The immunology of fibrosis

Annual Review of Immunology

Volumn 31, Issue , 2013, Pages 107-135

  Wick, Georg ^a   Grundtman, Cecilia ^a   Mayerl, Christina ^a   Wimpissinger, Thomas Florian ^c   Feichtinger, Johann ^c   Zelger, Bettina ^b   Sgonc, Roswitha ^a   Wolfram, Dolores ^a  

^a INNSBRUCK MEDICAL UNIVERSITY   (Austria)

^b MEDICAL UNIVERSITY OF INNSBRUCK   (Austria)

^c Hospital Rudolfstiftung   (Austria)

Author keywords

Adaptive immunity; Fibrotic disorders; Innate immunity; Myofibroblasts; Signal transduction; Stellate cells

Indexed keywords

ANTIFIBROTIC AGENT; BACTERIUM LIPOPOLYSACCHARIDE; CATHEPSIN; CHAPERONIN 60; CHEMOKINE; COLLAGEN TYPE 1; COLLAGEN TYPE 3; COLLAGENASE; CONNECTIVE TISSUE GROWTH FACTOR; ELASTASE; GAMMA INTERFERON; GRANULOCYTE COLONY STIMULATING FACTOR; HYPOXIA INDUCIBLE FACTOR 1ALPHA; INDUCIBLE NITRIC OXIDE SYNTHASE; INTERLEUKIN 1; INTERLEUKIN 13; INTERLEUKIN 13 RECEPTOR ALPHA2; INTERLEUKIN 17; INTERLEUKIN 4; INTERLEUKIN 6; MAJOR BASIC PROTEIN; MATRIX METALLOPROTEINASE; MICRORNA; NITRIC OXIDE; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA ANTAGONIST; REACTIVE OXYGEN METABOLITE; TISSUE INHIBITOR OF METALLOPROTEINASE 1; TRANSFORMING GROWTH FACTOR BETA; TUMOR NECROSIS FACTOR ALPHA;

ADAPTIVE IMMUNITY; ADULT RESPIRATORY DISTRESS SYNDROME; ALCOHOL LIVER CIRRHOSIS; ATHEROSCLEROSIS; AUTOIMMUNE DISEASE; BURN; CD25+ T LYMPHOCYTE; CONNECTIVE TISSUE; CYTOKINE PRODUCTION; EPITHELIAL MESENCHYMAL TRANSITION; FIBROGENESIS; FIBROSIS; FOREIGN BODY REACTION; GLOMERULOSCLEROSIS; HUMAN; INFLAMMATION; INNATE IMMUNITY; KELOID; KIDNEY FIBROSIS; LUNG FIBROSIS; MACROPHAGE; MAST CELL; MECHANICAL STRESS; MYOFIBROBLAST; NATURAL KILLER CELL; NATURAL KILLER T CELL; NEOPLASM; NEUTROPHIL; PEYRONIE DISEASE; PRIORITY JOURNAL; PROTEIN EXPRESSION; REGULATORY T LYMPHOCYTE; REVIEW; SCAR FORMATION; SIGNAL TRANSDUCTION; STELLATE CELL; STROMA CELL; SYSTEMIC SCLEROSIS; TH17 CELL; TISSUE INJURY; WOUND HEALING;

ADAPTIVE IMMUNITY; ANIMALS; CELL PROLIFERATION; CELL TRANSDIFFERENTIATION; FIBROBLASTS; FIBROSIS; HUMANS; IMMUNITY, INNATE; INFLAMMATION; MYOFIBROBLASTS;

EID: 84875535234     PISSN: 07320582     EISSN: 15453278     Source Type: Book Series    
DOI: 10.1146/annurev-immunol-032712-095937     Document Type: Review

References (161)

1. Wynn AT. 2004. Fibrotic disease and the Th1/Th2 paradigm. Nat. Rev. Immunol. 4:583-94
2. Wick G, Backovic A, Rabensteiner E, Plank N, Schwentner C, Sgonc R. 2010. The immunology of fibrosis: innate and adaptive responses. Trends Immunol. 31:110-19
3. + perivascular cells identify a major source of profibrotic cells during acute tissue injury. Nat. Med. 18:1262-70
4. Lefkowitz DL, Lefkowitz SS. 2001. Macrophage-neutrophil interaction: a paradigm for chronic inflammation revisited. Immunol. Cell Biol. 79:502-6
5. Gasse P, Mary C, Guenon I, Noulin N, Charron S, et al. 2007. IL-1R1/MyD88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in mice. J. Clin. Investig. 117:3786-99
6. Cassel SL, Eisenbarth SC, Iyer SS, Sadler JJ, Colegio OR, et al. 2008. The Nalp3 inflammasome is essential for the development of silicosis. Proc. Natl. Acad. Sci. USA 105:9035-40
7. Gasse P, Riteau N, Charron S, Girre S, Fick L, et al. 2009. Uric acid is a danger signal activatingNALP3 inflammasome in lung injury inflammation and fibrosis. Am. J. Respir. Crit. CareMed. 179:903-13
8. Munitz A, Levi-Schaffer F. 2004. Eosinophils: 'new' roles for 'old' cells. Allergy 59:268-75
9. Bavbek N, Kargili AE, Cipil H, Kosar A, Karaaslan Y. 2004. Rheumatologic disease with peripheral eosinophilia. Rheumatol. Int. 24:317-20
10. Wehling-Henricks M, Sokolow S, Lee JJ, Myung KH, Villalta SA, Tidball JG. 2008. Major basic protein-1 promotes fibrosis of dystrophic muscle and attenuates the cellular immune response in muscular dystrophy. Hum. Mol. Genet. 17:2280-92
11. Claman HN. 1985. Mast-cells, T-cells and abnormal fibrosis. Immunol. Today 6:192-95
12. Gruber BL. 2003. Mast cells in the pathogenesis of fibrosis. Curr. Rheumatol. Rep. 5:147-53
13. Garbuzenko E, Nagler A, Pickholtz D, Gillery P, Reich R, et al. 2002. Human mast cells stimulate fibroblast proliferation, collagen synthesis and lattice contraction: a direct role for mast cells in skin fibrosis. Clin. Exp. Allergy 32:237-46
14. Gharaee-Kermani M, McCullumsmith RE, Charo IF, Kunkel SL, Phan SH. 2003. CC-chemokine receptor 2 required for bleomycin-induced pulmonary fibrosis. Cytokine 24:266-76
15. Sica A, Mantovani A. 2012. Macrophage plasticity and polarization: in vivo veritas. J. Clin. Investig. 122:787-95
16. Gao B, Radaeva S, JeongWI. 2007. Activation of natural killer cells inhibits liver fibrosis: a novel strategy to treat liver fibrosis. Expert Rev. Gastroenterol. Hepatol. 1:173-80
17. Kim JH, Kim HY, Kim S, Chung JH, Park WS, Chung DH. 2005. Natural killer T (NKT) cells attenuate bleomycin-induced pulmonary fibrosis by producing interferon-γ.Am. J. Pathol. 167:1231-41
18. Melhem A, Muhanna N, Bishara A, Alvarez CE, Ilan Y, et al. 2006. Anti-fibrotic activity of NK cells in experimental liver injury through killing of activated HSC. J. Hepatol. 45:60-71
19. Muhanna N, Doron S, Wald O, Horani A, Eid A, et al. 2008. Activation of hepatic stellate cells after phagocytosis of lymphocytes: a novel pathway of fibrogenesis. Hepatology 48:963-77
20. Simonian PL, Wehrmann F, Roark CL, BornWK, O'Brien RL, Fontenot AP. 2010. γ∞T cells protect against lung fibrosis via IL-22. J. Exp. Med. 207:2239-53
21. Simonian PL, Roark CL, Born WK, O'Brien RL, Fontenot AP. 2009. γ∞ T cells and Th17 cytokines in hypersensitivity pneumonitis and lung fibrosis. Transl. Res. 154:222-27
22. Lo Re S, Dumoutier L, Couillin I, Van Vyve C, Yakoub Y, et al. 2010. IL-17A-producing γ∞ T and Th17 lymphocytes mediate lung inflammation but not fibrosis in experimental silicosis. J. Immunol. 184:6367-77
23. Wilson MS, Madala SK, Ramalingam TR, Gochuico BR, Rosas IO, et al. 2010. Bleomycin and IL-1β-mediated pulmonary fibrosis is IL-17A dependent. J. Exp. Med. 207:535-52
24. Braun RK, Ferrick C, Neubauer P, Sjoding M, Sterner-Kock A, et al. 2008. IL-17 producing γ∞T cells are required for a controlled inflammatory response after bleomycin-induced lung injury. Inflammation 31:167-79
25. Nakashima T, JinninM, Yamane K, Honda N, Kajihara I, et al. 2012. Impaired IL-17 signaling pathway contributes to the increased collagen expression in scleroderma fibroblasts. J. Immunol. 188:3573-83
26. Foster RG, Golden-Mason L, Rutebemberwa A, Rosen HR. 2012. Interleukin (IL)-17/IL-22-producing T cells enriched within the liver of patients with chronic hepatitis C viral (HCV) infection. Dig. Dis. Sci. 57:381-89
27. +CD25-Foxp3-T cells or are self-induced to become Th17 cells in the absence of exogenous TGF-β. J. Immunol. 178:6725-29
28. Sakaki M, Hiroishi K, Baba T, Ito T, Hirayama Y, et al. 2008. Intrahepatic status of regulatory T cells in autoimmune liver diseases and chronic viral hepatitis. Hepatol. Res. 38:354-61
29. WolframD, Rabensteiner E, Grundtman C, Bock G, Mayerl C, et al. 2012. T regulatory cells and TH17 cells in peri-silicone implant capsular fibrosis. Plast. Reconstr. Surg. 129:327e-37e
30. + regulatory T cells. J. Leukoc. Biol. 86:567-72
31. Hart J. 2002. Inflammation. 1: Its role in the healing of acute wounds. J. Wound Care 11:205-9
32. Levi-Schaffer F, Piliponsky AM. 2003. Tryptase, a novel link between allergic inflammation and fibrosis. Trends Immunol. 24:158-61
33. RaoKN, BrownMA. 2008. Mast cells:multifaceted immune cells with diverse roles in health and disease. Ann. N. Y. Acad. Sci. 1143:83-104
34. Jameson J, Ugarte K, Chen N, Yachi P, Fuchs E, et al. 2002. A role for skin γ∞T cells in wound repair. Science 296:747-49
35. Shih B, Garside E, McGrouther DA, Bayat A. 2010. Molecular dissection of abnormal wound healing processes resulting in keloid disease. Wound Repair Regen. 18:139-53
36. Wolfram D, Tzankov A, Pulzl P, Piza-Katzer H. 2009. Hypertrophic scars and keloids- A review of their pathophysiology, risk factors, and therapeutic management. Dermatol. Surg. 35:171-81
37. Craig SS, DeBlois G, Schwartz LB. 1986. Mast cells in human keloid, small intestine, and lung by an immunoperoxidase technique using a murine monoclonal antibody against tryptase. Am. J. Pathol. 124:427-35
38. Friedman DW, Boyd CD, Mackenzie JW, Norton P, Olson RM, Deak SB. 1993. Regulation of collagen gene expression in keloids and hypertrophic scars. J. Surg. Res. 55:214-22
39. McCauley RL, Chopra V, Li YY, Herndon DN, Robson MC. 1992. Altered cytokine production in black patients with keloids. J. Clin. Immunol. 12:300-8
40. Brigham PA, McLoughlin E. 1996. Burn incidence and medical care use in the United States: estimates, trends, and data sources. J. Burn Care Rehabil. 17:95-107
41. Kasten KR, Prakash PS, Unsinger J, Goetzman HS, England LG, et al. 2010. Interleukin-7 (IL-7) treatment accelerates neutrophil recruitment through γ∞T-cell IL-17 production in a murine model of sepsis. Infect. Immun. 78:4714-22
42. Roark CL, Simonian PL, Fontenot AP, Born WK, O'Brien RL. 2008. γ∞T cells: an important source of IL-17. Curr. Opin. Immunol. 20:353-57
43. Murphy TJ, Paterson HM, Mannick JA, Lederer JA. 2004. Injury, sepsis, and the regulation of Toll-like receptor responses. J. Leukoc. Biol. 75:400-7
44. Shirali AC, Goldstein DR. 2008. Activation of the innate immune system by the endogenous ligand hyaluronan. Curr. Opin. Organ. Transplant. 13:20-25
45. Oppeltz RF, Rani M, Zhang Q, Schwacha MG. 2011. Burn-induced alterations in Toll-like receptormediated responses by bronchoalveolar lavage cells. Cytokine 55:396-401
46. Shimabukuro DW, Sawa T, Gropper MA. 2003. Injury and repair in lung and airways. Crit. Care Med. 31:S524-31
47. Governa M, Benedetti E, Lorenzini M, Barisoni D. 1987. Autoantibodies in 16 patients with extensive burns and a review of the literature. Burns 13:469-75
48. Leguit P Jr, Feltkamp TE, van Rossum AL, van Loghem E, Eijsvoogel VP. 1973. Immunological studies in burn patients. 3. Autoimmune phenomena. Int. Arch. Allergy Appl. Immunol. 45:392-404
49. Leguit P Jr, Meinesz A, Zeijlemaker WP, Schellekens PT, Eijsvoogel VP. 1973. Immunological studies in burn patients. I. Lymphocyte transformation in vitro. Int. Arch. Allergy Appl. Immunol. 44:101-21
50. Duryee MJ, Klassen LW, Thiele GM. 2007. Immunological response in alcoholic liver disease. World J. Gastroenterol. 13:4938-46
51. Voican CS, Perlemuter G, Naveau S. 2011. Mechanisms of the inflammatory reaction implicated in alcoholic hepatitis: 2011 update. Clin. Res. Hepatol. Gastroenterol. 35:465-74
52. Clot P, Bellomo G, Tabone M, Arico S, Albano E. 1995. Detection of antibodies against proteins modified by hydroxyethyl free radicals in patients with alcoholic cirrhosis. Gastroenterology 108:201-7
53. Worrall S, de Jersey J, Nicholls R, Wilce P. 1993. Acetaldehyde/protein interactions: Are they involved in the pathogenesis of alcoholic liver disease? Dig. Dis. 11:265-77
54. Miller YI, Choi SH, Wiesner P, Fang L, Harkewicz R, et al. 2011. Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity. Circ. Res. 108:235-48
55. Wick G, Brunner H, Penner E, Timpl R. 1978. The diagnostic application of specific antiprocollagen sera. II. Analysis of liver biopsies. Int. Arch. Allergy Appl. Immunol. 56:316-24
56. Thiele GM, Tuma DJ, Willis MS, Miller JA, McDonald TL, et al. 1998. Soluble proteins modified with acetaldehyde and malondialdehyde are immunogenic in the absence of adjuvant. Alcohol. Clin. Exp. Res. 22:1731-39
57. Hines IN, Wheeler MD. 2004. Recent advances in alcoholic liver disease III. Role of the innate immune response in alcoholic hepatitis. Am. J. Physiol. Gastrointest. Liver Physiol. 287:G310-14
58. Bode C, Bode JC. 2005. Activation of the innate immune system and alcoholic liver disease: effects of ethanol per se or enhanced intestinal translocation of bacterial toxins induced by ethanol? Alcohol. Clin. Exp. Res. 29(Suppl.):166S-71
59. Seki E, Schnabl B. 2012. Role of innate immunity and the microbiota in liver fibrosis: crosstalk between the liver and gut. J. Physiol. 590:447-58
60. Kobold D, Grundmann A, Piscaglia F, Eisenbach C, Neubauer K, et al. 2002. Expression of reelin in hepatic stellate cells and during hepatic tissue repair: a novel marker for the differentiation of HSC from other liver myofibroblasts. J. Hepatol. 36:607-13
61. Lemmers A, Moreno C, Gustot T, Marechal R, Degre D, et al. 2009. The interleukin-17 pathway is involved in human alcoholic liver disease. Hepatology 49:646-57
62. Caldas IR, Campi-Azevedo AC, Oliveira LF, Silveira AM, Oliveira RC, Gazzinelli G. 2008. Human schistosomiasis mansoni: immune responses during acute and chronic phases of the infection. Acta Trop. 108:109-17
63. Anthony B, Allen JT, Li YS, McManus DP. 2010. Hepatic stellate cells and parasite-induced liver fibrosis. Parasite Vectors 3:60
64. Sher A, Coffman RL, Hieny S, Scott P, Cheever AW. 1990. Interleukin 5 is required for the blood and tissue eosinophilia but not granuloma formation induced by infection with Schistosoma mansoni. Proc. Natl. Acad. Sci. USA 87:61-65
65. Singh KP, Gerard HC, Hudson AP, Boros DL. 2004. Expression of matrix metalloproteinases and their inhibitors during the resorption of schistosome egg-induced fibrosis in praziquantel-treated mice. Immunology 111:343-52
66. Zaccone P, Fehervari Z, Jones FM, Sidobre S, Kronenberg M, et al. 2003. Schistosoma mansoni antigens modulate the activity of the innate immune response and prevent onset of type 1 diabetes. Eur. J. Immunol. 33:1439-49
67. Novobrantseva TI, Majeau GR, Amatucci A, Kogan S, Brenner I, et al. 2005. Attenuated liver fibrosis in the absence of B cells. J. Clin. Investig. 115:3072-82
68. Mentink-Kane MM, Cheever AW, Thompson RW, Hari DM, Kabatereine NB, et al. 2004. IL-13 receptorα2 down-modulates granulomatous inflammation and prolongs host survival in schistosomiasis. Proc. Natl. Acad. Sci. USA 101:586-90
69. Hou X, Yu F, Man S, Huang D, Zhang Y, et al. 2012. Negative regulation of Schistosoma japonicum egg-induced liver fibrosis by natural killer cells. PLoS Negl. Trop. Dis. 6:e1456
70. Bartley PB, Ramm GA, Jones MK, Ruddell RG, Li Y, McManus DP. 2006. A contributory role for activated hepatic stellate cells in the dynamics of Schistosoma japonicum egg-induced fibrosis. Int. J. Parasitol. 36:993-1001
71. Sgonc R, GruschwitzMS, Boeck G, Sepp N, Gruber J, Wick G. 2000. Endothelial cell apoptosis in systemic sclerosis is induced by antibody-dependent cell-mediated cytotoxicity via CD95. Arthritis Rheum. 43:2550-62
72. Sgonc R, Gruschwitz MS, Dietrich H, Recheis H, Gershwin ME, Wick G. 1996. Endothelial cell apoptosis is a primary pathogenetic event underlying skin lesions in avian and human scleroderma. J. Clin. Investig. 98:785-92
73. Chizzolini C, Brembilla NC, Montanari E, TruchetetME. 2011. Fibrosis and immune dysregulation in systemic sclerosis. Autoimmun. Rev. 10:276-81
74. Fineschi S, Goffin L, Rezzonico R, Cozzi F, Dayer JM, et al. 2008. Antifibroblast antibodies in systemic sclerosis induce fibroblasts to produce profibrotic chemokines, with partial exploitation of Toll-like receptor 4. Arthritis Rheum. 58:3913-23
75. Muro AF, Moretti FA, Moore BB, YanM, Atrasz RG, et al. 2008. An essential role for fibronectin extra type III domain A in pulmonary fibrosis. Am. J. Respir. Crit. CareMed. 177:638-45
76. Laplante P, Raymond MA, Gagnon G, Vigneault N, Sasseville AM, et al. 2005. Novel fibrogenic pathways are activated in response to endothelial apoptosis: implications in the pathophysiology of systemic sclerosis. J. Immunol. 174:5740-49
77. Rajkumar VS, Howell K, Csiszar K, Denton CP, Black CM, Abraham DJ. 2005. Shared expression of phenotypic markers in systemic sclerosis indicates a convergence of pericytes and fibroblasts to a myofibroblast lineage in fibrosis. Arthritis Res. Ther. 7:R1113-23
78. Li Z, Jimenez SA. 2011. Protein kinase C∞and c-Abl kinase are required for transforming growth factor βinduction of endothelial- mesenchymal transition in vitro. Arthritis Rheum. 63:2473-83
79. Verrecchia F, Mauviel A, Farge D. 2006. Transforming growth factor-β signaling through the Smad proteins: role in systemic sclerosis. Autoimmun. Rev. 5:563-69
80. Prelog M, Scheidegger P, Peter S, Gershwin ME, Wick G, Sgonc R. 2005. Diminished transforming growth factorβ2 production leads to increased expression of a profibrotic procollagenα2 type I messenger RNA variant in embryonic fibroblasts of UCD-200 chickens, a model for systemic sclerosis. Arthritis Rheum. 52:1804-11
81. Whitfield ML, Finlay DR, Murray JI, Troyanskaya OG, Chi JT, et al. 2003. Systemic and cell typespecific gene expression patterns in scleroderma skin. Proc. Natl. Acad. Sci. USA 100:12319-24
82. Libby P, Hansson GK. 1991. Involvement of the immune system in human atherogenesis: current knowledge and unanswered questions. Lab Investig. 64(1):5-15
83. Grundtman C, Kreutmayer SB, Almanzar G, Wick MC, Wick G. 2011. Heat shock protein 60 and immune inflammatory responses in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 31:960-68
84. Wick G, Knoflach M, Xu Q. 2004. Autoimmune and inflammatory mechanisms in atherosclerosis. Annu. Rev. Immunol. 22:361-403
85. Grenier S, Sandig M, Mequanint K. 2009. Smooth muscle α-actin and calponin expression and extracellular matrix production of human coronary artery smooth muscle cells in 3D scaffolds. Tissue Eng. Part A 15:3001-11
86. Rzucidlo EM, Martin KA, Powell RJ. 2007. Regulation of vascular smooth muscle cell differentiation. J. Vasc. Surg. 45(Suppl. A):A25-32
87. Grainger DJ, Kemp PR, Liu AC, Lawn RM, Metcalfe JC. 1994. Activation of transforming growth factor-βis inhibited in transgenic apolipoprotein(a) mice. Nature 370:460-62
88. Gojova A, Brun V, Esposito B, Cottrez F, Gourdy P, et al. 2003. Specific abrogation of transforming growth factor-β signaling in T cells alters atherosclerotic lesion size and composition in mice. Blood 102:4052-58
89. Robertson AK, Rudling M, Zhou X, Gorelik L, Flavell RA, Hansson GK. 2003. Disruption of TGF-β signaling in T cells accelerates atherosclerosis. J. Clin. Investig. 112:1342-50
90. Nikol S, Isner JM, Pickering JG, Kearney M, Leclerc G, Weir L. 1992. Expression of transforming growth factor-β1 is increased in human vascular restenosis lesions. J. Clin. Investig. 90:1582-92
91. BackM, KetelhuthDF, Agewall S. 2010. Matrix metalloproteinases in atherothrombosis. Prog.Cardiovasc. Dis. 52:410-28
92. Rajavashisth TB, Xu XP, Jovinge S, Meisel S, Xu XO, et al. 1999. Membrane type 1 matrix metalloproteinase expression in human atherosclerotic plaques: evidence for activation by proinflammatory mediators. Circulation 99:3103-9
93. Zaltsman AB, George SJ, Newby AC. 1999. Increased secretion of tissue inhibitors of metalloproteinases 1 and 2 from the aortas of cholesterol fed rabbits partially counterbalances increased metalloproteinase activity. Arterioscler. Thromb. Vasc. Biol. 19:1700-7
94. Sartore S, Chiavegato A, Faggin E, Franch R, Puato M, et al. 2001. Contribution of adventitial fibroblasts to neointima formation and vascular remodeling: from innocent bystander to active participant. Circ. Res. 89:1111-21
95. Sata M, Saiura A, Kunisato A, Tojo A, Okada S, et al. 2002. Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis. Nat. Med. 8:403-9
96. Rieder F, Brenmoehl J, Leeb S, Scholmerich J, Rogler G. 2007. Wound healing and fibrosis in intestinal disease. Gut 56:130-39
97. Mifflin RC, Pinchuk IV, Saada JI, Powell DW. 2011. Intestinal myofibroblasts: targets for stem cell therapy. Am. J. Physiol. Gastrointest. Liver Physiol. 300:G684-96
98. Rieder F, Fiocchi C. 2009. Intestinal fibrosis in IBD- A dynamic, multifactorial process. Nat. Rev. Gastroenterol. Hepatol. 6:228-35
99. Henckaerts L, Vermeire S. 2007. NOD2/CARD15 disease associations other than Crohn's disease. Inflamm. Bowel Dis. 13:235-41
100. Fiocchi C, Lund PK. 2011. Themes in fibrosis and gastrointestinal inflammation. Am. J. Physiol. Gastrointest. Liver Physiol. 300:G677-83
101. Jiang X, Tsitsiou E, Herrick SE, Lindsay MA. 2010. MicroRNAs and the regulation of fibrosis. FEBS J. 277:2015-21
102. Krawitt EL. 2006. Autoimmune hepatitis. N. Engl. J. Med. 354:54-66
103. Siegel SM, Selmi C, Dottorini L, AntelmiM, ZuinM, et al. 2008. Late-onset autoimmunity: the paradigm of primary biliary cirrhosis- A mini-review. Gerontology 54:193-201
104. Kershenobich Stalnikowitz D, Weissbrod AB. 2003. Liver fibrosis and inflammation. A review. Ann. Hepatol. 2:159-63
105. Bertola A, Bonnafous S, Anty R, Patouraux S, Saint-Paul MC, et al. 2010. Hepatic expression patterns of inflammatory and immune response genes associated with obesity andNASH inmorbidly obese patients. PLoS One 5:e13577
106. Hintermann E, BayerM, Pfeilschifter JM, Luster AD, Christen U. 2010.CXCL10 promotes liver fibrosis by prevention of NK cell mediated hepatic stellate cell inactivation. J. Autoimmun. 35:424-35
107. Bataller R, Brenner DA. 2005. Liver fibrosis. J. Clin. Investig. 115:209-18
108. Connolly MK, Bedrosian AS, Mallen-St Clair J, Mitchell AP, Ibrahim J, et al. 2009. In liver fibrosis, dendritic cells govern hepatic inflammation in mice via TNF-α. J. Clin. Investig. 119:3213-25
109. Reeves HL, Friedman SL. 2002. Activation of hepatic stellate cells- A key issue in liver fibrosis. Front. Biosci. 7:d808-26
110. Leemans JC, Butter LM, Pulskens WP, Teske GJ, ClaessenN, et al. 2009. The role ofToll-like receptor 2 in inflammation and fibrosis during progressive renal injury. PLoS One 4:e5704
111. Skuginna V, Lech M, Allam R, Ryu M, Clauss S, et al. 2011. Toll-like receptor signaling and SIGIRR in renal fibrosis upon unilateral ureteral obstruction. PLoS One 6:e19204
112. Lan HY. 2011. Diverse roles of TGF-β/Smads in renal fibrosis and inflammation. Int. J. Biol. Sci. 7:1056-67
113. Ka SM, Huang XR, Lan HY, Tsai PY, Yang SM, et al. 2007. Smad7 gene therapy ameliorates an autoimmune crescentic glomerulonephritis in mice. J. Am. Soc. Nephrol. 18:1777-88
114. Yang L, BesschetnovaTY, BrooksCR, Shah JV, Bonventre JV. 2010. Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury. Nat. Med. 16:535-43
115. BechtelW, McGoohan S, Zeisberg EM, Muller GA, Kalbacher H, et al. 2010. Methylation determines fibroblast activation and fibrogenesis in the kidney. Nat. Med. 16:544-50
116. Liu Z, Huang XR, Chen HY, Penninger JM, Lan HY. 2012. Loss of angiotensin-converting enzyme 2 enhances TGF-β/Smad-mediated renal fibrosis and NF-κB-driven renal inflammation in a mouse model of obstructive nephropathy. Lab. Investig. 92:650-61
117. Strutz F, Neilson EG. 2003. New insights into mechanisms of fibrosis in immune renal injury. Springer Semin. Immunopathol. 24:459-76
118. Kim KK, Kugler MC, Wolters PJ, Robillard L, Galvez MG, et al. 2006. Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc. Natl. Acad. Sci. USA 103:13180-85
119. Gross TJ, Hunninghake GW. 2001. Idiopathic pulmonary fibrosis. N. Engl. J. Med. 345:517-25
120. Turner-Warwick M. 1963. Precapillary systemic-pulmonary anastomoses. Thorax 18:225-37
121. KeaneMP, Arenberg DA, Lynch JP 3rd, Whyte RI, Iannettoni MD, et al. 1997. The CXC chemokines, IL-8 and IP-10, regulate angiogenic activity in idiopathic pulmonary fibrosis. J. Immunol. 159:1437-43
122. Keane MP, Belperio JA, Burdick MD, Strieter RM. 2001. IL-12 attenuates bleomycin-induced pulmonary fibrosis. Am. J. Physiol. Lung. Cell Mol. Physiol. 281:L92-97
123. Gharaee-Kermani M, Denholm EM, Phan SH. 1996. Costimulation of fibroblast collagen and transforming growth factorβ1 gene expression by monocyte chemoattractant protein-1 via specific receptors. J. Biol. Chem. 271:17779-84
124. Ma B, Zhu Z, Homer RJ, Gerard C, Strieter R, Elias JA. 2004. The C10/CCL6 chemokine and CCR1 play critical roles in the pathogenesis of IL-13-induced inflammation and remodeling. J. Immunol. 172:1872-81
125. Horowitz JC, Rogers DS, Sharma V, Vittal R, White ES, et al. 2007. Combinatorial activation of FAK and AKT by transforming growth factor-β1 confers an anoikis-resistant phenotype to myofibroblasts. Cell Signal. 19:761-71
126. Hagimoto N, Kuwano K, Inoshima I, YoshimiM, Nakamura N, et al. 2002. TGF-β1 as an enhancer of Fas-mediated apoptosis of lung epithelial cells. J. Immunol. 168:6470-78
127. Lagares D, BusnadiegoO, Garcia-Fernandez RA, Kapoor M, Liu S, et al. 2012. Inhibition of focal adhesion kinase prevents experimental lung fibrosis and myofibroblast formation. Arthritis Rheum. 64:1653-64
128. Liu G, Friggeri A, Yang Y, Milosevic J, Ding Q, et al. 2010. miR-21 mediates fibrogenic activation of pulmonary fibroblasts and lung fibrosis. J. Exp. Med. 207:1589-97
129. Bergeron A, Soler P, KambouchnerM, Loiseau P, Milleron B, et al. 2003. Cytokine profiles in idiopathic pulmonary fibrosis suggest an important role for TGF-βand IL-10. Eur. Respir. J. 22:69-76
130. Ramirez G, Hagood JS, Sanders Y, Ramirez R, Becerril C, et al. 2011. Absence of Thy-1 results in TGF-βinduced MMP-9 expression and confers a profibrotic phenotype to human lung fibroblasts. Lab. Investig. 91:1206-18
131. + T regulatory cells that modulate pulmonary interstitial fibrosis. J. Immunol. 172:178-85
132. Handel N, Cordray T, Gutierrez J, Jensen JA. 2006. A long-term study of outcomes, complications, and patient satisfaction with breast implants. Plast Reconstr. Surg. 117:757-72
133. Backovic A, Wolfram D, Del-Frari B, Piza H, Huber LA, Wick G. 2007. Simultaneous analysis of multiple serum proteins adhering to the surface of medical grade polydimethylsiloxane elastomers. J. Immunol. Methods 328:118-27
134. Shanklin DR, Smalley DL. 1999. Dynamics of wound healing after silicone device implantation. Exp. Mol. Pathol. 67:26-39
135. Wolfram D, Rainer C, Niederegger H, Piza H, Wick G. 2004. Cellular and molecular composition of fibrous capsules formed around silicone breast implants with special focus on local immune reactions. J. Autoimmun. 23:81-91
136. Korn T, Bettelli E, Oukka M, KuchrooVK. 2009. IL-17 and Th17 cells. Annu. Rev. Immunol. 27:485-517
137. Monarca C, Maruccia M, Palumbo F, Parisi P, Scuderi N. 2012. A rare case of postauricular spontaneous keloid in an elderly patient. In Vivo 26:173-75
138. Oittinen HA, O'Shaughnessy M. 2007. Multiple nonsyndromic spontaneous keloids in allergic disease. Plast Reconstr. Surg. 119:762-63
139. Shih B, Watson S, Bayat A. 2012. Whole genome and global expression profiling ofDupuytren's disease: systematic review of current findings and future perspectives. Ann. Rheum. Dis. 71:1440-47
140. Shih B, Bayat A. 2010. Scientific understanding and clinical management of Dupuytren disease. Nat. Rev. Rheumatol. 6:715-26
141. Qian A, Meals RA, Rajfer J, Gonzalez-Cadavid NFG. 2004. Comparison of gene expression profiles between Peyronie's disease and Dupuytren's contracture. Urology 64:399-404
142. Whitcomb DC. 2004. Inflammation and cancer V. Chronic pancreatitis and pancreatic cancer. Am. J. Physiol. Gastrointest. Liver Physiol. 287:G315-19
143. Staser K, Yang FC, ClappDW.2010. Mast cells and the neurofibromamicroenvironment. Blood 116:157-64
144. Lopez-Novoa JM, Nieto MA. 2009. Inflammation and EMT: an alliance towards organ fibrosis and cancer progression. EMBO Mol. Med. 1:303-14
145. Heldin CH, VanlandewijckM, Moustakas A. 2012. Regulation of EMT by TGFβin cancer. FEBS Lett. 586:1959-70
146. Higgins DF, Kimura K, BernhardtWM, ShrimankerN, Akai Y, et al. 2007. Hypoxia promotes fibrogenesis in vivo viaHIF-1 stimulation of epithelial-to-mesenchymal transition. J. Clin. Investig. 117:3810-20
147. Berhe N, Myrvang B, Gundersen SG. 2008. Reversibility of schistosomal periportal thickening/fibrosis after praziquantel therapy: a twenty-six month follow-up study in Ethiopia. Am. J. Trop. Med. Hyg. 78:228-34
148. Fallowfield JA, Kendall TJ, Iredale JP. 2006. Reversal of fibrosis: no longer a pipe dream? Clin. Liver Dis. 10:481-97
149. Hurst LC, Badalamente MA, Hentz VR, Hotchkiss RN, Kaplan FT, et al. 2009. Injectable collagenase clostridium histolyticum for Dupuytren's contracture. N. Engl. J. Med. 361:968-79
150. Denton CP, Merkel PA, Furst DE, Khanna D, Emery P, et al. 2007. Recombinant human antitransforming growth factor β1 antibody therapy in systemic sclerosis: a multicenter, randomized, placebo-controlled phase I/II trial of CAT-192. Arthritis Rheum. 56:323-33
151. Akhmetshina A, Venalis P, Dees C, Busch N, Zwerina J, et al. 2009. Treatment with imatinib prevents fibrosis in different preclinical models of systemic sclerosis and induces regression of established fibrosis. Arthritis Rheum. 60:219-24
152. Daniels CE, Lasky JA, Limper AH, Mieras K, Gabor E, et al. 2010. Imatinib treatment for idiopathic pulmonary fibrosis: randomized placebo-controlled trial results. Am. J. Respir. Crit. Care Med. 181:604-10
153. Pope J, McBain D, Petrlich L, Watson S, Vanderhoek L, et al. 2011. Imatinib in active diffuse cutaneous systemic sclerosis: results of a six-month, randomized, double-blind, placebo-controlled, proofof-concept pilot study at a single center. Arthritis Rheum. 63:3547-51
154. Ikawa Y, Ng PS, Endo K, Kondo M, Chujo S, et al. 2008. Neutralizing monoclonal antibody to human connective tissue growth factor ameliorates transforming growth factor-β-induced mouse fibrosis. J. Cell Physiol. 216:680-87
155. Li G, Xie Q, Shi Y, Li D, Zhang M, et al. 2006. Inhibition of connective tissue growth factor by siRNA prevents liver fibrosis in rats. J. Gene Med. 8:889-900
156. van Roeyen CR, Boor P, Borkham-Kamphorst E, Rong S, Kunter U, et al. 2012. A novel, dual role of CCN3 in experimental glomerulonephritis: pro-angiogenic and antimesangioproliferative effects. Am. J. Pathol. 180:1979-90
157. Chen H, He YW, Liu WQ, Zhang JH. 2008. Rosiglitazone prevents murine hepatic fibrosis induced by Schistosoma japonicum. World J. Gastroenterol. 14:2905-11
158. WuM, Melichian DS, Chang E, Warner-BlankenshipM, Ghosh AK, Varga J. 2009. Rosiglitazone abrogates bleomycin-induced scleroderma and blocks profibrotic responses through peroxisome proliferatoractivated receptor-γ. Am. J. Pathol. 174:519-33
159. Dees C, Zerr P, Tomcik M, Beyer C, Horn A, et al. 2011. Inhibition of Notch signaling prevents experimental fibrosis and induces regression of established fibrosis. Arthritis Rheum. 63:1396-404
160. Lam AP, Gottardi CJ. 2011. β-catenin signaling: a novel mediator of fibrosis and potential therapeutic target. Curr. Opin. Rheumatol. 23:562-67
161. Horn A, Kireva T, Palumbo-Zerr K, Dees C, Tomcik M, et al. Inhibition of hedgehog signalling prevents experimental fibrosis and induces regression of established fibrosis. Ann. Rheum. Dis. 71:785-89