TGF-β1 signaling and tissue fibrosis

Cold Spring Harbor Perspectives in Biology

Volumn 10, Issue 4, 2018, Pages

  Kim, Kevin K ^a   Sheppard, Dean ^b   Chapman, Harold A ^b  

^a UNIVERSITY OF MICHIGAN MEDICAL SCHOOL   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

COLLAGEN; INTEGRIN; TRANSFORMING GROWTH FACTOR BETA1;

ANIMAL; APOPTOSIS; BIOLOGICAL MODEL; CELL PROLIFERATION; EPITHELIAL MESENCHYMAL TRANSITION; FIBROSIS; GENETICS; HUMAN; METABOLISM; MOUSE; PHYSIOLOGICAL FEEDBACK; PHYSIOLOGY; SIGNAL TRANSDUCTION; WOUND HEALING;

ANIMALS; APOPTOSIS; CELL PROLIFERATION; COLLAGEN; EPITHELIAL-MESENCHYMAL TRANSITION; FEEDBACK, PHYSIOLOGICAL; FIBROSIS; HUMANS; INTEGRINS; MICE; MODELS, BIOLOGICAL; SIGNAL TRANSDUCTION; TRANSFORMING GROWTH FACTOR BETA1; WOUND HEALING;

EID: 85041207065     PISSN: None     EISSN: 19430264     Source Type: Journal    
DOI: 10.1101/cshperspect.a022293     Document Type: Article

References (251)

1. Acloque H, Adams MS, Fishwick K, Bronner-Fraser M, Nieto MA. 2009. Epithelial–mesenchymal transitions: The importance of changing cell state in development and disease. J Clin Invest 119: 1438–1449.
2. Adamali HI, Maher TM. 2012. Current and novel drug therapies for idiopathic pulmonary fibrosis. Drug Des Devel Ther 6: 261–272.
3. Ahluwalia N, Shea BS, Tager AM. 2014. New therapeutic targets in idiopathic pulmonary fibrosis. Aiming to rein in runaway wound-healing responses. Am J Respir Crit Care Med 190: 867–878.
4. Akagi K, Sandig V, Vooijs M, Van der Valk M, Giovannini M, Strauss M, Berns A. 1997. Cre-mediated somatic site-specific recombination in mice. Nucleic Acids Res 25: 1766–1773.
5. Al-Alawi M, Hassan T, Chotirmall SH. 2014. Transforming growth factor β and severe asthma: A perfect storm. Respir Med 108: 1409–1423.
6. 8-integrins reproduce the abnormalities of Tgfb1- and Tgfb3-null mice. J Cell Sci 122: 227–232.
7. 6 binds and activates latent TGFβ3. FEBS Lett 511: 65–68.
8. 6-mediated activation of latent TGF-β requires the latent TGF-β binding protein-1. J Cell Biol 165: 723–734.
9. Aoshiba K, Nagai A. 2004. Differences in airway remodeling between asthma and chronic obstructive pulmonary disease. Clin Rev Allergy Immunol 27: 35–43.
10. Aoshiba K, Tsuji T, Nagai A. 2003. Bleomycin induces cellular senescence in alveolar epithelial cells. Eur Respir J 22: 436–443.
11. Aoshiba K, Tsuji T, Kameyama S, Itoh M, Semba S, Yamaguchi K, Nakamura H. 2013. Senescence-associated secretory phenotype in a mouse model of bleomycin-induced lung injury. Exp Toxicol Pathol 65: 1053–1062.
12. Araya J, Cambier S, Markovics JA, Wolters P, Jablons D, Hill A, Finkbeiner W, Jones K, Broaddus VC, Sheppard D, et al. 2007. Squamous metaplasia amplifies pathologic epithelial–mesenchymal interactions in COPD patients. J Clin Invest 117: 3551–3562.
13. Asharani PV, Keupp K, Semler O, Wang W, Li Y, Thiele H, Yigit G, Pohl E, Becker J, Frommolt P, et al. 2012. Attenuated BMP1 function compromises osteogenesis, leading to bone fragility in humans and zebrafish. Am J Hum Genet 90: 661–674.
14. Ask K, Bonniaud P, Maass K, Eickelberg O, Margetts PJ, Warburton D, Groffen J, Gauldie J, Kolb M. 2008. Progressive pulmonary fibrosis is mediated by TGF-β isoform 1 but not TGF-β3. Int J Biochem Cell Biol 40: 484–495.
15. Balli D, Ustiyan V, Zhang Y, Wang IC, Masino AJ, Ren X, Whitsett JA, Kalinichenko VV, Kalin TV. 2013. Foxm1 transcription factor is required for lung fibrosis and epithelial-to-mesenchymal transition. EMBO J 32: 231– 244.
16. Barbas-Filho JV, Ferreira MA, Sesso A, Kairalla RA, Carvalho CR, Capelozzi VL. 2001. Evidence of type II pneumocyte apoptosis in the pathogenesis of idiopathic pulmonary fibrosis (IFP)/usual interstitial pneumonia (UIP). J Clin Pathol 54: 132–138.
17. Barcellos-Hoff MH, Derynck R, Tsang ML, Weatherbee JA. 1994. Transforming growth factor-β activation in irradiated murine mammary gland. J Clin Invest 93: 892–899.
18. Barry-Hamilton V, Spangler R, Marshall D, McCauley S, Rodriguez HM, Oyasu M, Mikels A, Vaysberg M, Gher-mazien H, Wai C, et al. 2010. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat Med 16: 1009–1017.
19. Bartram U, Speer CP. 2004. The role of transforming growth factor β in lung development and disease. Chest 125: 754–765.
20. Beers MF, Morrisey EE. 2011. The three R’s of lung health and disease: Repair, remodeling, and regeneration. J Clin Invest 121: 2065–2073.
21. Bendris N, Arsic N, Lemmers B, Blanchard JM. 2012. Cyclin A2, Rho GTPases and EMT. Small GTPases 3: 225–228.
22. Biasin V, Marsh LM, Egemnazarov B, Wilhelm J, Ghanim B, Klepetko W, Wygrecka M, Olschewski H, Eferl R, Olschewski A, et al. 2014. Meprin β, a novel mediator of vascular remodelling underlying pulmonary hypertension. J Pathol 233: 7–17.
23. Blaauboer ME, Emson CL, Verschuren L, van Erk M, Turner SM, Everts V, Hanemaaijer R, Stoop R. 2013. Novel combination of collagen dynamics analysis and transcriptional profiling reveals fibrosis-relevant genes and pathways. Matrix Biol 32: 424–431.
24. Blackwell TS, Tager AM, Borok Z, Moore BB, Schwartz DA, Anstrom KJ, Bar-Joseph Z, Bitterman P, Blackburn MR, Bradford W, et al. 2014. Future directions in idiopathic pulmonary fibrosis research. An NHLBI workshop report. Am J Respir Crit Care Med 189: 214–222.
25. Blagosklonny MV. 2003. Cell senescence and hypermito-genic arrest. EMBO Rep 4: 358–362.
26. Bosse Y, Pare PD, Seow CY. 2008. Airway wall remodeling in asthma: From the epithelial layer to the adventitia. Curr Allergy Asthma Rep 8: 357–366.
27. Bourhis JM, Mariano N, Zhao Y, Harlos K, Exposito JY, Jones EY, Moali C, Aghajari N, Hulmes DJ. 2012. Structural basis of fibrillar collagen trimerization and related genetic disorders. Nat Struct Mol Biol 19: 1031–1036.
28. Bowen T, Jenkins RH, Fraser DJ. 2013. MicroRNAs, transforming growth factor β-1, and tissue fibrosis. J Pathol 229: 274–285.
29. Boxall C, Holgate ST, Davies DE. 2006. The contribution of transforming growth factor-β and epidermal growth factor signalling to airway remodelling in chronic asthma. Eur Respir J 27: 208–229.
30. Broder C, Arnold P, Vadon-Le Goff S, Konerding MA, Bahr K, Muller S, Overall CM, Bond JS, Koudelka T, Tholey A, et al. 2013. Metalloproteases meprin α and meprin β are C- and N-procollagen proteinases important for collagen assembly and tensile strength. Proc Natl Acad Sci 110: 14219–14224.
31. Burke MA, Chang S, Wakimoto H, Gorham JM, Conner DA, Christodoulou DC, Parfenov MG, DePalma SR, Eminaga S, Konno T, et al. 2016. Molecular profiling of dilated cardiomyopathy that progresses to heart failure. JCI Insight 1: e86898.
32. Campisi J. 2003. Cellular senescence and apoptosis: How cellular responses might influence aging phenotypes. Exp Gerontol 38: 5–11.
33. Campisi J. 2013. Aging, cellular senescence, and cancer. Annu Rev Physiol 75: 685–705.
34. Campisi J, Robert L. 2014. Cell senescence: Role in aging and age-related diseases. Interdiscip Top Gerontol 39: 45–61.
35. Cardiff RD. 2005. Epithelial to mesenchymal transition tumors: Fallacious or snail’s pace? Clin Cancer Res 11: 8534–8537.
36. Chang Y JH, Reed NI, Wang Y, Atakilit A, DeGrado WF, Sheppard D. 2017. Fibroblast αvβ1 integrin is a key regulator of renal fibrosis and pharmacological blockage of αvβ1 ameliorates renal fibrosis in vivo. J Am Soc Nephrol. In press.
37. Chapman HA. 2010. Epithelial–mesenchymal interactions in pulmonary fibrosis. Annu Rev Physiol 73: 413–435.
38. Chen SJ, Ning H, Ishida W, Sodin-Semrl S, Takagawa S, Mori Y, Varga J. 2006. The early-immediate gene EGR-1 is induced by transforming growth factor-β and mediates stimulation of collagen gene expression. J Biol Chem 281: 21183–21197.
39. Chilosi M, Poletti V, Zamo A, Lestani M, Montagna L, Pic-coli P, Pedron S, Bertaso M, Scarpa A, Murer B, et al. 2003. Aberrant Wnt/β-catenin pathway activation in idiopathic pulmonary fibrosis. Am J Pathol 162: 1495–1502.
40. Chodon T, Sugihara T, Igawa HH, Funayama E, Furukawa H. 2000. Keloid-derived fibroblasts are refractory to Fas-mediated apoptosis and neutralization of autocrine transforming growth factor-β1 can abrogate this resistance. Am J Pathol 157: 1661–1669.
41. Chu AS, Diaz R, Hui JJ, Yanger K, Zong Y, Alpini G, Stanger BZ, Wells RG. 2011. Lineage tracing demonstrates no evidence of cholangiocyte epithelial-to-mesenchymal transition in murine models of hepatic fibrosis. Hepatology 53: 1685–1695.
42. ARF in fibroblasts from idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 303: L295–L303.
43. Coppe JP, Patil CK, Rodier F, Sun Y, Munoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J. 2008. Senescence-associated secretory phenotypes reveal cell-nonautono-mous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 6: 2853–2868.
44. Coppe JP, Desprez PY, Krtolica A, Campisi J. 2010. The senescence-associated secretory phenotype: The dark side of tumor suppression. Annu Rev Pathol 5: 99–118.
45. Cox TR, Erler JT. 2011. Remodeling and homeostasis of the extracellular matrix: Implications for fibrotic diseases and cancer. Dis Model Mech 4: 165–178.
46. Crawford SE, Stellmach V, Murphy-Ullrich JE, Ribeiro SM, Lawler J, Hynes RO, Boivin GP, Bouck N. 1998. Throm-bospondin-1 is a major activator of TGF-β1invivo.Cell 93: 1159–1170.
47. Das S, Kumar M, Negi V, Pattnaik B, Prakash YS, Agrawal A, Ghosh B. 2014. MicroRNA-326 regulates profibrotic
48. Gordon ED, Sidhu SS, Wang ZE, Woodruff PG, Yuan S, Solon MC, Conway SJ, Huang X, Locksley RM, Fahy JV. 2012. A protective role for periostin and TGF-β in IgE-mediated allergy and airway hyperresponsiveness. Clin Exp Allergy 42: 144–155.
49. Grande MT, Sanchez-Laorden B, Lopez-Blau C, De Frutos CA, Boutet A, Arevalo M, Rowe RG, Weiss SJ, Lopez-Novoa JM, Nieto MA. 2015. Snail1-induced partial epithelial-to-mesenchymal transition drives renal fibrosis in mice and can be targeted to reverse established disease. Nat Med 21: 989–997.
50. Griffith CM, Hay ED. 1992. Epithelial–mesenchymal transformation during palatal fusion: Carboxyfluorescein traces cells at light and electron microscopic levels. Development 116: 1087–1099.
51. Grotendorst GR, Rahmanie H, Duncan MR. 2004. Combinatorial signaling pathways determine fibroblast proliferation and myofibroblast differentiation. FASEB J 18: 469–479.
52. 6 integrin regulates renal fibrosis and inflammation in Alport mouse. Am J Pathol 170: 110–125.
53. Halwani R, Al-Muhsen S, Al-Jahdali H, Hamid Q. 2011. Role of transforming growth factor-β in airway remodeling in asthma. Am J Respir Cell Mol Biol 44: 127–133.
54. Harris WT, Kelly DR, Zhou Y, Wang D, MacEwen M, Hagood JS, Clancy JP, Ambalavanan N, Sorscher EJ. 2013. Myofibroblast differentiation and enhanced TGF-β signaling in cystic fibrosis lung disease. PLoS ONE 8: e70196.
55. Hashimoto N, Jin H, Liu T, Chensue SW, Phan SH. 2004. Bone marrow-derived progenitor cells in pulmonary fibrosis. J Clin Invest 113: 243–252.
56. Hashimoto N, Phan SH, Imaizumi K, Matsuo M, Nakashima H, Kawabe T, Shimokata K, Hasegawa Y. 2010. Endothelial–mesenchymal transition in bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol 43: 161–172.
57. Hecker L, Thannickal VJ. 2016. Getting to the core of fibrosis: Targeting redox imbalance in aging. Ann Transl Med 4: 93.
58. Hecker L, Vittal R, Jones T, Jagirdar R, Luckhardt TR, Horowitz JC, Pennathur S, Martinez FJ, Thannickal VJ. 2009. NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury. Nat Med 15: 1077–1081.
59. Heimark RL, Twardzik DR, Schwartz SM. 1986. Inhibition of endothelial regeneration by type-β transforming growth factor from platelets. Science 233: 1078–1080.
60. Heindryckx F, Binet F, Ponticos M, Rombouts K, Lau J, Kreuger J, Gerwins P. 2016. Endoplasmic reticulum stress enhances fibrosis through IRE1α-mediated degradation of miR-150 and XBP-1 splicing. EMBO Mol Med 8: 729– 744.
61. Heldin C-H, Moustakas A. 2016. Signaling receptors for TGF-β family members. Cold Spring Harbor Perspect Biol 8: a022053.
62. v integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat Med 19: 1617–1624.
63. Hernnas J, Nettelbladt O, Bjermer L, Sarnstrand B, Malmstrom A, Hallgren R. 1992. Alveolar accumulation of fibronectin and hyaluronan precedes bleomycin-induced pulmonary fibrosis in the rat. Eur Respir J 5: 404–410.
64. Higashiyama R, Moro T, Nakao S, Mikami K, Fukumitsu H, Ueda Y, Ikeda K, Adachi E, Bou-Gharios G, Okazaki I, et al. 2009. Negligible contribution of bone marrow-derived cells to collagen production during hepatic fibrogenesis in mice. Gastroenterology 137: 1459–1466 e1451.
65. Hill DJ, Strain AJ, Elstow SF, Swenne I, Milner RD. 1986. Bi-functional action of transforming growth factor-β on DNA synthesis in early passage human fetal fibroblasts. J Cell Physiol 128: 322–328.
66. Hinck AP, Mueller TD, Springer TA. 2016. Structural biology and evolution of the TGF-β family. Cold Spring Harbor Perspect Biol 8: a022103.
67. Hinz B. 2013. Matrix mechanics and regulation of the fibroblast phenotype. Periodontology 2000 63: 14–28.
68. Hirota N, Martin JG. 2013. Mechanisms of airway remodeling. Chest 144: 1026–1032.
69. Hofmann U, Bonz A, Frantz S, Hu K, Waller C, Roemer K, Wolf J, Gattenlohner S, Bauersachs J, Ertl G. 2012. A collagen α2(I) mutation impairs healing after experimental myocardial infarction. Am J Pathol 180: 113–122.
70. Holgate ST, Holloway J, Wilson S, Bucchieri F, Puddicombe S, Davies DE. 2004. Epithelial–mesenchymal communication in the pathogenesis of chronic asthma. Proc Am Thorac Soc 1: 93–98.
71. Honda N, Jinnin M, Kira-Etoh T, Makino K, Kajihara I, Makino T, Fukushima S, Inoue Y, Okamoto Y, Hasegawa M, et al. 2013. miR-150 down-regulation contributes to the constitutive type I collagen overexpression in scleroderma dermal fibroblasts via the induction of integrin β3. Am J Pathol 182: 206–216.
72. 6 prevents pulmonary fibrosis without exacerbating inflammation. Am J Respir Crit Care Med 177: 56–65.
73. Horowitz JC, Rogers DS, Sharma V, Vittal R, White ES, Cui Z, Thannickal VJ. 2007. Combinatorial activation of FAK and AKT by transforming growth factor-β1 confers an anoikis-resistant phenotype to myofibroblasts. Cell Signal 19: 761–771.
74. Horowitz JC, Ajayi IO, Kulasekaran P, Rogers DS, White JB, Townsend SK, White ES, Nho RS, Higgins PD, Huang SK, et al. 2012. Survivin expression induced by endothelin-1 promotes myofibroblast resistance to apoptosis. Int J Biochem Cell Biol 44: 158–169.
75. Hostettler KE, Roth M, Burgess JK, Gencay MM, Gambazzi F, Black JL, Tamm M, Borger P. 2008. Airway epithelium-derived transforming growth factor-β is a regulator of fibroblast proliferation in both fibrotic and normal subjects. Clin Exp Allergy 38: 1309–1317.
76. Hoyles RK, Derrett-Smith EC, Khan K, Shiwen X, Howat SL, Wells AU, Abraham DJ, Denton CP. 2011. An essential role for resident fibroblasts in experimental lung fibrosis is defined by lineage-specific deletion of high-affinity type II transforming growth factor β receptor. Am J Respir Crit Care Med 183: 249–261.
77. Hoyt DG LJ. 1988. Alterations in pulmonary mRNA encoding procollagens, fibronectin, and transforming growth factor-β precede bleomycin-induced pulmonary fibrosis in mice. J Pharmacol Exp Ther 246: 765–771.
78. Huang XZ, Wu JF, Cass D, Erle DJ, Corry D, Young SG, Farese RVJr., Sheppard D. 1996. Inactivation of the integrin β6 subunit gene reveals a role of epithelial integrins in regulating inflammation in the lung and skin. J Cell Biol 133: 921–928.
79. Huang M, Sharma S, Zhu LX, Keane MP, Luo J, Zhang L, Burdick MD, Lin YQ, Dohadwala M, Gardner B, et al. 2002. IL-7 inhibits fibroblast TGF-β production and signaling in pulmonary fibrosis. J Clin Invest 109: 931–937.
80. Hulmes DJ. 2002. Building collagen molecules, fibrils, and suprafibrillar structures. J Struct Biol 137: 2–10.
81. Hulmes DJ. 2008. Collagen diversity, synthesis, and assembly. In Collagen: Structure and mechanics (ed. Fratzl P), pp. 1–47. Springer Science+Business Media, New York.
82. Humphreys BD, Lin SL, Kobayashi A, Hudson TE, Nowlin BT, Bonventre JV, Valerius MT, McMahon AP, Duffield JS. 2010. Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am J Pathol 176: 85–97.
83. Hung C, Linn G, Chow YH, Kobayashi A, Mittelsteadt K, Altemeier WA, Gharib SA, Schnapp LM, Duffield JS. 2013. Role of lung pericytes and resident fibroblasts in the pathogenesis of pulmonary fibrosis. Am J Respir Crit Care Med 188: 820–830.
84. Hynes RO. 2012. The evolution of metazoan extracellular matrix. J Cell Biol 196: 671–679.
85. Ignotz RA, Massagué J. 1986. Transforming growth factor-β stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. J Biol Chem 261: 4337–4345.
86. Ishida Y, Nagata K. 2011. Hsp47 as a collagen-specific molecular chaperone. Methods Enzymol 499: 167–182.
87. Ishikawa Y, Bachinger HP. 2013. A molecular ensemble in the rER for procollagen maturation. Biochim Biophys Acta 1833: 2479–2491.
88. Iwano M, Plieth D, Danoff TM, Xue C, Okada H, Neilson EG. 2002. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest 110: 341–350.
89. Jaramillo A, Smith CR, Maruyama T, Zhang L, Patterson GA, Mohanakumar T. 2003. Anti-HLA class I antibody binding to airway epithelial cells induces production of fibrogenic growth factors and apoptotic cell death: A possible mechanism for bronchiolitis obliterans syndrome. Hum Immunol 64: 521–529.
90. Jeffery PK. 2001. Remodeling in asthma and chronic obstructive lung disease. Am J Respir Crit Care Med 164: S28–S38.
91. 6 integrin-dependent TGF-β activation and promotes acute lung injury. J Clin Invest 116: 1606–1614.
92. Johansson KA, Grapin-Botton A. 2002. Development and diseases of the pancreas. Clin Genet 62: 14–23.
93. 6 integrin-mediated transforming growth factor β activation. J Biol Chem 289: 35246–35263.
94. Jolly MK, Tripathi SC, Jia D, Mooney SM, Celiktas M, Ha-nash SM, Mani SA, Pienta KJ, Ben-Jacob E, Levine H. 2016. Stability of the hybrid epithelial/mesenchymal phenotype. Oncotarget 10: 27067–27084.
95. Kagan HM, Trackman PC. 1991. Properties and function of lysyl oxidase. Am J Respir Cell Mol Biol 5: 206–210.
96. Kakugawa T, Mukae H, Hayashi T, Ishii H, Nakayama S, Sakamoto N, Yoshioka S, Sugiyama K, Mine M, Mizuta Y, et al. 2005. Expression of HSP47 in usual interstitial pneumonia and nonspecific interstitial pneumonia. Respir Res 6: 57.
97. Kalluri R, Neilson EG. 2003. Epithelial–mesenchymal transition and its implications for fibrosis. J Clin Invest 112: 1776–1784.
98. Kalluri R, Weinberg RA. 2009. The basics of epithelial–mesenchymal transition. J Clin Invest 119: 1420–1428.
99. Kaminski N, Allard JD, Pittet JF, Zuo F, Griffiths MJ, Morris D, Huang X, Sheppard D, Heller RA. 2000. Global analysis of gene expression in pulmonary fibrosis reveals distinct programs regulating lung inflammation and fibrosis. Proc Natl Acad Sci 97: 1778–1783.
100. Kang HR, Cho SJ, Lee CG, Homer RJ, Elias JA. 2007. Transforming growth factor (TGF)-β1 stimulates pulmonary fibrosis and inflammation via a Bax-dependent, bid-ac-tivated pathway that involves matrix metalloproteinase-12. J Biol Chem 282: 7723–7732.
101. Katsuno Y, Lamouille S, Derynck R. 2013. TGF-β signaling and epithelial–mesenchymal transition in cancer progression. Curr Opin Onocol 25: 76–84.
102. Kay EP, Lee HK, Park KS, Lee SC. 1998. Indirect mitogenic effect of transforming growth factor-β on cell proliferation of subconjunctival fibroblasts. Invest Ophthalmol Vis Sci 39: 481–486.
103. Keerthisingam CB, Jenkins RG, Harrison NK, Hernandez-Rodriguez NA, Booth H, Laurent GJ, Hart SL, Foster ML, McAnulty RJ. 2001. Cyclooxygenase-2 deficiency results in a loss of the anti-proliferative response to transforming growth factor-β in human fibrotic lung fibroblasts and promotes bleomycin-induced pulmonary fibrosis in mice. Am J Pathol 158: 1411–1422.
104. Kim KK, Kugler MC, Wolters PJ, Robillard L, Galvez MG, Brumwell AN, Sheppard D, Chapman HA. 2006. Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci 103: 13180–13185.
105. 1-dependent β-catenin phosphorylation links epithelial Smad signaling to cell contacts. J Cell Biol 184: 309–322.
106. Kisseleva T, Uchinami H, Feirt N, Quintana-Bustamante O, Segovia JC, Schwabe RF, Brenner DA. 2006. Bone marrow-derived fibrocytes participate in pathogenesis of liver fibrosis. J Hepatol 45: 429–438.
107. Kokudo T, Suzuki Y, Yoshimatsu Y, Yamazaki T, Watabe T, Miyazono K. 2008. Snail is required for TGFβ-induced endothelial-mesenchymal transition of embryonic stem cell-derived endothelial cells. J Cell Sci 121: 3317–3324.
108. Kottmann RM, Kulkarni AA, Smolnycki KA, Lyda E, Daha-nayake T, Salibi R, Honnons S, Jones C, Isern NG, Hu JZ, et al. 2012. Lactic acid is elevated in idiopathic pulmonary fibrosis and induces myofibroblast differentiation via pH-dependent activation of transforming growth factor-β. Am J Respir Crit Care Med 186: 740–751.
109. Kovacic JC, Mercader N, Torres M, Boehm M, Fuster V. 2012. Epithelial-to-mesenchymal and endothelial-to-mesenchymal transition: From cardiovascular development to disease. Circulation 125: 1795–1808.
110. Kudo M, Melton AC, Chen C, Engler MB, Huang KE, Ren X, Wang Y, Bernstein X, Li JT, Atabai K, et al. 2012. IL-17A produced by αβ T cells drives airway hyper-responsive-ness in mice and enhances mouse and human airway smooth muscle contraction. Nat Med 18: 547–554.
111. Kuilman T, Michaloglou C, Mooi WJ, Peeper DS. 2010. The essence of senescence. Genes Dev 24: 2463–2479.
112. Kulasekaran P, Scavone CA, Rogers DS, Arenberg DA, Thannickal VJ, Horowitz JC. 2009. Endothelin-1 and transforming growth factor-β1 independently induce fibroblast resistance to apoptosis via AKT activation. Am J Respir Cell Mol Biol 41: 484–493.
113. Kulkarni AB, Huh CG, Becker D, Geiser A, Lyght M, Flanders KC, Roberts AB, Sporn MB, Ward JM, Karlsson S. 1993. Transforming growth factor β1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci 90: 770–774.
114. Kuwano K. 2007. Epithelial cell apoptosis and lung remodeling. Cell Mol Immunol 4: 419–429.
115. Kuwano K, Hagimoto N, Kawasaki M, Hara N. 1998. The roles of apoptosis in lung injury and fibrosis. Nihon Ko-kyuki Gakkai Zasshi 36: 739–744.
116. Kuwano K, Hagimoto N, Nakanishi Y. 2004. The role of apoptosis in pulmonary fibrosis. Histol Histopathol 19: 867–881.
117. Lamouille S, Xu J, Derynck R. 2014. Molecular mechanisms of epithelial–mesenchymal transition. Nat Rev Mol Cell Biol 15: 178–196.
118. Larsson O, Diebold D, Fan D, Peterson M, Nho RS, Bitterman PB, Henke CA. 2008. Fibrotic myofibroblasts manifest genome-wide derangements of translational control. PLoS ONE 3: e3220.
119. Lawson WE, Crossno PF, Polosukhin VV, Roldan J, Cheng DS, Lane KB, Blackwell TR, Xu C, Markin C, Ware LB, et al. 2008. 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.
120. Lawson WE, Cheng DS, Degryse AL, Tanjore H, Polosukhin VV, Xu XC, Newcomb DC, Jones BR, Roldan J, Lane KB, et al. 2011. Endoplasmic reticulum stress enhances fibrotic remodeling in the lungs. Proc Natl Acad Sci 108: 10562–10567.
121. Leask A. 2009. Signaling in fibrosis: Targeting the TGFβ, endothelin-1 and CCN2 axis in scleroderma. Front Biosci 1: 115–122.
122. Leask A, Abraham DJ. 2003. The role of connective tissue growth factor, a multifunctional matricellular protein, in fibroblast biology. Biochem Cell Biol 81: 355–363.
123. Leask A, Abraham DJ. 2004. TGF-β signaling and the fibrotic response. FASEB J 18: 816–827.
124. LeBleu VS, Taduri G, O’Connell J, Teng Y, Cooke VG, Woda C, Sugimoto H, Kalluri R. 2013. Origin and function of myofibroblasts in kidney fibrosis. Nat Med 19: 1047– 1053.
125. Lee CG, Cho SJ, Kang MJ, Chapoval SP, Lee PJ, Noble PW, Yehualaeshet T, Lu B, Flavell RA, Milbrandt J, et al. 2004. Early growth response gene 1-mediated apoptosis is essential for transforming growth factor β1-induced pulmonary fibrosis. J Exp Med 200: 377–389.
126. Lee CG, Kang HR, Homer RJ, Chupp G, Elias JA. 2006. Transgenic modeling of transforming growth factor-β1: Role of apoptosis in fibrosis and alveolar remodeling. Proc Am Thorac Soc 3: 418–423.
127. Le Saux CJ, Davy P, Brampton C, Ahuja SS, Fauce S, Shivshankar P, Nguyen H, Ramaseshan M, Tressler R, Pirot Z, et al. 2013. A novel telomerase activator suppresses lung damage in a murine model of idiopathic pulmonary fibrosis. PLoS ONE 8: e58423.
128. Li SW, Sieron AL, Fertala A, Hojima Y, Arnold WV, Prockop DJ. 1996. The C-proteinase that processes procollagens to fibrillar collagens is identical to the protein previously identified as bone morphogenic protein-1. Proc Natl Acad Sci 93: 5127–5130.
129. Li M, Krishnaveni MS, Li C, Zhou B, Xing Y, Banfalvi A, Li A, Lombardi V, Akbari O, Borok Z, et al. 2011. Epithelium-specific deletion of TGF-β receptor type II protects mice from bleomycin-induced pulmonary fibrosis. J Clin Invest 121: 277–287.
130. Li A, Gao HF, Wu YL. 2014. Targeting the MET pathway for potential treatment of NSCLC. Expert Opin Ther Targets 19: 663–674.
131. Liu F, Mih JD, Shea BS, Kho AT, Sharif AS, Tager AM, Tschumperlin DJ. 2010. Feedback amplification of fibrosis through matrix stiffening and COX-2 suppression. J Cell Biol 190: 693–706.
132. Lomas NJ, Watts KL, Akram KM, Forsyth NR, Spiteri MA. 2012. Idiopathic pulmonary fibrosis: Immunohisto-chemical analysis provides fresh insights into lung tissue remodelling with implications for novel prognostic markers. Int J Clin Exp Pathol 5: 58–71.
133. Lovisa S, LeBleu VS, Tampe B, Sugimoto H, Vadnagara K, Carstens JL, Wu CC, Hagos Y, Burckhardt BC, Pentcheva-Hoang T, et al. 2015. Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis. Nat Med 21: 998–1009.
134. Lutz D, Gazdhar A, Lopez-Rodriguez E, Ruppert C, Maha-vadi P, Gunther A, Klepetko W, Bates JH, Smith B, Geiser T, et al. 2015. Alveolar derecruitment and collapse indu-ration as crucial mechanisms in lung injury and fibrosis. Am J Respir Cell Mol Biol 52: 232–243.
135. Madala SK, Edukulla R, Schmidt S, Davidson C, Ikegami M, Hardie WD. 2014. Bone marrow-derived stromal cells are invasive and hyperproliferative and alter transforming growth factor-α-induced pulmonary fibrosis. Am J Respir Cell Mol Biol 50: 777–786.
136. Makinde T, Murphy RF, Agrawal DK. 2007. The regulatory role of TGF-β in airway remodeling in asthma. Immunol Cell Biol 85: 348–356.
137. Makino K, Jinnin M, Hirano A, Yamane K, Eto M, Kusano T, Honda N, Kajihara I, Makino T, Sakai K, et al. 2013. The downregulation of microRNA let-7a contributes to the excessive expression of type I collagen in systemic and localized scleroderma. J Immunol 190: 3905–3915.
138. Marmai C, Sutherland RE, Kim KK, Dolganov GM, Fang X, Kim SS, Jiang S, Golden JA, Hoopes CW, Matthay MA, et al. 2011. Alveolar epithelial cells express mesenchymal proteins in patients with idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 301: L71–L78.
139. McAnulty RJ, Hernandez-Rodriguez NA, Mutsaers SE, Coker RK, Laurent GJ. 1997. Indomethacin suppresses the anti-proliferative effects of transforming growth factor-β isoforms on fibroblast cell cultures. Biochem J 321: 639–643.
140. McMillan SJ, Xanthou G, Lloyd CM. 2005. Manipulation of allergen-induced airway remodeling by treatment with anti-TGF-β antibody: Effect on the Smad signaling pathway. J Immunol 174: 5774–5780.
141. Melton AC, Bailey-Bucktrout SL, Travis MA, Fife BT, Blue-stone JA, Sheppard D. 2010. Expression of αvβ8 integrin on dendritic cells regulates Th17 cell development and experimental autoimmune encephalomyelitis in mice. J Clin Invest 120: 4436–4444.
142. Minagawa S, Lou J, Seed RI, Cormier A, Wu S, Cheng Y, Murray L, Tsui P, Connor J, Herbst R, et al. 2014. Selective targeting of TGF-β activation to treat fibroinflammatory airway disease. Sci Transl Med 6: 241ra279.
143. Minutti CM, Knipper JA, Allen JE, Zaiss DM. 2017. Tissue-specific contribution of macrophages to wound healing. Semin Cell Dev Biol 61: 3–11.
144. Moore BB, Peters-Golden M, Christensen PJ, Lama V, Kuziel WA, Paine RIII, Toews GB. 2003. Alveolar epithelial cell inhibition of fibroblast proliferation is regulated by MCP-1/CCR2 and mediated by PGE2. Am J Physiol Lung Cell Mol Physiol 284: L342–L349.
145. Moses HL, Coffey RJJr., Leof EB, Lyons RM, Keski-Oja J. 1987. Transforming growth factor β regulation of cell proliferation. J Cell Physiol 133: 1–7.
146. Moses HL, Yang EY, Pietenpol JA. 1990. TGF-β stimulation and inhibition of cell proliferation: New mechanistic insights. Cell 63: 245–247.
147. Moses HL, Arteaga CL, Alexandrow MG, Dagnino L, Kawabata M, Pierce DFJr, Serra R. 1994. TGFβ regulation of cell proliferation. Princess Takamatsu Symp 24: 250–263.
148. Moses HL, Roberts AB, Derynck R. 2016. The discovery and early days of TGF-β: A historical perspective. Cold Spring Harbor Perspect Biol 8: a021865.
149. 8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-β1. J Cell Biol 157: 493–507.
150. Munger JS, Harpel JG, Gleizes PE, Mazzieri R, Nunes I, Rifkin DB. 1997. Latent transforming growth factor-β: Structural features and mechanisms of activation. Kidney Int 51: 1376–1382.
151. 6 binds and activates latent TGFβ1: A mechanism for regulating pulmonary inflammation and fibrosis. Cell 96: 319–328.
152. Munoz-Espin D, Serrano M. 2014. Cellular senescence: From physiology to pathology. Nat Rev Mol Cell Biol 15: 482–496.
153. Munoz-Espin D, Canamero M, Maraver A, Gomez-Lopez G, Contreras J, Murillo-Cuesta S, Rodriguez-Baeza A, Varela-Nieto I, Ruberte J, Collado M, et al. 2013. Programmed cell senescence during mammalian embryonic development. Cell 155: 1104–1118.
154. Muro AF, Moretti FA, Moore BB, Yan M, Atrasz RG, Wilke CA, Flaherty KR, Martinez FJ, Tsui JL, Sheppard D, et al. 2008. An essential role for fibronectin extra type III domain A in pulmonary fibrosis. Am J Respir Crit Care Med 177: 638–645.
155. Myers JL, Katzenstein AL. 1988. Epithelial necrosis and alveolar collapse in the pathogenesis of usual interstitial pneumonia. Chest 94: 1309–1311.
156. Nakajima Y, Yamagishi T, Hokari S, Nakamura H. 2000. Mechanisms involved in valvuloseptal endocardial cushion formation in early cardiogenesis: Roles of transforming growth factor (TGF)-β and bone morphogenetic protein (BMP). Anat Rec 258: 119–127.
157. Nieto MA. 2011. The ins and outs of the epithelial to mesenchymal transition in health and disease. Annu Rev Cell Dev Biol 27: 347–376.
158. Nieto MA, Sargent MG, Wilkinson DG, Cooke J. 1994. Control of cell behavior during vertebrate development by Slug, a zinc finger gene. Science 264: 835–839.
159. Nieto MA, Huang RY, Jackson RA, Thiery JP. 2016. EMT: 2016. Cell 166: 21–45.
160. Nogee LM, Dunbar AE III, Wert SE, Askin F, Hamvas A, Whitsett JA. 2001. A mutation in the surfactant protein C gene associated with familial interstitial lung disease. N Engl J Med 344: 573–579.
161. Nusrat A, Parkos CA, Bacarra AE, Godowski PJ, Delp-Ar-cher C, Rosen EM, Madara JL. 1994. Hepatocyte growth factor/scatter factor effects on epithelia. Regulation of intercellular junctions in transformed and nontrans-formed cell lines, basolateral polarization of c-met receptor in transformed and natural intestinal epithelia, and induction of rapid wound repair in a transformed model epithelium. J Clin Invest 93: 2056–2065.
162. Okada T, Sinha S, Esposito I, Schiavon G, Lopez-Lago MA, Su W, Pratilas CA, Abele C, Hernandez JM, Ohara M, et al. 2015. The Rho GTPase Rnd1 suppresses mammary tumorigenesis and EMT by restraining Ras-MAPK signalling. Nat Cell Biol 17: 81–94.
163. Oku E, Kanaji T, Takata Y, Oshima K, Seki R, Morishige S, Imamura R, Ohtsubo K, Hashiguchi M, Osaki K, et al. 2008. Periostin and bone marrow fibrosis. Int J Hematol 88: 57–63.
164. high monocytes in CCR2-dependent lung fibrosis following gene-targeted alveolar injury. J Immunol 190: 3447–3457.
165. Pittet JF, Griffiths MJ, Geiser T, Kaminski N, Dalton SL, Huang X, Brown LA, Gotwals PJ, Koteliansky VE, Matthay MA, et al. 2001. TGF-β is a critical mediator of acute lung injury. J Clin Invest 107: 1537–1544.
166. Postma DS, Timens W. 2006. Remodeling in asthma and chronic obstructive pulmonary disease. Proc Am Thorac Soc 3: 434–439.
167. Prele CM, Yao E, O’Donoghue RJ, Mutsaers SE, Knight DA. 2012. STAT3: A central mediator of pulmonary fibrosis? Proc Am Thorac Soc 9: 177–182.
168. Prockop DJ, Sieron AL, Li SW. 1998. Procollagen N-protein-ase and procollagen C-proteinase. Two unusual metal-loproteinases that are essential for procollagen processing probably have important roles in development and cell signaling. Matrix Biol 16: 399–408.
169. Prox J, Arnold P, Becker-Pauly C. 2015. Meprin α and meprin β: Procollagen proteinases in health and disease. Matrix Biol 44–46: 7–13.
170. 6, an activator of latent transforming growth factor-β, prevents radia-tion-induced lung fibrosis. Am J Respir Crit Care Med 177: 82–90.
171. 1 integrin plays a critical in vivo role in tissue fibrosis. Sci Transl Med 7: 288ra279.
172. Reinert RB, Kantz J, Misfeldt AA, Poffenberger G, Gannon M, Brissova M, Powers AC. 2012. Tamoxifen-induced Cre-loxP recombination is prolonged in pancreatic islets of adult mice. PLoS ONE 7: e33529.
173. Rhim AD, Thege FI, Santana SM, Lannin TB, Saha TN, Tsai S, Maggs LR, Kochman ML, Ginsberg GG, Lieb JG, et al. 2014. Detection of circulating pancreas epithelial cells in patients with pancreatic cystic lesions. Gastroenterology 146: 647–651.
174. Roberts AB, Lamb LC, Newton DL, Sporn MB, De Larco JE, Todaro GJ. 1980. Transforming growth factors: Isolation of polypeptides from virally and chemically transformed cells by acid/ethanol extraction. Proc Natl Acad Sci 77: 3494–3498.
175. Roberts AB SM, Assoian RK, Smith JM, Rocke NS, Wake-field LM, Heine UI, Liotta LA, Falanga V, Kehrl JH, Fauci AS. 1986. Transforming growth factor β: Rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci 83: 4167– 4171.
176. * Robertson IB, Rifkin DB. 2016. Regulation of the bioavail-ability of TGF-β and TGF-β-related proteins. Cold Spring Harbor Perspect Biol 8: a021907.
177. Rock JR, Barkauskas CE, Cronce MJ, Xue Y, Harris JR, Liang J, Noble PW, Hogan BL. 2011. Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition. Proc Natl Acad Sci 108: E1475–E1483.
178. Rodier F, Campisi J. 2011. Four faces of cellular senescence. J Cell Biol 192: 547–556.
179. Rowe RG, Lin Y, Shimizu-Hirota R, Hanada S, Neilson EG, Greenson JK, Weiss SJ. 2011. Hepatocyte-derived Snail1 propagates liver fibrosis progression. Mol Cell Biol 31: 2392–2403.
180. Saglani S, Molyneux C, Gong H, Rogers A, Malmstrom K, Pelkonen A, Makela M, Adelroth E, Bush A, Payne DN, et al. 2006. Ultrastructure of the reticular basement membrane in asthmatic adults, children and infants. Eur Respir J 28: 505–512.
181. Saito A, Okazaki H, Sugawara I, Yamamoto K, Takizawa H. 2003. Potential action of IL-4 and IL-13 as fibrogenic factors on lung fibroblasts in vitro. Int Arch Allergy Immunol 132: 168–176.
182. Sanders YY, Liu H, Zhang X, Hecker L, Bernard K, Desai L, Liu G, Thannickal VJ. 2013. Histone modifications in senescence-associated resistance to apoptosis by oxidative stress. Redox Biol 1: 8–16.
183. Sauka-Spengler T, Bronner-Fraser M. 2008. Evolution of the neural crest viewed from a gene regulatory perspective. Genesis 46: 673–682.
184. Savagner P, Kusewitt DF, Carver EA, Magnino F, Choi C, Gridley T, Hudson LG. 2005. Developmental transcription factor slug is required for effective re-epithelialization by adult keratinocytes. J Cell Physiol 202: 858–866.
185. Schmidt M, Sun G, Stacey MA, Mori L, Mattoli S. 2003. Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma. J Immunol 171: 380–389.
186. Schreier T, Degen E, Baschong W. 1993. Fibroblast migration and proliferation during in vitro wound healing. A quantitative comparison between various growth factors and a low molecular weight blood dialysate used in the clinic to normalize impaired wound healing. Res Exp Med 193: 195–205.
187. Seeger W, Gunther A, Walmrath HD, Grimminger F, Lasch HG. 1993. Alveolar surfactant and adult respiratory distress syndrome. Pathogenetic role and therapeutic prospects. Clin Investig 71: 177–190.
188. Senturk S, Mumcuoglu M, Gursoy-Yuzugullu O, Cingoz B, Akcali KC, Ozturk M. 2010. Transforming growth factor-β induces senescence in hepatocellular carcinoma cells and inhibits tumor growth. Hepatology 52: 966–974.
189. Shi M, Zhu J, Wang R, Chen X, Mi L, Walz T, Springer TA. 2011. Latent TGF-β structure and activation. Nature 474: 343–349.
190. Shibanuma M, Mashimo J, Kuroki T, Nose K. 1994. Characterization of the TGFβ1-inducible hic-5 gene that encodes a putative novel zinc finger protein and its possible involvement in cellular senescence. J Biol Chem 269: 26767–26774.
191. Shivshankar P, Brampton C, Miyasato S, Kasper M, Thannickal VJ, Le Saux CJ. 2012. Caveolin-1 deficiency protects from pulmonary fibrosis by modulating epithelial cell senescence in mice. Am J Respir Cell Mol Biol 47: 28– 36.
192. Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, Allen R, Sidman C, Proetzel G, Calvin D, et al. 1992. Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease. Nature 359: 693–699.
193. Sime PJ, Xing Z, Graham FL, Csaky KG, Gauldie J. 1997. Adenovector-mediated gene transfer of active transforming growth factor-β1 induces prolonged severe fibrosis in rat lung. J Clin Invest 100: 768–776.
194. Sisson TH, Maher TM, Ajayi IO, King JE, Higgins PD, Booth AJ, Sagana RL, Huang SK, White ES, Moore BB, et al. 2012. Increased survivin expression contributes to apo-ptosis-resistance in IPF fibroblasts. Adv Biosci Biotechnol 3: 657–664.
195. Sisson TH, Ajayi IO, Subbotina N, Dodi AE, Rodansky ES, Chibucos LN, Kim KK, Keshamouni VG, White ES, Zhou Y, et al. 2015. Inhibition of myocardin-related transcription factor/serum response factor signaling decreases lung fibrosis and promotes mesenchymal cell apoptosis. Am J Pathol 185: 969–986.
196. Staab-Weijnitz CA, Fernandez IE, Knuppel L, Maul J, Hein-zelmann K, Juan-Guardela BM, Hennen E, Preissler G, Winter H, Neurohr C, et al. 2015. FK506-binding protein 10 is a potential novel drug target for idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 192: 455–467.
197. Stockis J, Colau D, Coulie PG, Lucas S. 2009. Membrane protein GARP is a receptor for latent TGF-β on the surface of activated human Treg. Eur J Immunol 39: 3315–3322.
198. Stoker M, Perryman M. 1985. An epithelial scatter factor released by embryo fibroblasts. J Cell Sci 77: 209–223.
199. Strutz F, Okada H, Lo CW, Danoff T, Carone RL, Tomas-zewski JE, Neilson EG. 1995. Identification and characterization of a fibroblast marker: FSP1. J Cell Biol 130: 393–405.
200. Strutz F, Zeisberg M, Renziehausen A, Raschke B, Becker V, van Kooten C, Muller G. 2001. TGF-β1 induces proliferation in human renal fibroblasts via induction of basic fibroblast growth factor (FGF-2). Kidney Int 59: 579–592.
201. Sugimoto H, LeBleu VS, Bosukonda D, Keck P, Taduri G, Bechtel W, Okada H, Carlson WJr., Bey P, Rusckowski M, et al. 2012. Activin-like kinase 3 is important for kidney regeneration and reversal of fibrosis. Nat Med 18: 396– 404.
202. Takehara K, LeRoy EC, Grotendorst GR. 1987. TGF-β inhibition of endothelial cell proliferation: Alteration of EGF binding and EGF-induced growth-regulatory (compe-tence) gene expression. Cell 49: 415–422.
203. Tanaka T, Yoshimi M, Maeyama T, Hagimoto N, Kuwano K, Hara N. 2002. Resistance to Fas-mediated apoptosis in human lung fibroblast. Eur Respir J 20: 359–368.
204. Tanjore H, Xu XC, Polosukhin VV, Degryse AL, Li B, Han W, Sherrill TP, Plieth D, Neilson EG, Blackwell TS, et al. 2009. Contribution of epithelial-derived fibroblasts to bleomycin-induced lung fibrosis. Am J Respir Crit Care Med 180: 657–665.
205. Tanjore H, Cheng DS, Degryse AL, Zoz DF, Abdolrasulnia R, Lawson WE, Blackwell TS. 2011. Alveolar epithelial cells undergo epithelial-to-mesenchymal transition in response to endoplasmic reticulum stress. J Biol Chem 286: 30972–30980.
206. Tanjore H, Blackwell TS, Lawson WE. 2012. Emerging evidence for endoplasmic reticulum stress in the pathogenesis of idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 302: L721–L729.
207. Tanjore H, Lawson WE, Blackwell TS. 2013. Endoplasmic reticulum stress as a pro-fibrotic stimulus. Biochim Biophys Acta 1832: 940–947.
208. Tarin D, Thompson EW, Newgreen DF. 2005. The fallacy of epithelial mesenchymal transition in neoplasia. Cancer Res 65: 5996–6000.
209. Taura K, Miura K, Iwaisako K, Osterreicher CH, Kodama Y, Penz-Osterreicher M, Brenner DA. 2010. Hepatocytes do not undergo epithelial–mesenchymal transition in liver fibrosis in mice. Hepatology 51: 1027–1036.
210. Teng Y, Zeisberg M, Kalluri R. 2007. Transcriptional regulation of epithelial–mesenchymal transition. J Clin Invest 117: 304–306.
211. Thannickal VJ. 2013. Mechanistic links between aging and lung fibrosis. Biogerontology 14: 609–615.
212. Thannickal VJ, Horowitz JC. 2006. Evolving concepts of apoptosis in idiopathic pulmonary fibrosis. Proc Am Thorac Soc 3: 350–356.
213. Thannickal VJ, Henke CA, Horowitz JC, Noble PW, Roman J, Sime PJ, Zhou Y, Wells RG, White ES, Tschumperlin DJ. 2014. Matrix biology of idiopathic pulmonary fibrosis: A workshop report of the national heart, lung, and blood institute. Am J Pathol 184: 1643–1651.
214. Theriault BL, Shepherd TG, Mujoomdar ML, Nachtigal MW. 2007. BMP4 induces EMTand Rho GTPase activation in human ovarian cancer cells. Carcinogenesis 28: 1153–1162.
215. Thiery JP, Acloque H, Huang RY, Nieto MA. 2009. Epithelial–mesenchymal transitions in development and disease. Cell 139: 871–890.
216. Thomas AQ, Lane K, Phillips JIII, Prince M, Markin C, Speer M, Schwartz DA, Gaddipati R, Marney A, Johnson J, et al. 2002. Heterozygosity for a surfactant protein C gene mutation associated with usual interstitial pneumonitis and cellular nonspecific interstitial pneumonitis in one kindred. Am J Respir Crit Care Med 165: 1322–1328.
217. Torres-Gonzalez E, Bueno M, Tanaka A, Krug LT, Cheng DS, Polosukhin VV, Sorescu D, Lawson WE, Blackwell TS, Rojas M, et al. 2012. Role of endoplasmic reticulum stress in age-related susceptibility to lung fibrosis. Am J Respir Cell Mol Biol 46: 748–756.
218. Trackman PC. 2005. Diverse biological functions of extracellular collagen processing enzymes. J Cell Biochem 96: 927–937.
219. Travis MA, Sheppard D. 2014. TGF-β activation and function in immunity. Annu Rev Immunol 32: 51–82.
220. Trian T, Allard B, Dupin I, Carvalho G, Ousova O, Maurat E, Bataille J, Thumerel M, Begueret H, Girodet PO, et al. 2015. House dust mites induce proliferation of severe asthmatic smooth muscle cells via an epithelium-depen-dent pathway. Am J Respir Crit Care Med 191: 538–546.
221. Tucker RF, Shipley GD, Moses HL, Holley RW. 1984. Growth inhibitor from BSC-1 cells closely related to platelet type β transforming growth factor. Science 226: 705–707.
222. Tzouvelekis A, Harokopos V, Paparountas T, Oikonomou N, Chatziioannou A, Vilaras G, Tsiambas E, Karameris A, Bouros D, Aidinis V. 2007. Comparative expression profiling in pulmonary fibrosis suggests a role of hypoxia-inducible factor-1α in disease pathogenesis. Am J Respir Crit Care Med 176: 1108–1119.
223. Uhal BD, Joshi I, Hughes WF, Ramos C, Pardo A, Selman M. 1998. Alveolar epithelial cell death adjacent to underlying myofibroblasts in advanced fibrotic human lung. Am J Physiol 275: L1192–L1199.
224. Valles AM, Boyer B, Badet J, Tucker GC, Barritault D, Thiery JP. 1990. Acidic fibroblast growth factor is a modulator of epithelial plasticity in a rat bladder carcinoma cell line. Proc Natl Acad Sci 87: 1124–1128.
225. Vannella KM, Wynn TA. 2016. Mechanisms of organ injury and repair by macrophages. Annul Rev Physiol 79: 593– 617.
226. Vaughan AE, Brumwell AN, Xi Y, Gotts JE, Brownfield DG, Treutlein B, Tan K, Tan V, Liu FC, Looney MR, et al. 2015. Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury. Nature 517: 621–625.
227. Viebahn C. 1995. Epithelio-mesenchymal transformation during formation of the mesoderm in the mammalian embryo. Acta Anat 154: 79–97.
228. Viebahn C, Mayer B, Miething A. 1995. Morphology of incipient mesoderm formation in the rabbit embryo: A light- and retrospective electron-microscopic study. Acta Anat 154: 99–110.
229. Wan YY, Flavell RA. 2007. ‘Yin-Yang’ functions of transforming growth factor-β and T regulatory cells in immune regulation. Immunol Rev 220: 199–213.
230. Wang R, Ramos C, Joshi I, Zagariya A, Pardo A, Selman M, Uhal BD. 1999. Human lung myofibroblast-derived in-ducers of alveolar epithelial apoptosis identified as an-giotensin peptides. Am J Physiol 277: L1158–L1164.
231. Wang Y, Kuan PJ, Xing C, Cronkhite JT, Torres F, Rosenblatt RL, DiMaio JM, Kinch LN, Grishin NV, Garcia CK. 2009. Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer. Am J Hum Genet 84: 52–59.
232. 6 monoclonal antibodies: Distinct ligand-mimetic and nonli-gand-mimetic classes. J Biol Chem 279: 17875–17887.
233. Willis BC, Liebler JM, Luby-Phelps K, Nicholson AG, Cran-dall ED, du Bois RM, Borok Z. 2005. Induction of epithelial–mesenchymal transition in alveolar epithelial cells by transforming growth factor-β1: Potential role in idiopathic pulmonary fibrosis. Am J Pathol 166: 1321– 1332.
234. Wilm B, Ipenberg A, Hastie ND, Burch JB, Bader DM. 2005. The serosal mesothelium is a major source of smooth muscle cells of the gut vasculature. Development 132: 5317–5328.
235. Wipff PJ, Rifkin DB, Meister JJ, Hinz B. 2007. Myofibroblast contraction activates latent TGF-β1 from the extracellular matrix. J Cell Biol 179: 1311–1323.
236. Wynn TA. 2007. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest 117: 524–529.
237. Xiao L, Du Y, Shen Y, He Y, Zhao H, Li Z. 2012. TGF-β1 induced fibroblast proliferation is mediated by the FGF-2/ERK pathway. Front Biosci 17: 2667–2674.
238. Yang T, Liang Y, Lin Q, Liu J, Luo F, Li X, Zhou H, Zhuang S, Zhang H. 2013. miR-29 mediates TGFβ1-induced extracellular matrix synthesis through activation of PI3K-AKT pathway in human lung fibroblasts. J Cell Biochem 114: 1336–1342.
239. Yu AL, Fuchshofer R, Kook D, Kampik A, Bloemendal H, Welge-Lussen U. 2009. Subtoxic oxidative stress induces senescence in retinal pigment epithelial cells via TGF-β release. Invest Ophthalmol Vis Sci 50: 926–935.
240. Zeisberg M, Duffield JS. 2010. Resolved: EMT produces fibroblasts in the kidney. J Am Soc Nephrol 21: 1247– 1253.
241. Zeisberg M, Neilson EG. 2009. Biomarkers for epithelial– mesenchymal transitions. J Clin Invest 119: 1429–1437.
242. Zeisberg EM, Tarnavski O, Zeisberg M, Dorfman AL, McMullen JR, Gustafsson E, Chandraker A, Yuan X, Pu WT, Roberts AB, et al. 2007a. Endothelial-to-mesenchy-mal transition contributes to cardiac fibrosis. Nat Med 13: 952–961.
243. Zeisberg M, Yang C, Martino M, Duncan MB, Rieder F, Tanjore H, Kalluri R. 2007b. Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. J Biol Chem 282: 23337–23347.
244. Zeisberg EM, Potenta SE, Sugimoto H, Zeisberg M, Kalluri R. 2008. Fibroblasts in kidney fibrosis emerge via endo-thelial-to-mesenchymal transition. J Am Soc Nephrol 19: 2282–2287.
245. Zhang HY, Phan SH. 1999. Inhibition of myofibroblast apoptosis by transforming growth factor β1. Am J Respir Cell Mol Biol 21: 658–665.
246. Zhang K, Rekhter MD, Gordon D, Phan SH. 1994. Myofibroblasts and their role in lung collagen gene expression during pulmonary fibrosis. A combined immunohisto-chemical and in situ hybridization study. Am J Pathol 145: 114–125.
247. Zhang Y, Feng XH, Derynck R. 1998. Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-β-induced transcription. Nature 394: 909–913.
248. Zhang X, Li J, Sejas DP, Pang Q. 2005. The ATM/p53/p21 pathway influences cell fate decision between apoptosis and senescence in reoxygenated hematopoietic progenitor cells. J Biol Chem 280: 19635–19640.
249. Zhou B, Pu WT. 2011. Epicardial epithelial-to-mesenchymal transition in injured heart. J Cell Mol Med 15: 2781– 2783.
250. Zhou G, Dada LA, Wu M, Kelly A, Trejo H, Zhou Q, Varga J, Sznajder JI. 2009. Hypoxia-induced alveolar epithelial– mesenchymal transition requires mitochondrial ROS and hypoxia-inducible factor 1. Am J Physiol Lung Cell Mol Physiol 297: L1120–L1130.
251. Zhu J, Motejlek K, Wang D, Zang K, Schmidt A, Reichardt LF. 2002. β8 integrins are required for vascular morphogenesis in mouse embryos. Development 129: 2891– 2903.