their accumulation in fibrotic tissues. The cause of resistance to apoptosis in myofibroblasts is under ongoing investigation, but many of the same stimuli that regulate their differentiation are involved. The contributions of oxidative stress, the WNT–β-catenin pathway and PPARγ to myofibroblast differentiation and survival are increasingly appreciated.

Copyright

Corresponding author

*Corresponding author: James S. Hagood, University of California-San Diego, 9500 Gilman Drive, MC 0731, San Diego, CA 92093-0731. E-mail: jhagood@ucsd.edu

References

Hide All
1Clark, R.A.F. (1996) Wound repair: overview and general considerations. In The Molecular and Cellular Biology of Wound Repair (Clark, R.A.F., ed.), pp. 3-50, Plenum Press, New York
2Gabbiani, G. (2003) The myofibroblast in wound healing and fibrocontractive diseases. Journal of Pathology 200, 500-503
3Hardie, W.D., Glasser, S.W. and Hagood, J.S. (2009) Emerging concepts in the pathogenesis of lung fibrosis. American Journal of Pathology 175, 3-16
4Hinz, B. (2007) Formation and function of the myofibroblast during tissue repair. Journal of Investigative Dermatology 127, 526-537
5Thiery, J.P. et al. (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139, 871-890
6Kalluri, R. and Neilson, E.G. (2003) Epithelial-mesenchymal transition and its implications for fibrosis. Journal of Clinical Investigation 112, 1776-1784
7Zavadil, J. and Böttinger, E.P. (2005) TGF-beta and epithelial-to-mesenchymal transitions. Oncogene 24, 5764-5774
8Iwano, M. et al. (2002) Evidence that fibroblasts derive from epithelium during tissue fibrosis. Journal of Clinical Investigation 110, 341-350
9Osterreicher, C.H. et al. (2011) Fibroblast-specific protein 1 identifies an inflammatory subpopulation of macrophages in the liver. Proceedings of the National Academy of Sciences of the United States of America 108, 308-313
10Zeisberg, M. et al. (2007) Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. Journal of Biological Chemistry 282, 23337-23347
11Zeisberg, E.M. et al. (2007) Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nature Medicine 13, 952-961
12Zeisberg, E.M. et al. (2008) Fibroblasts in kidney fibrosis emerge via endothelial-to-mesenchymal transition. Journal of the American Society of Nephrology 19, 2282-2287
13Kim, K.K. et al. (2009) Epithelial cell alpha3beta1 integrin links beta-catenin and Smad signaling to promote myofibroblast formation and pulmonary fibrosis. Journal of Clinical Investigation 119, 213-224
14Câmara, J. and Jarai, G. (2010) Epithelial-mesenchymal transition in primary human bronchial epithelial cells is Smad-dependent and enhanced by fibronectin and TNF-alpha. Fibrogenesis & Tissue Repair 3, 2
15Scholten, D. et al. (2010) Genetic labeling does not detect epithelial-to-mesenchymal transition of cholangiocytes in liver fibrosis in mice. Gastroenterology 139, 987-998
16Humphreys, B.D. et al. (2010) Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. American Journal of Pathology 176, 85-97
17Tanjore, H. et al. (2009) Contribution of epithelial-derived fibroblasts to bleomycin-induced lung fibrosis. American Journal of Respiratory and Critical Care Medicine 180, 657-665
18Li, J. and Bertram, J.F. (2010) Review: endothelial–myofibroblast transition, a new player in diabetic renal fibrosis. Nephrology (Carlton, Victoria) 15, 507-512
19Nataraj, D., Ernst, A. and Kalluri, R. (2010) Idiopathic pulmonary fibrosis is associated with endothelial to mesenchymal transition. American Journal of Respiratory Cell and Molecular Biology 43, 129-130
20Potenta, S., Zeisberg, E. and Kalluri, R. (2008) The role of endothelial-to-mesenchymal transition in cancer progression. British Journal of Cancer 99, 1375-1379
21Widyantoro, B. et al. (2010) Endothelial cell-derived endothelin-1 promotes cardiac fibrosis in diabetic hearts through stimulation of endothelial-to-mesenchymal transition. Circulation 121, 2407-2418
22Hashimoto, N. et al. (2010) Endothelial-mesenchymal transition in bleomycin-induced pulmonary fibrosis. American Journal of Respiratory Cell and Molecular Biology 43, 161-172
23Arciniegas, E. et al. (2007) Perspectives on endothelial-to-mesenchymal transition: potential contribution to vascular remodeling in chronic pulmonary hypertension. American Journal of Physiology. Lung Cellular and Molecular Physiology 293, L1-L8
24Hashimoto, N. et al. (2004) Bone marrow-derived progenitor cells in pulmonary fibrosis. Journal of Clinical Investigation 113, 243-252
25Moeller, A. et al. (2009) Circulating fibrocytes are an indicator of poor prognosis in idiopathic pulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine 179, 588-594
26Moore, B.B. et al. (2005) CCR2-mediated recruitment of fibrocytes to the alveolar space after fibrotic injury. American Journal of Pathology 166, 675-684
27Andersson-Sjöland, A. et al. (2008) Fibrocytes are a potential source of lung fibroblasts in idiopathic pulmonary fibrosis. The International Journal of Biochemistry and Cell Biology 40, 2129-2140
28García-de-Alba, C. et al. (2010) Expression of matrix metalloproteases by fibrocytes: possible role in migration and homing. American Journal of Respiratory and Critical Care Medicine 182, 1144-1152
29Phillips, R.J. et al. (2004) Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. Journal of Clinical Investigation 114, 438-446
30Abe, R. et al. (2001) Peripheral blood fibrocytes: differentiation pathway and migration to wound sites. Journal of Immunology 166, 7556-7562
31Strieter, R.M. et al. (2009) The role of circulating mesenchymal progenitor cells, fibrocytes, in promoting pulmonary fibrosis. Transactions of the American Clinical and Climatological Association 120, 49-59
32Asanuma, H. et al. (2011) Arterially delivered mesenchymal stem cells prevent obstruction-induced renal fibrosis. Journal of Surgical Research 168, e51-e59
33Popova, A.P. et al. (2010) Autocrine production of TGF-beta1 promotes myofibroblastic differentiation of neonatal lung mesenchymal stem cells. American Journal of Physiology. Lung Cellular and Molecular Physiology 298, L735-L743
34Lee, C.H. et al. (2010) CTGF directs fibroblast differentiation from human mesenchymal stem/stromal cells and defines connective tissue healing in a rodent injury model. Journal of Clinical Investigation 120, 3340-3349
35Atamas, S.P. and White, B. (2003) Cytokine regulation of pulmonary fibrosis in scleroderma. Cytokine and Growth Factor Reviews 14, 537-550
36Knight, D.A. et al. (2003) The role of gp130/IL-6 cytokines in the development of pulmonary fibrosis: critical determinants of disease susceptibility and progression? Pharmacology and Therapeutics 99, 327-338
37Lasky, J.A. and Brody, A.R. (2000) Interstitial fibrosis and growth factors. Environmental Health Perspectives 108 (Suppl 4), 751-762
38Yang, L. et al. (2008) IL-21 and TGF-beta are required for differentiation of human T(H)17 cells. Nature 454, 350-352
39Wilson, M.S. et al. (2010) Bleomycin and IL-1beta-mediated pulmonary fibrosis is IL-17A dependent. Journal of Experimental Medicine 207, 535-552
40Yagi, Y. et al. (2007) Inflammatory responses induced by interleukin-17 family members in human colonic subepithelial myofibroblasts. Journal of Gastroenterology 42, 746-753
41Turner, N.A. et al. (2009) Interleukin-1alpha stimulates proinflammatory cytokine expression in human cardiac myofibroblasts. American Journal of Physiology. Heart and Circulatory Physiology 297, H1117-H1127
42Collard, H.R. et al. (2010) Plasma biomarker profiles in acute exacerbation of idiopathic pulmonary fibrosis. American Journal of Physiology. Lung Cellular and Molecular Physiology 299, L3-L7
43Huaux, F. et al. (2003) Dual roles of IL-4 in lung injury and fibrosis. Journal of Immunology 170, 2083-2092
44Zhou, Y., Hagood, J.S. and Murphy-Ullrich, J.E. (2004) Thy-1 expression regulates the ability of rat lung fibroblasts to activate transforming growth factor-{beta} in response to fibrogenic stimuli. American Journal of Pathology 165, 659-669
45Waddington, S.N. et al. (2010) Gene delivery of a mutant TGFβ3 reduces markers of scar tissue formation after cutaneous wounding. Molecular Therapy: The Journal of the American Society of Gene Therapy 18, 2104-2111
46Liu, X., Kelm, R.J. and Strauch, A.R. (2009) Transforming growth factor beta1-mediated activation of the smooth muscle alpha-actin gene in human pulmonary myofibroblasts is inhibited by tumor necrosis factor-alpha via mitogen-activated protein kinase kinase 1-dependent induction of the Egr-1 transcriptional repressor. Molecular Biology of the Cell 20, 2174-2185
47Bhatnagar, S. et al. (2010) Transforming growth factor-beta-activated kinase 1 is an essential regulator of myogenic differentiation. Journal of Biological Chemistry 285, 6401-6411
48Liu, T. et al. (2004) FIZZ1 stimulation of myofibroblast differentiation. American Journal of Pathology 164, 1315-1326
49Lin, X. et al. (2010) Yin Yang 1 is a novel regulator of pulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine 183, 1689-1697
50Hagood, J.S. et al. (2005) Loss of fibroblast Thy-1 expression correlates with lung fibrogenesis. American Journal of Pathology 167, 365-379
51Sanders, Y.Y. et al. (2008) Epigenetic regulation mediates thy-1 gene silencing and induction of the myofibroblast phenotype. Proceedings of the American Thoracic Society 5, 363-364
52Sanders, Y.Y., Kumbla, P. and Hagood, J.S. (2007) Enhanced myofibroblastic differentiation and survival in Thy-1(-) lung fibroblasts. American Journal of Respiratory Cell and Molecular Biology 36, 226-235
53Sanders, Y.Y. et al. (2008) Thy-1 promoter hypermethylation: a novel epigenetic pathogenic mechanism in pulmonary fibrosis. American Journal of Respiratory Cell and Molecular Biology 39, 610-618
54Zhou, Y. et al. (2010) Thy-1-integrin alphav beta5 interactions inhibit lung fibroblast contraction-induced latent transforming growth factor-beta1 activation and myofibroblast differentiation. Journal of Biological Chemistry 285, 22382-22393
55Koumas, L. et al. (2003) Thy-1 expression in human fibroblast subsets defines myofibroblastic or lipofibroblastic phenotypes. American Journal of Pathology 163, 1291-1300
56Lehmann, G.M. et al. (2010) Novel anti-adipogenic activity produced by human fibroblasts. American Journal of Physiology. Cell Physiology 299, C672-C681
57Eckes, B. et al. (2006) Mechanical tension and integrin alpha 2 beta 1 regulate fibroblast functions. Journal of Investigative Dermatology. Symposium Proceedings/the Society for Investigative Dermatology, Inc. [and] European Society for Dermatological Research 11, 66-72
58Tomasek, J.J. et al. (2002) Myofibroblasts and mechano-regulation of connective tissue remodelling. Nature Reviews. Molecular Cell Biology 3, 349-363
59Katsumi, A. et al. (2004) Integrins in mechanotransduction. Journal of Biological Chemistry 279, 12001-12004
60Jenkins, R.G. et al. (2006) Ligation of protease-activated receptor 1 enhances alpha(v)beta6 integrin-dependent TGF-beta activation and promotes acute lung injury. Journal of Clinical Investigation 116, 1606-1614
61Wang, X. et al. (2009) Silencing CD36 gene expression results in the inhibition of latent-TGF-beta1 activation and suppression of silica-induced lung fibrosis in the rat. Respiratory Research 10, 36
62Wipff, P.-J. et al. (2007) Myofibroblast contraction activates latent TGF-beta1 from the extracellular matrix. Journal of Cell Biology 179, 1311-1323
63Zhou, Y. et al. (2009) Latent transforming growth factor-beta-binding protein-4 regulates transforming growth factor-beta1 bioavailability for activation by fibrogenic lung fibroblasts in response to bleomycin. American Journal of Pathology 174, 21-33
64Giancotti, F.G. and Ruoslahti, E. (1999) Integrin signaling. Science 285, 1028-1032
65Choi, S.S. et al. (2010) Activation of Rac1 promotes hedgehog-mediated acquisition of the myofibroblastic phenotype in rat and human hepatic stellate cells. Hepatology 52, 278-290
66Margadant, C. and Sonnenberg, A. (2010) Integrin-TGF-beta crosstalk in fibrosis, cancer and wound healing. EMBO Reports 11, 97-105
67Chan, M.W.C. et al. (2010) Force-induced myofibroblast differentiation through collagen receptors is dependent on mammalian diaphanous (mDia). Journal of Biological Chemistry 285, 9273-9281
68Follonier Castella, L. et al. (2010) Regulation of myofibroblast activities: calcium pulls some strings behind the scene. Experimental Cell Research 316, 2390-2401
69Couchman, J.R. and Woods, A. (1996) Syndecans, signaling, and cell adhesion. Journal of Cellular Biochemistry 61, 578-584
70Yoneda, A. and Couchman, J.R. (2003) Regulation of cytoskeletal organization by syndecan transmembrane proteoglycans. Matrix Biology: Journal of the International Society for Matrix Biology 22, 25-33
71Kennedy, L. et al. (2007) CCN2 is necessary for the function of mouse embryonic fibroblasts. Experimental Cell Research 313, 952-964
72Jiang, D. et al. (2010) Inhibition of pulmonary fibrosis in mice by CXCL10 requires glycosaminoglycan binding and syndecan-4. Journal of Clinical Investigation 120, 2049-2057
73Avalos, A.M. et al. (2009) Neuronal Thy-1 induces astrocyte adhesion by engaging syndecan-4 in a cooperative interaction with alphavbeta3 integrin that activates PKCalpha and RhoA. Journal of Cell Science 122, 3462-3471
74Leto, T.L. et al. (2009) Targeting and regulation of reactive oxygen species generation by Nox family NADPH oxidases. Antioxidants and Redox Signaling 11, 2607-2619
75Kinnula, V.L. et al. (2005) Oxidative stress in pulmonary fibrosis: a possible role for redox modulatory therapy. American Journal of Respiratory and Critical Care Medicine 172, 417-422
76Hecker, L. et al. (2009) NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury. Nature Medicine 15, 1077-1081
77Cucoranu, I. et al. (2005) NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts. Circulation Research 97, 900-907
78Amara, N. et al. (2010) NOX4/NADPH oxidase expression is increased in pulmonary fibroblasts from patients with idiopathic pulmonary fibrosis and mediates TGFbeta1-induced fibroblast differentiation into myofibroblasts. Thorax 65, 733-738
79Toullec, A. et al. (2010) Oxidative stress promotes myofibroblast differentiation and tumour spreading. EMBO Molecular Medicine 2, 211-230
80Van Rheen, Z. et al. (2011) Lung extracellular superoxide dismutase overexpression lessens bleomycin-induced pulmonary hypertension and vascular remodeling. American Journal of Respiratory Cell and Molecular Biology 44, 500-508
81Burgess, H.A. et al. (2005) PPARgamma agonists inhibit TGF-beta induced pulmonary myofibroblast differentiation and collagen production: implications for therapy of lung fibrosis. American Journal of Physiology. Lung Cellular and Molecular Physiology 288, L1146-L1153
82Milam, J.E. et al. (2008) PPAR-gamma agonists inhibit profibrotic phenotypes in human lung fibroblasts and bleomycin-induced pulmonary fibrosis. American Journal of Physiology. Lung Cellular and Molecular Physiology 294, L891-L901
83Lin, Q. et al. (2010) Rosiglitazone inhibits migration, proliferation, and phenotypic differentiation in cultured human lung fibroblasts. Experimental Lung Research 36, 120-128
84Kulkarni, A.A. et al. (2011) PPAR-γ ligands repress TGFβ-induced myofibroblast differentiation by targeting the PI3K/Akt pathway: implications for therapy of fibrosis. PLoS One 6, e15909
85Ferguson, H.E. et al. (2009) Electrophilic peroxisome proliferator-activated receptor-gamma ligands have potent antifibrotic effects in human lung fibroblasts. American Journal of Respiratory Cell and Molecular Biology 41, 722-730
86Ferguson, H.E. et al. (2009) Peroxisome proliferator-activated receptor-gamma ligands induce heme oxygenase-1 in lung fibroblasts by a PPARgamma-independent, glutathione-dependent mechanism. American Journal of Physiology. Lung Cellular and Molecular Physiology 297, L912-L919
87Fagone, E. et al. (2011) Resveratrol inhibits transforming growth factor-beta-induced proliferation and differentiation of ex vivo human lung fibroblasts into myofibroblasts through ERK/Akt inhibition and PTEN restoration. Experimental Lung Research 37, 162-174
88Kikuchi, A., Yamamoto, H. and Kishida, S. (2007) Multiplicity of the interactions of Wnt proteins and their receptors. Cellular Signalling 19, 659-671
89Chang, W. et al. (2010) SPARC suppresses apoptosis of idiopathic pulmonary fibrosis fibroblasts through constitutive activation of beta-catenin. Journal of Biological Chemistry 285, 8196-8206
90He, W. et al. (2009) Wnt/beta-catenin signaling promotes renal interstitial fibrosis. Journal of the American Society of Nephrology 20, 765-776
91Lee, S.H. et al. (2010) ERK activation drives intestinal tumorigenesis in Apc(min/+) mice. Nature Medicine 16, 665-670
92Egger, G. et al. (2004) Epigenetics in human disease and prospects for epigenetic therapy. Nature 429, 457-463
93Reik, W. (2007) Stability and flexibility of epigenetic gene regulation in mammalian development. Nature 447, 425-432
94Laurent, L. et al. (2010) Dynamic changes in the human methylome during differentiation. Genome Research 20, 320-331
95Wang, Y., Fan, P.S. and Kahaleh, B. (2006) Association between enhanced type I collagen expression and epigenetic repression of the FLI1 gene in scleroderma fibroblasts. Arthritis and Rheumatism 54, 2271-2279
96Glenisson, W., Castronovo, V. and Waltregny, D. (2007) Histone deacetylase 4 is required for TGFbeta1-induced myofibroblastic differentiation. Biochimica et Biophysica Acta 1773, 1572-1582
97Guo, W. et al. (2009) Abrogation of TGF-beta1-induced fibroblast-myofibroblast differentiation by histone deacetylase inhibition. American Journal of Physiology. Lung Cellular and Molecular Physiology 297, L864-L870
98Hu, B. et al. (2010) Epigenetic regulation of myofibroblast differentiation by DNA methylation. American Journal of Pathology 177, 21-28
99van Rooij, E. et al. (2008) Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis. Proceedings of the National Academy of Sciences of the United States of America 105, 13027-13032
100Liu, G. et al. (2010) miR-21 mediates fibrogenic activation of pulmonary fibroblasts and lung fibrosis. Journal of Experimental Medicine 207, 1589-1597
101Yao, Q. et al. (2011) Micro-RNA-21 regulates TGF-beta-induced myofibroblast differentiation by targeting PDCD4 in tumor-stroma interaction. International Journal of Cancer 128, 1783-1792
102Mann, J. et al. (2010) MeCP2 controls an epigenetic pathway that promotes myofibroblast transdifferentiation and fibrosis. Gastroenterology 138, 705-714, 714 e701–704
103Chabaud, S. et al. (2011) Decreased secretion of MMP by non-lesional late-stage scleroderma fibroblasts after selection via activation of the apoptotic fas-pathway. Journal of Cellular Physiology 226, 1907-1914
104Fattman, C.L. (2008) Apoptosis in pulmonary fibrosis: too much or not enough? Antioxidants and Redox Signaling 10, 379-385
105Maher, T.M. et al. (2010) Diminished prostaglandin E2 contributes to the apoptosis paradox in idiopathic pulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine 182, 73-82
106Jinta, T. et al. (2010) The pathogenesis of chronic hypersensitivity pneumonitis in common with idiopathic pulmonary fibrosis: expression of apoptotic markers. American Journal of Clinical Pathology 134, 613-620
107Kuhn, C. and McDonald, J.A. (1991) The roles of the myofibroblast in idiopathic pulmonary fibrosis. Ultrastructural and immunohistochemical features of sites of active extracellular matrix synthesis. American Journal of Pathology 138, 1257-1265
108Drakopanagiotakis, F. et al. (2008) Apoptosis in lung injury and fibrosis. European Respiratory Journal 32, 1631-1638
109Beon, M. et al. (2004) Myofibroblast induction and microvascular alteration in scleroderma lung fibrosis. Clinical and Experimental Rheumatology 22, 733-742
110Uhal, B.D. (2002) Apoptosis in lung fibrosis and repair. Chest 122, 293S-298S
111Vittal, R. et al. (2005) Modulation of prosurvival signaling in fibroblasts by a protein kinase inhibitor protects against fibrotic tissue injury. American Journal of Pathology 166, 367-375
112Horowitz, J.C. et al. (2004) 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. Journal of Biological Chemistry 279, 1359-1367
113Garneau-Tsodikova, S. and Thannickal, V.J. (2008) Protein kinase inhibitors in the treatment of pulmonary fibrosis. Current Medicinal Chemistry 15, 2632-2640
114Vuga, L.J. et al. (2009) WNT5A is a regulator of fibroblast proliferation and resistance to apoptosis. American Journal of Respiratory Cell and Molecular Biology 41, 583-589
115Xia, H. et al. (2010) Pathologic caveolin-1 regulation of PTEN in idiopathic pulmonary fibrosis. American Journal of Pathology 176, 2626-2637
116Huang, S.K. et al. (2009) Prostaglandin E(2) induces fibroblast apoptosis by modulating multiple survival pathways. FASEB Journal 23, 4317-4326
117Wynes, M.W., Frankel, S.K. and Riches, D.W. (2004) IL-4-induced macrophage-derived IGF-I protects myofibroblasts from apoptosis following growth factor withdrawal. Journal of Leukocyte Biology 76, 1019-1027
118Selman, M. and Pardo, A. (2004) Idiopathic pulmonary fibrosis: misunderstandings between epithelial cells and fibroblasts? Sarcoidosis, Vasculitis and Diffuse Lung Diseases 21, 165-172
119Chapman, H.A. (2011) Epithelial-mesenchymal interactions in pulmonary fibrosis. Annual Review of Physiology 73, 413-435
120Horowitz, J.C. and Thannickal, V.J. (2006) Epithelial-mesenchymal interactions in pulmonary fibrosis. Seminars in Respiratory and Critical Care Medicine 27, 600-612
121Selman, M. and Pardo, A. (2006) Role of epithelial cells in idiopathic pulmonary fibrosis: from innocent targets to serial killers. Proceedings of the American Thoracic Society 3, 364-372
122Golan-Gerstl, R. et al. (2007) Epithelial cell apoptosis by fas ligand-positive myofibroblasts in lung fibrosis. American Journal of Respiratory Cell and Molecular Biology 36, 270-275
123Kuwano, K. et al. (1999) Essential roles of the Fas-Fas ligand pathway in the development of pulmonary fibrosis. Journal of Clinical Investigation 104, 13-19
124Aoshiba, K. et al. (2000) The Fas/Fas-ligand system is not required for bleomycin-induced pulmonary fibrosis in mice. American Journal of Respiratory and Critical Care Medicine 162, 695-700
125Moodley, Y.P. et al. (2004) Comparison of the morphological and biochemical changes in normal human lung fibroblasts and fibroblasts derived from lungs of patients with idiopathic pulmonary fibrosis during FasL-induced apoptosis. Journal of Pathology 202, 486-495
126Buhling, F. et al. (2005) Altered expression of membrane-bound and soluble CD95/Fas contributes to the resistance of fibrotic lung fibroblasts to FasL induced apoptosis. Respiratory Research 6, 37
127Kolodsick, J.E. et al. (2003) Prostaglandin E2 inhibits fibroblast to myofibroblast transition via E. prostanoid receptor 2 signaling and cyclic adenosine monophosphate elevation. American Journal of Respiratory Cell and Molecular Biology 29, 537-544
128Wilborn, J. et al. (1995) Cultured lung fibroblasts isolated from patients with idiopathic pulmonary fibrosis have a diminished capacity to synthesize prostaglandin E2 and to express cyclooxygenase-2. Journal of Clinical Investigation 95, 1861-1868
129Horowitz, J.C. and Peters-Golden, M. (2010) Prostaglandin E2's new trick: “decider” of differential alveolar cell life and death. American Journal of Respiratory and Critical Care Medicine 182, 2-3
130Hagimoto, N. et al. (2002) TGF-beta 1 as an enhancer of Fas-mediated apoptosis of lung epithelial cells. Journal of Immunology 168, 6470-6478
131Chodon, T. et al. (2000) Keloid-derived fibroblasts are refractory to Fas-mediated apoptosis and neutralization of autocrine transforming growth factor-beta1 can abrogate this resistance. American Journal of Pathology 157, 1661-1669
132Tanaka, T. et al. (2002) Resistance to Fas-mediated apoptosis in human lung fibroblast. European Respiratory Journal 20, 359-368
133Kazufumi, M. et al. (1997) Expression of bcl-2 protein and APO-1 (Fas antigen) in the lung tissue from patients with idiopathic pulmonary fibrosis. Microscopy Research and Technique 38, 480-487
134Marcotte, R., Lacelle, C. and Wang, E. (2004) Senescent fibroblasts resist apoptosis by downregulating caspase-3. Mechanisms of Ageing and Development 125, 777-783
135Budinger, G.R. et al. (2006) Proapoptotic bid is required for pulmonary fibrosis. Proceedings of the National Academy of Sciences of the United States of America 103, 4604-4609
136Yamada, M. et al. (2007) Gene transfer of soluble transforming growth factor type II receptor by in vivo electroporation attenuates lung injury and fibrosis. Journal of Clinical Pathology 60, 916-920
137Bonner, J.C. (2004) Regulation of PDGF and its receptors in fibrotic diseases. Cytokine and Growth Factor Reviews 15, 255-273
138Bonner, J.C. (2010) Mesenchymal cell survival in airway and interstitial pulmonary fibrosis. Fibrogenesis Tissue Repair 3, 15
139Shao, H., Yi, X.M. and Wells, A. (2008) Epidermal growth factor protects fibroblasts from apoptosis via PI3 kinase and Rac signaling pathways. Wound Repair and Regeneration 16, 551-558
140Moodley, Y.P. et al. (2003) Inverse effects of interleukin-6 on apoptosis of fibroblasts from pulmonary fibrosis and normal lungs. American Journal of Respiratory Cell and Molecular Biology 29, 490-498
141Santiago, B. et al. (2004) Intracellular regulation of Fas-induced apoptosis in human fibroblasts by extracellular factors and cycloheximide. Journal of Immunology 172, 560-566
142White, E.S. et al. (2006) Negative regulation of myofibroblast differentiation by PTEN (Phosphatase and Tensin Homolog Deleted on chromosome 10). American Journal of Respiratory and Critical Care Medicine 173, 112-121
143Nho, R.S. et al. (2006) PTEN regulates fibroblast elimination during collagen matrix contraction. Journal of Biological Chemistry 281, 33291-33301
144Kulasekaran, P. et al. (2009) Endothelin-1 and transforming growth factor-beta1 independently induce fibroblast resistance to apoptosis via AKT activation. American Journal of Respiratory Cell and Molecular Biology 41, 484-493
145Chung, M.J. et al. (2007) Antiapoptotic effect of found in inflammatory zone (FIZZ)1 on mouse lung fibroblasts. Journal of Pathology 212, 180-187
146Bridges, R.S. et al. (2009) Gene expression profiling of pulmonary fibrosis identifies Twist1 as an antiapoptotic molecular “rectifier” of growth factor signaling. American Journal of Pathology 175, 2351-2361
147Nishimura, S.L. (2009) Integrin-mediated transforming growth factor-beta activation, a potential therapeutic target in fibrogenic disorders. American Journal of Pathology 175, 1362-1370
148Farias, E. et al. (2005) Integrin alpha8beta1-fibronectin interactions promote cell survival via PI3 kinase pathway. Biochemical and Biophysical Research Communications 329, 305-311
149Lin, F. et al. (2011) Fibronectin growth factor-binding domains are required for fibroblast survival. Journal of Investigative Dermatology 131, 84-98
150Hadden, H.L. and Henke, C.A. (2000) Induction of lung fibroblast apoptosis by soluble fibronectin peptides. American Journal of Respiratory and Critical Care Medicine 162, 1553-1560
151Horowitz, J.C. et al. (2007) Combinatorial activation of FAK and AKT by transforming growth factor-beta1 confers an anoikis-resistant phenotype to myofibroblasts. Cellular Signalling 19, 761-771
152Nho, R.S. et al. (2005) Role of integrin-linked kinase in regulating phosphorylation of Akt and fibroblast survival in type I collagen matrices through a beta1 integrin viability signaling pathway. Journal of Biological Chemistry 280, 26630-26639
153Janssen-Heininger, Y.M. et al. (2010) Regulation of apoptosis through cysteine oxidation: implications for fibrotic lung disease. Annals of the New York Academy of Sciences 1203, 23-28
154Tzouvelekis, A. et al. (2007) Comparative expression profiling in pulmonary fibrosis suggests a role of hypoxia-inducible factor-1alpha in disease pathogenesis. American Journal of Respiratory and Critical Care Medicine 176, 1108-1119
155Chilosi, M. et al. (2003) Aberrant Wnt/beta-catenin pathway activation in idiopathic pulmonary fibrosis. American Journal of Pathology 162, 1495-1502
156Pecina-Slaus, N. (2010) Wnt signal transduction pathway and apoptosis: a review. Cancer Cell International 10, 22
157Hueber, A.O. et al. (1994) Thy-1 triggers mouse thymocyte apoptosis through a bcl-2-resistant mechanism. Journal of Experimental Medicine 179, 785-796
158Morita, H. et al. (1996) Thy-1 antigen mediates apoptosis of rat glomerular cells in vitro and in vivo. Nephron 73, 293-298
159Kotaru, C. et al. (2006) Regional fibroblast heterogeneity in the lung: implications for remodeling. American Journal of Respiratory and Critical Care Medicine 173, 1208-1215
160Xie, X.-S. et al. (2010) LSKL, a peptide antagonist of thrombospondin-1, attenuates renal interstitial fibrosis in rats with unilateral ureteral obstruction. Archives of Pharmacal Research 33, 275-284
161Nakashima, T. et al. (2008) Suppressor of cytokine signaling 1 inhibits pulmonary inflammation and fibrosis. Journal of Allergy and Clinical Immunology 121, 1269-1276
162Moore, B.B. et al. (2001) Protection from pulmonary fibrosis in the absence of CCR2 signaling. Journal of Immunology 167, 4368-4377
163Cho, M.E. et al. (2007) Pirfenidone slows renal function decline in patients with focal segmental glomerulosclerosis. Clinical Journal of the American Society of Nephrology 2, 906-913
164Kakugawa, T. et al. (2004) Pirfenidone attenuates expression of HSP47 in murine bleomycin-induced pulmonary fibrosis. European Respiratory Journal 24, 57-65
165Lasky, J. (2004) Pirfenidone. IDrugs 7, 166-172
166Noble, P.W. et al. (2011) Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 377, 1760-1769
167Douglass, A. et al. (2008) Antibody-targeted myofibroblast apoptosis reduces fibrosis during sustained liver injury. Journal of Hepatology 49, 88-98
168Vittal, R. et al. (2007) Effects of the protein kinase inhibitor, imatinib mesylate, on epithelial/mesenchymal phenotypes: implications for treatment of fibrotic diseases. Journal of Pharmacology and Experimental Therapeutics 321, 35-44
169Kisseleva, T. and Brenner, D.A. (2011) Is it the end of the line for the EMT? Hepatology 53, 1433-1435
170Kinoshita, K. et al. (2007) Adenovirus-mediated expression of BMP-7 suppresses the development of liver fibrosis in rats. Gut 56, 706-714
171Crosby, L.M. and Waters, C.M. (2010) Epithelial repair mechanisms in the lung. American Journal of Physiology. Lung Cellular and Molecular Physiology 298, L715-L731
172Nho, R. and Kahm, J. (2010) β1-Integrin-collagen interaction suppresses FoxO3a by the coordination of Akt and PP2A. Journal of Biological Chemistry 285, 14195-14209
173Wang, X.M. et al. (2006) Caveolin-1: a critical regulator of lung fibrosis in idiopathic pulmonary fibrosis. Journal of Experimental Medicine 203, 2895-2906
Hinz, B. (2007) Formation and function of the myofibroblast during tissue repair. Journal of Investigative Dermatology 127, 526-537
Hinz, B. (2010) The myofibroblast: paradigm for a mechanically active cell. Journal of Biomechanics 43, 146-155
Wipff, P.-J. et al. (2007) Myofibroblast contraction activates latent TGF-beta1 from the extracellular matrix. Journal of Cell Biology 179, 1311-1323
Kisseleva, T. et al. (2011) Is it the end of the line for the EMT? Hepatology 53, 1433-1435 (Ref. 169).
A well-maintained website with excellent figures and movies, brief reviews, and helpful external links can be found at:http://www.cellmigration.org/.
Website of the American Society for Matrix Biology, with meeting announcements, resources and external links:http://www.asmb.net/.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Expert Reviews in Molecular Medicine
  • ISSN: -
  • EISSN: 1462-3994
  • URL: /core/journals/expert-reviews-in-molecular-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Metrics

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed