Semin Liver Dis 2015; 35(02): 184-198
DOI: 10.1055/s-0035-1550055
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Antifibrotic Therapies in the Liver

W. Z. Mehal
1   Section of Digestive Diseases, Yale University, New Haven, Connecticut
2   West Haven Veterans Medical Center, West Haven, Connecticut
,
D. Schuppan
3   Department of Medicine, Institute of Translational Immunology and Research Center for Immunotherapy, University of Mainz Medical Center, Mainz, Germany
4   Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
› Author Affiliations
Further Information

Publication History

Publication Date:
14 May 2015 (online)

Abstract

Significant progress has been made in understanding the principles underlying the development of liver fibrosis. This includes appreciating its dynamic nature, the importance of active fibrolysis in fibrosis regression, and the plasticity of cell populations endowing them with fibrogenic or fibrolytic properties. This is complemented by an increasing array of therapeutic targets with known roles in the progression or regression of fibrosis. With a key role for fibrosis in determining clinical outcomes and encouraging data from recently Food and Drug Administration-approved antifibrotics for pulmonary fibrosis, the development and validation of antifibrotic therapies has taken center stage in translational hepatology. In addition to summarizing the recent progress in antifibrotic therapies, the authors discuss some of the challenges ahead, such as achieving a better understanding of the interindividual heterogeneity of the fibrotic response, how to match interventions with the ideal patient population, and the development of better noninvasive methods to assess the dynamics of fibrogenesis and fibrolysis. Together, these advances will permit a better targeting and dose titration of individualized therapies. Finally, the authors discuss combination therapy with different antifibrotics as possibly the most potent approach for treating fibrosis in the liver.

 
  • References

  • 1 Schuppan D, Kim YO. Evolving therapies for liver fibrosis. J Clin Invest 2013; 123 (5) 1887-1901
  • 2 Mederacke I, Hsu CC, Troeger JS , et al. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat Commun 2013; 4: 2823
  • 3 Wells RG. Portal fibroblasts in biliary fibrosis. Curr Pathobiol Rep 2014; 2 (4) 185-190
  • 4 Luedde T, Kaplowitz N, Schwabe RF. Cell death and cell death responses in liver disease: mechanisms and clinical relevance. Gastroenterology 2014; 147 (4) 765-783.e4
  • 5 Friedman SL, Sheppard D, Duffield JS, Violette S. Therapy for fibrotic diseases: nearing the starting line. Sci Transl Med 2013; 5 (167) 167sr1
  • 6 Marcellin P, Cooper C, Balart L , et al. Randomized controlled trial of danoprevir plus peginterferon alfa-2a and ribavirin in treatment-naïve patients with hepatitis C virus genotype 1 infection. Gastroenterology 2013; 145 (4) 790-800.e3
  • 7 Popov Y, Schuppan D. Targeting liver fibrosis: strategies for development and validation of antifibrotic therapies. Hepatology 2009; 50 (4) 1294-1306
  • 8 Pockros PJ, Jeffers L, Afdhal N , et al. Final results of a double-blind, placebo-controlled trial of the antifibrotic efficacy of interferon-gamma1b in chronic hepatitis C patients with advanced fibrosis or cirrhosis. Hepatology 2007; 45 (3) 569-578
  • 9 McHutchison J, Goodman Z, Patel K , et al; Farglitizar Study Investigators. Farglitazar lacks antifibrotic activity in patients with chronic hepatitis C infection. Gastroenterology 2010; 138 (4) 1365-1373 , 1373.e1–1373.e2
  • 10 Grompe M, Strom S. Mice with human livers. Gastroenterology 2013; 145 (6) 1209-1214
  • 11 Popov Y, Sverdlov DY, Sharma AK , et al. Tissue transglutaminase does not affect fibrotic matrix stability or regression of liver fibrosis in mice. Gastroenterology 2011; 140 (5) 1642-1652
  • 12 Yoshida S, Ikenaga N, Liu SB , et al. Extrahepatic platelet-derived growth factor-β, delivered by platelets, promotes activation of hepatic stellate cells and biliary fibrosis in mice. Gastroenterology 2014; 147 (6) 1378-1392
  • 13 Takahashi Y, Soejima Y, Fukusato T. Animal models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol 2012; 18 (19) 2300-2308
  • 14 Hebbard L, George J. Animal models of nonalcoholic fatty liver disease. Nature reviews. Gastroenterol Hepatol 2011; 8: 35-44
  • 15 Charlton M, Krishnan A, Viker K , et al. Fast food diet mouse: novel small animal model of NASH with ballooning, progressive fibrosis, and high physiological fidelity to the human condition. Am J Physiol Gastrointest Liver Physiol 2011; 301 (5) G825-G834
  • 16 Ueberham E, Löw R, Ueberham U, Schönig K, Bujard H, Gebhardt R. Conditional tetracycline-regulated expression of TGF-beta1 in liver of transgenic mice leads to reversible intermediary fibrosis. Hepatology 2003; 37 (5) 1067-1078
  • 17 Czochra P, Klopcic B, Meyer E , et al. Liver fibrosis induced by hepatic overexpression of PDGF-B in transgenic mice. J Hepatol 2006; 45 (3) 419-428
  • 18 Campbell JS, Hughes SD, Gilbertson DG , et al. Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma. Proc Natl Acad Sci U S A 2005; 102 (9) 3389-3394
  • 19 Seki E, Schwabe RF. Hepatic inflammation and fibrosis: functional links and key pathways. Hepatology 2015; 61 (3) 1066-1079
  • 20 Olinga P, Schuppan D. Precision-cut liver slices: a tool to model the liver ex vivo. J Hepatol 2013; 58 (6) 1252-1253
  • 21 de Graaf IA, Olinga P, de Jager MH , et al. Preparation and incubation of precision-cut liver and intestinal slices for application in drug metabolism and toxicity studies. Nat Protoc 2010; 5 (9) 1540-1551
  • 22 Mestas J, Hughes CC. Of mice and not men: differences between mouse and human immunology. J Immunol 2004; 172 (5) 2731-2738
  • 23 Mehal WZ, Iredale J, Friedman SL. Scraping fibrosis: expressway to the core of fibrosis. Nat Med 2011; 17 (5) 552-553
  • 24 Pellicoro A, Ramachandran P, Iredale JP, Fallowfield JA. Liver fibrosis and repair: immune regulation of wound healing in a solid organ. Nat Rev Immunol 2014; 14 (3) 181-194
  • 25 Kubes P, Mehal WZ. Sterile inflammation in the liver. Gastroenterology 2012; 143 (5) 1158-1172
  • 26 Yona S, Kim KW, Wolf Y , et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 2013; 38 (1) 79-91
  • 27 Tacke F, Zimmermann HW. Macrophage heterogeneity in liver injury and fibrosis. J Hepatol 2014; 60 (5) 1090-1096
  • 28 Karlmark KR, Weiskirchen R, Zimmermann HW , et al. Hepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology 2009; 50 (1) 261-274
  • 29 Hayashidani S, Tsutsui H, Shiomi T , et al. Anti-monocyte chemoattractant protein-1 gene therapy attenuates left ventricular remodeling and failure after experimental myocardial infarction. Circulation 2003; 108 (17) 2134-2140
  • 30 Lucas T, Waisman A, Ranjan R , et al. Differential roles of macrophages in diverse phases of skin repair. J Immunol 2010; 184 (7) 3964-3977
  • 31 Lin SL, Castaño AP, Nowlin BT, Lupher Jr ML, Duffield JS. Bone marrow Ly6Chigh monocytes are selectively recruited to injured kidney and differentiate into functionally distinct populations. J Immunol 2009; 183 (10) 6733-6743
  • 32 Ramachandran P, Pellicoro A, Vernon MA , et al. Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis. Proc Natl Acad Sci U S A 2012; 109 (46) E3186-E3195
  • 33 Pradere JP, Kluwe J, De Minicis S , et al. Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice. Hepatology 2013; 58 (4) 1461-1473
  • 34 Wynn TA, Barron L. Macrophages: master regulators of inflammation and fibrosis. Semin Liver Dis 2010; 30 (3) 245-257
  • 35 Thompson JE, Vaughan TJ, Williams AJ , et al. A fully human antibody neutralising biologically active human TGFbeta2 for use in therapy. J Immunol Methods 1999; 227 (1-2) 17-29
  • 36 Mori Y, Ishida W, Bhattacharyya S, Li Y, Platanias LC, Varga J. Selective inhibition of activin receptor-like kinase 5 signaling blocks profibrotic transforming growth factor beta responses in skin fibroblasts. Arthritis Rheum 2004; 50 (12) 4008-4021
  • 37 Ueno H, Sakamoto T, Nakamura T , et al. A soluble transforming growth factor beta receptor expressed in muscle prevents liver fibrogenesis and dysfunction in rats. Hum Gene Ther 2000; 11 (1) 33-42
  • 38 Yata Y, Gotwals P, Koteliansky V, Rockey DC. Dose-dependent inhibition of hepatic fibrosis in mice by a TGF-beta soluble receptor: implications for antifibrotic therapy. Hepatology 2002; 35 (5) 1022-1030
  • 39 Vogt J, Traynor R, Sapkota GP. The specificities of small molecule inhibitors of the TGFß and BMP pathways. Cell Signal 2011; 23 (11) 1831-1842
  • 40 Gilliam BL, Riedel DJ, Redfield RR. Clinical use of CCR5 inhibitors in HIV and beyond. J Transl Med 2011; 9 (Suppl. 01) S9
  • 41 Zaldivar MM, Pauels K, von Hundelshausen P , et al. CXC chemokine ligand 4 (Cxcl4) is a platelet-derived mediator of experimental liver fibrosis. Hepatology 2010; 51 (4) 1345-1353
  • 42 Hawinkels LJ, Ten Dijke P. Exploring anti-TGF-β therapies in cancer and fibrosis. Growth Factors 2011; 29 (4) 140-152
  • 43 Duffield JS, Forbes SJ, Constandinou CM , et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest 2005; 115 (1) 56-65
  • 44 Pellicoro A, Aucott RL, Ramachandran P , et al. Elastin accumulation is regulated at the level of degradation by macrophage metalloelastase (MMP-12) during experimental liver fibrosis. Hepatology 2012; 55 (6) 1965-1975
  • 45 Popov Y, Sverdlov DY, Bhaskar KR , et al. Macrophage-mediated phagocytosis of apoptotic cholangiocytes contributes to reversal of experimental biliary fibrosis. Am J Physiol Gastrointest Liver Physiol 2010; 298 (3) G323-G334
  • 46 Wynn TA, Cheever AW, Jankovic D , et al. An IL-12-based vaccination method for preventing fibrosis induced by schistosome infection. Nature 1995; 376 (6541) 594-596
  • 47 Shi Z, Wakil AE, Rockey DC. Strain-specific differences in mouse hepatic wound healing are mediated by divergent T helper cytokine responses. Proc Natl Acad Sci U S A 1997; 94 (20) 10663-10668
  • 48 Chiaramonte MG, Donaldson DD, Cheever AW, Wynn TA. An IL-13 inhibitor blocks the development of hepatic fibrosis during a T-helper type 2-dominated inflammatory response. J Clin Invest 1999; 104 (6) 777-785
  • 49 May C, Sapra P, Gerber HP. Advances in bispecific biotherapeutics for the treatment of cancer. Biochem Pharmacol 2012; 84 (9) 1105-1112
  • 50 Wan J, Benkdane M, Teixeira-Clerc F , et al. M2 Kupffer cells promote M1 Kupffer cell apoptosis: a protective mechanism against alcoholic and nonalcoholic fatty liver disease. Hepatology 2014; 59 (1) 130-142
  • 51 Barron L, Wynn TA. Fibrosis is regulated by Th2 and Th17 responses and by dynamic interactions between fibroblasts and macrophages. Am J Physiol Gastrointest Liver Physiol 2011; 300 (5) G723-G728
  • 52 Duffield JS, Lupher M, Thannickal VJ, Wynn TA. Host responses in tissue repair and fibrosis. Annu Rev Pathol 2013; 8: 241-276
  • 53 Muhanna N, Abu Tair L, Doron S , et al. Amelioration of hepatic fibrosis by NK cell activation. Gut 2011; 60 (1) 90-98
  • 54 Radaeva S, Sun R, Jaruga B, Nguyen VT, Tian Z, Gao B. Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners. Gastroenterology 2006; 130 (2) 435-452
  • 55 Gao B, Radaeva S. Natural killer and natural killer T cells in liver fibrosis. Biochim Biophys Acta 2013; 1832 (7) 1061-1069
  • 56 McHedlidze T, Waldner M, Zopf S , et al. Interleukin-33-dependent innate lymphoid cells mediate hepatic fibrosis. Immunity 2013; 39 (2) 357-371
  • 57 Iwakiri Y, Shah V, Rockey DC. Vascular pathobiology in chronic liver disease and cirrhosis - current status and future directions. J Hepatol 2014; 61 (4) 912-924
  • 58 Bhunchet E, Fujieda K. Capillarization and venularization of hepatic sinusoids in porcine serum-induced rat liver fibrosis: a mechanism to maintain liver blood flow. Hepatology 1993; 18 (6) 1450-1458
  • 59 Herbst H, Frey A, Heinrichs O , et al. Heterogeneity of liver cells expressing procollagen types I and IV in vivo. Histochem Cell Biol 1997; 107 (5) 399-409
  • 60 Shah V, Haddad FG, Garcia-Cardena G , et al. Liver sinusoidal endothelial cells are responsible for nitric oxide modulation of resistance in the hepatic sinusoids. J Clin Invest 1997; 100 (11) 2923-2930
  • 61 Langer DA, Das A, Semela D , et al. Nitric oxide promotes caspase-independent hepatic stellate cell apoptosis through the generation of reactive oxygen species. Hepatology 2008; 47 (6) 1983-1993
  • 62 Deleve LD, Wang X, Guo Y. Sinusoidal endothelial cells prevent rat stellate cell activation and promote reversion to quiescence. Hepatology 2008; 48 (3) 920-930
  • 63 Tugues S, Fernandez-Varo G, Muñoz-Luque J , et al. Antiangiogenic treatment with sunitinib ameliorates inflammatory infiltrate, fibrosis, and portal pressure in cirrhotic rats. Hepatology 2007; 46 (6) 1919-1926
  • 64 Thabut D, Routray C, Lomberk G , et al. Complementary vascular and matrix regulatory pathways underlie the beneficial mechanism of action of sorafenib in liver fibrosis. Hepatology 2011; 54 (2) 573-585
  • 65 Yang L, Kwon J, Popov Y , et al. Vascular endothelial growth factor promotes fibrosis resolution and repair in mice. Gastroenterology 2014; 146 (5) 1339-50.e1
  • 66 Ding BS, Cao Z, Lis R , et al. Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis. Nature 2014; 505 (7481) 97-102
  • 67 Marra F, Tacke F. Roles for chemokines in liver disease. Gastroenterology 2014; 147 (3) 577-594.e1
  • 68 Kinnman N, Francoz C, Barbu V , et al. The myofibroblastic conversion of peribiliary fibrogenic cells distinct from hepatic stellate cells is stimulated by platelet-derived growth factor during liver fibrogenesis. Lab Invest 2003; 83 (2) 163-173
  • 69 Nocito A, Georgiev P, Dahm F , et al. Platelets and platelet-derived serotonin promote tissue repair after normothermic hepatic ischemia in mice. Hepatology 2007; 45 (2) 369-376
  • 70 Schuppan D, Cramer T, Bauer M, Strefeld T, Hahn EG, Herbst H. Hepatocytes as a source of collagen type XVIII endostatin. Lancet 1998; 352 (9131) 879-880
  • 71 Schuppan D, Ruehl M, Somasundaram R, Hahn EG. Matrix as a modulator of hepatic fibrogenesis. Semin Liver Dis 2001; 21 (3) 351-372
  • 72 Myers JC, Li D, Bageris A, Abraham V, Dion AS, Amenta PS. Biochemical and immunohistochemical characterization of human type XIX defines a novel class of basement membrane zone collagens. Am J Pathol 1997; 151 (6) 1729-1740
  • 73 Schuppan D. Structure of the extracellular matrix in normal and fibrotic liver: collagens and glycoproteins. Semin Liver Dis 1990; 10 (1) 1-10
  • 74 Arthur MJ, Iredale JP, Mann DA. Tissue inhibitors of metalloproteinases: role in liver fibrosis and alcoholic liver disease. Alcohol Clin Exp Res 1999; 23 (5) 940-943
  • 75 Iredale JP, Thompson A, Henderson NC. Extracellular matrix degradation in liver fibrosis: biochemistry and regulation. Biochim Biophys Acta 2013; 1832 (7) 876-883
  • 76 Janmey PA, Wells RG, Assoian RK, McCulloch CA. From tissue mechanics to transcription factors. Differentiation 2013; 86 (3) 112-120
  • 77 Sheppard D. Integrin-mediated activation of latent transforming growth factor beta. Cancer Metastasis Rev 2005; 24 (3) 395-402
  • 78 Aluwihare P, Mu Z, Zhao Z , et al. Mice that lack activity of alphavbeta6- and alphavbeta8-integrins reproduce the abnormalities of Tgfb1- and Tgfb3-null mice. J Cell Sci 2009; 122 (Pt 2) 227-232
  • 79 Henderson NC, Sheppard D. Integrin-mediated regulation of TGFβ in fibrosis. Biochim Biophys Acta 2013; 1832 (7) 891-896
  • 80 Hynes RO. Integrins: bidirectional, allosteric signaling machines. Cell 2002; 110 (6) 673-687
  • 81 Huttenlocher A, Horwitz AR. Integrins in cell migration. Cold Spring Harb Perspect Biol 2011; 3 (9) a005074
  • 82 Campbell ID, Humphries MJ. Integrin structure, activation, and interactions. Cold Spring Harb Perspect Biol 2011; 3 (3) 4994
  • 83 Munger JS, Huang X, Kawakatsu H , et al. The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 1999; 96 (3) 319-328
  • 84 Mu D, Cambier S, Fjellbirkeland L , et al. The integrin alpha(v)beta8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-beta1. J Cell Biol 2002; 157 (3) 493-507
  • 85 Wipff PJ, Rifkin DB, Meister JJ, Hinz B. Myofibroblast contraction activates latent TGF-beta1 from the extracellular matrix. J Cell Biol 2007; 179 (6) 1311-1323
  • 86 Patsenker E, Popov Y, Stickel F, Jonczyk A, Goodman SL, Schuppan D. Inhibition of integrin alphavbeta6 on cholangiocytes blocks transforming growth factor-beta activation and retards biliary fibrosis progression. Gastroenterology 2008; 135 (2) 660-670
  • 87 Kitamura H, Cambier S, Somanath S , et al. Mouse and human lung fibroblasts regulate dendritic cell trafficking, airway inflammation, and fibrosis through integrin αvβ8-mediated activation of TGF-β. J Clin Invest 2011; 121 (7) 2863-2875
  • 88 Popov Y, Patsenker E, Stickel F , et al. Integrin alphavbeta6 is a marker of the progression of biliary and portal liver fibrosis and a novel target for antifibrotic therapies. J Hepatol 2008; 48 (3) 453-464
  • 89 Wang B, Dolinski BM, Kikuchi N , et al. Role of alphavbeta6 integrin in acute biliary fibrosis. Hepatology 2007; 46 (5) 1404-1412
  • 90 Shull MM, Ormsby I, Kier AB , et al. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 1992; 359 (6397) 693-699
  • 91 Henderson NC, Arnold TD, Katamura Y , et al. Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat Med 2013; 19 (12) 1617-1624
  • 92 Zhou X, Murphy FR, Gehdu N, Zhang J, Iredale JP, Benyon RC. Engagement of alphavbeta3 integrin regulates proliferation and apoptosis of hepatic stellate cells. J Biol Chem 2004; 279 (23) 23996-24006
  • 93 Patsenker E, Popov Y, Stickel F , et al. Pharmacological inhibition of integrin alphavbeta3 aggravates experimental liver fibrosis and suppresses hepatic angiogenesis. Hepatology 2009; 50 (5) 1501-1511
  • 94 Issa R, Zhou X, Constandinou CM , et al. Spontaneous recovery from micronodular cirrhosis: evidence for incomplete resolution associated with matrix cross-linking. Gastroenterology 2004; 126 (7) 1795-1808
  • 95 Lucero HA, Kagan HM. Lysyl oxidase: an oxidative enzyme and effector of cell function. Cell Mol Life Sci 2006; 63 (19-20) 2304-2316
  • 96 Kagan HM, Li W. Lysyl oxidase: properties, specificity, and biological roles inside and outside of the cell. J Cell Biochem 2003; 88 (4) 660-672
  • 97 Barker HE, Cox TR, Erler JT. The rationale for targeting the LOX family in cancer. Nat Rev Cancer 2012; 12 (8) 540-552
  • 98 Kagan HM. Lysyl oxidase: mechanism, regulation and relationship to liver fibrosis. Pathol Res Pract 1994; 190 (9-10) 910-919
  • 99 Barry-Hamilton V, Spangler R, Marshall D , et al. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat Med 2010; 16 (9) 1009-1017
  • 100 Vadasz Z, Kessler O, Akiri G , et al. Abnormal deposition of collagen around hepatocytes in Wilson's disease is associated with hepatocyte specific expression of lysyl oxidase and lysyl oxidase like protein-2. J Hepatol 2005; 43 (3) 499-507
  • 101 Perepelyuk M, Terajima M, Wang AY , et al. Hepatic stellate cells and portal fibroblasts are the major cellular sources of collagens and lysyl oxidases in normal liver and early after injury. Am J Physiol Gastrointest Liver Physiol 2013; 304 (6) G605-G614
  • 102 Kisseleva T, Cong M, Paik Y , et al. Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis. Proc Natl Acad Sci U S A 2012; 109 (24) 9448-9453
  • 103 Troeger JS, Mederacke I, Gwak GY , et al. Deactivation of hepatic stellate cells during liver fibrosis resolution in mice. Gastroenterology 2012; 143 (4) 1073-83.e22
  • 104 Olsen AL, Bloomer SA, Chan EP , et al. Hepatic stellate cells require a stiff environment for myofibroblastic differentiation. Am J Physiol Gastrointest Liver Physiol 2011; 301 (1) G110-G118
  • 105 Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med 2012; 18 (7) 1028-1040
  • 106 Baeck C, Wei X, Bartneck M , et al. Pharmacological inhibition of the chemokine C-C motif chemokine ligand 2 (monocyte chemoattractant protein 1) accelerates liver fibrosis regression by suppressing Ly-6C(+) macrophage infiltration in mice. Hepatology 2014; 59 (3) 1060-1072
  • 107 Samarakoon R, Overstreet JM, Higgins PJ. TGF-β signaling in tissue fibrosis: redox controls, target genes and therapeutic opportunities. Cell Signal 2013; 25 (1) 264-268
  • 108 Wang Q, Usinger W, Nichols B , et al. Cooperative interaction of CTGF and TGF-β in animal models of fibrotic disease. Fibrogenesis Tissue Repair 2011; 4 (1) 4
  • 109 Muñoz-Luque J, Ros J, Fernández-Varo G , et al. Regression of fibrosis after chronic stimulation of cannabinoid CB2 receptor in cirrhotic rats. J Pharmacol Exp Ther 2008; 324 (2) 475-483
  • 110 Tam J, Cinar R, Liu J , et al. Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance. Cell Metab 2012; 16 (2) 167-179
  • 111 Henao-Mejia J, Elinav E, Jin C , et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 2012; 482 (7384) 179-185
  • 112 Mehal WZ. The Gordian Knot of dysbiosis, obesity and NAFLD. Nat Rev Gastroenterol Hepatol 2013; 10 (11) 637-644
  • 113 Bohinc BN, Diehl AM. Mechanisms of disease progression in NASH: new paradigms. Clin Liver Dis 2012; 16 (3) 549-565
  • 114 Mudaliar S, Henry RR, Sanyal AJ , et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 2013; 145 (3) 574-82.e1
  • 115 Guy CD, Suzuki A, Zdanowicz M , et al; NASH CRN. Hedgehog pathway activation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease. Hepatology 2012; 55 (6) 1711-1721
  • 116 Wood NJ. Microbiota: dysbiosis driven by inflammasome deficiency exacerbates hepatic steatosis and governs rate of NAFLD progression. Nat Rev Gastroenterol Hepatol 2012; 9 (3) 123
  • 117 Phung N, Pera N, Farrell G, Leclercq I, Hou JY, George J. Pro-oxidant-mediated hepatic fibrosis and effects of antioxidant intervention in murine dietary steatohepatitis. Int J Mol Med 2009; 24 (2) 171-180
  • 118 Paik YH, Iwaisako K, Seki E , et al. The nicotinamide adenine dinucleotide phosphate oxidase (NOX) homologues NOX1 and NOX2/gp91(phox) mediate hepatic fibrosis in mice. Hepatology 2011; 53 (5) 1730-1741
  • 119 Jiang JX, Venugopal S, Serizawa N , et al. Reduced nicotinamide adenine dinucleotide phosphate oxidase 2 plays a key role in stellate cell activation and liver fibrogenesis in vivo. Gastroenterology 2010; 139 (4) 1375-1384
  • 120 Jiang JX, Chen X, Serizawa N , et al. Liver fibrosis and hepatocyte apoptosis are attenuated by GKT137831, a novel NOX4/NOX1 inhibitor in vivo. Free Radic Biol Med 2012; 53 (2) 289-296
  • 121 Thannickal VJ. Mechanisms of pulmonary fibrosis: role of activated myofibroblasts and NADPH oxidase. Fibrogenesis Tissue Repair 2012; 5 (Suppl 1 Proceedings of Fibroproliferative disorders: from biochemical analysis to targeted therapies Petro E Petrides and David Brenner) S23
  • 122 Aoyama T, Paik YH, Watanabe S , et al. Nicotinamide adenine dinucleotide phosphate oxidase in experimental liver fibrosis: GKT137831 as a novel potential therapeutic agent. Hepatology 2012; 56 (6) 2316-2327
  • 123 Torok NJ, Dranoff JA, Schuppan D , et al. Strategies and endpoints of antifibrotic drug trials. Summary and Recommendations from the AASLD Emerging Trends Conference 2014. Hepatology 2015, in press
  • 124 Vilar Gomez E, Gra Oramas B, Soler E, Llanio Navarro R, Ruenes Domech C. Viusid, a nutritional supplement, in combination with interferon alpha-2b and ribavirin in patients with chronic hepatitis C. Liver Int 2007; 27 (2) 247-259
  • 125 Liu P, Hu YY, Liu C , et al. Clinical observation of salvianolic acid B in treatment of liver fibrosis in chronic hepatitis B. World J Gastroenterol 2002; 8 (4) 679-685
  • 126 Liu P, Hu YY, Liu C , et al. Multicenter clinical study on Fuzhenghuayu capsule against liver fibrosis due to chronic hepatitis B. World J Gastroenterol 2005; 11 (19) 2892-2899
  • 127 Poupon RE, Poupon R, Balkau B ; The UDCA-PBC Study Group. Ursodiol for the long-term treatment of primary biliary cirrhosis. N Engl J Med 1994; 330 (19) 1342-1347
  • 128 Corpechot C, Carrat F, Bonnand AM, Poupon RE, Poupon R. The effect of ursodeoxycholic acid therapy on liver fibrosis progression in primary biliary cirrhosis. Hepatology 2000; 32 (6) 1196-1199
  • 129 Kim MY, Cho MY, Baik SK , et al. Beneficial effects of candesartan, an angiotensin-blocking agent, on compensated alcoholic liver fibrosis - a randomized open-label controlled study. Liver Int 2012; 32 (6) 977-987
  • 130 Belfort R, Harrison SA, Brown K , et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006; 355 (22) 2297-2307
  • 131 Aithal GP, Thomas JA, Kaye PV , et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology 2008; 135 (4) 1176-1184
  • 132 Sanyal AJ, Chalasani N, Kowdley KV , et al; NASH CRN. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010; 362 (18) 1675-1685
  • 133 Ratziu V, Charlotte F, Bernhardt C , et al; LIDO Study Group. Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial. Hepatology 2010; 51 (2) 445-453
  • 134 Zein CO, Yerian LM, Gogate P , et al. Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology 2011; 54 (5) 1610-1619
  • 135 Torres DM, Jones FJ, Shaw JC, Williams CD, Ward JA, Harrison SA. Rosiglitazone versus rosiglitazone and metformin versus rosiglitazone and losartan in the treatment of nonalcoholic steatohepatitis in humans: a 12-month randomized, prospective, open-label trial. Hepatology 2011; 54 (5) 1631-1639
  • 136 Ratziu V, de Ledinghen V, Oberti F , et al; FRESGUN. A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis. J Hepatol 2011; 54 (5) 1011-1019
  • 137 Neuschwander-Tetri BA, Loomba R, Sanyal AJ , et al; for the NASH Clinical Research Network. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 2014; 14: 61934
  • 138 Chavez-Tapia NC, Tellez-Avila FI, Barrientos-Gutierrez T, Mendez-Sanchez N, Lizardi-Cervera J, Uribe M. Bariatric surgery for non-alcoholic steatohepatitis in obese patients. Cochrane Database Syst Rev 2010; 1 (1) CD007340
  • 139 Raghu G, Brown KK, Costabel U , et al. Treatment of idiopathic pulmonary fibrosis with etanercept: an exploratory, placebo-controlled trial. Am J Respir Crit Care Med 2008; 178 (9) 948-955
  • 140 Demedts M, Behr J, Buhl R , et al; IFIGENIA Study Group. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2005; 353 (21) 2229-2242
  • 141 Daniels CE, Lasky JA, Limper AH, Mieras K, Gabor E, Schroeder DR ; Imatinib-IPF Study Investigators. Imatinib treatment for idiopathic pulmonary fibrosis: Randomized placebo-controlled trial results. Am J Respir Crit Care Med 2010; 181 (6) 604-610
  • 142 Raghu G, Behr J, Brown KK , et al; ARTEMIS-IPF Investigators*. Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial. Ann Intern Med 2013; 158 (9) 641-649
  • 143 Noble PW, Albera C, Bradford WZ , et al; CAPACITY Study Group. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 2011; 377 (9779) 1760-1769
  • 144 Taniguchi H, Ebina M, Kondoh Y , et al. Pirfenidone in idiopathic pulmonary fibrosis. Eur Resp J 2010; 35 (4) 821-829
  • 145 King Jr TE, Bradford WZ, Castro-Bernardini S , et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med 2014; 370: 2083-2092
  • 146 Richeldi L, du Bois RM, Raghu G , et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014; 370: 2071-2082