Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

Emerging therapies for hepatic fibrosis

Scott L Friedman, MD
Section Editor
Bruce A Runyon, MD
Deputy Editor
Kristen M Robson, MD, MBA, FACG


Hepatic fibrosis is a scarring response to liver damage, which may be considered beneficial since it can encapsulate injury. However, in doing so liver function may ultimately become impaired [1].

There has been exciting progress in understanding hepatic fibrosis, which represents a paradigm for wound healing in other tissues, including skin, lung, and kidney, since it involves many of the same cell types and mediators [1,2]. An understanding of these mechanisms has a number of clinical implications, including the development of interventions designed to impede or reverse hepatic fibrosis, some of which are already available [3]. Perhaps the greatest change in the past two years in the field of antifibrotic therapy has been the intense focus on NASH as a therapeutic target, reflecting the growing appreciation of this disease as a public health threat [4], combined with the realization that with cures for hepatitis C virus (HCV) in the majority of patients due to direct acting antiviral therapies, fewer HCV and hepatitis B virus patients will need antifibrotic therapies, although in reality cirrhosis due to HCV remains a large unmet need [5]. This topic review will focus on possible future treatments aimed at impeding or reversing fibrosis. The pathogenesis of hepatic fibrosis is presented elsewhere. (See "Pathogenesis of hepatic fibrosis".)


The exact moment at which fibrosis becomes irreversible is unknown, either in terms of a histologic marker or a specific change in the matrix composition or content. Dense cirrhosis with nodule formation, portal hypertension, and early liver failure is generally considered irreversible, but less advanced lesions can show remarkable reversibility when the underlying cause of the liver injury is controlled and possibly by other therapeutic interventions. In studies of patients with hepatitis B hepatitis C, and NASH, up to 70 percent of patients had reversal of cirrhosis following successful antiviral therapies or bariatric surgery, respectively [6-8].

The development of targeted therapies is moving closer to reality (table 1) [3,9]. The ideal drug would be the one which could be easily delivered, is well tolerated, has high liver specificity, and promotes the resorption of excess interstitial matrix without abolishing the salutary effects of the normal hepatic extracellular matrix. The hope is not necessarily to eliminate fibrosis entirely, but rather to attenuate its development so that patients with chronic liver disease do not succumb to the end organ failure that it creates (eg, portal hypertension, ascites, liver failure). While no therapy yet meets these goals, the framework for developing such treatments is in place and progress is accelerating.

As a general rule, the currently available antifibrotic therapies have been directed against suppressing hepatic inflammation or injury rather than subduing fibrosis. However, targeting of stellate cells and fibrogenic mediators has emerged as an equally promising complement to therapies that reduce injury. Points of therapeutic intervention may include efforts to remove the injurious stimuli, suppress hepatic inflammation, downregulate stellate cell activation, and promote matrix degradation [10].


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Dec 2016. | This topic last updated: Wed Dec 14 00:00:00 GMT 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology 2008; 134:1655.
  2. Friedman SL. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 2008; 88:125.
  3. Yoon YJ, Friedman SL, Lee YA. Antifibrotic Therapies: Where Are We Now? Semin Liver Dis 2016; 36:87.
  4. Sanyal AJ, Chalasani N. Trials and tribulations in drug development for nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2014; 12:2104.
  5. Udompap P, Mannalithara A, Heo NY, et al. Increasing prevalence of cirrhosis among U.S. adults aware or unaware of their chronic hepatitis C virus infection. J Hepatol 2016; 64:1027.
  6. Marcellin P, Gane E, Buti M, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet 2013; 381:468.
  7. D'Ambrosio R, Aghemo A, Rumi MG, et al. A morphometric and immunohistochemical study to assess the benefit of a sustained virological response in hepatitis C virus patients with cirrhosis. Hepatology 2012; 56:532.
  8. Lassailly G, Caiazzo R, Buob D, et al. Bariatric Surgery Reduces Features of Nonalcoholic Steatohepatitis in Morbidly Obese Patients. Gastroenterology 2015; 149:379.
  9. Friedman SL, Sheppard D, Duffield JS, Violette S. Therapy for fibrotic diseases: nearing the starting line. Sci Transl Med 2013; 5:167sr1.
  10. Lee YA, Wallace MC, Friedman SL. Pathobiology of liver fibrosis: a translational success story. Gut 2015; 64:830.
  11. Hammel P, Couvelard A, O'Toole D, et al. Regression of liver fibrosis after biliary drainage in patients with chronic pancreatitis and stenosis of the common bile duct. N Engl J Med 2001; 344:418.
  12. Bonis PA, Friedman SL, Kaplan MM. Is liver fibrosis reversible? N Engl J Med 2001; 344:452.
  13. Dienstag JL, Goldin RD, Heathcote EJ, et al. Histological outcome during long-term lamivudine therapy. Gastroenterology 2003; 124:105.
  14. Falize L, Guillygomarc'h A, Perrin M, et al. Reversibility of hepatic fibrosis in treated genetic hemochromatosis: a study of 36 cases. Hepatology 2006; 44:472.
  15. Hirschfield GM, Mason A, Luketic V, et al. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology 2015; 148:751.
  16. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm503964.htm (Accessed on June 01, 2016).
  17. Mallet V, Gilgenkrantz H, Serpaggi J, et al. Brief communication: the relationship of regression of cirrhosis to outcome in chronic hepatitis C. Ann Intern Med 2008; 149:399.
  18. Veldt BJ, Heathcote EJ, Wedemeyer H, et al. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Ann Intern Med 2007; 147:677.
  19. Lee YA, Friedman SL. Reversal, maintenance or progression: what happens to the liver after a virologic cure of hepatitis C? Antiviral Res 2014; 107:23.
  20. Roberts S, Gordon A, McLean C, et al. Effect of sustained viral response on hepatic venous pressure gradient in hepatitis C-related cirrhosis. Clin Gastroenterol Hepatol 2007; 5:932.
  21. Ripoll C, Groszmann R, Garcia-Tsao G, et al. Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis. Gastroenterology 2007; 133:481.
  22. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. Gastroenterology 2006; 131:1743.
  23. Chang TT, Liaw YF, Wu SS, et al. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology 2010; 52:886.
  24. Farci P, Roskams T, Chessa L, et al. Long-term benefit of interferon alpha therapy of chronic hepatitis D: regression of advanced hepatic fibrosis. Gastroenterology 2004; 126:1740.
  25. Chan HL, Wong GL, Tse CH, et al. Hepatitis B virus genotype C is associated with more severe liver fibrosis than genotype B. Clin Gastroenterol Hepatol 2009; 7:1361.
  26. Klein S, Mittendorfer B, Eagon JC, et al. Gastric bypass surgery improves metabolic and hepatic abnormalities associated with nonalcoholic fatty liver disease. Gastroenterology 2006; 130:1564.
  27. Modi AA, Feld JJ, Park Y, et al. Increased caffeine consumption is associated with reduced hepatic fibrosis. Hepatology 2010; 51:201.
  28. Ruhl CE, Everhart JE. Coffee and caffeine consumption reduce the risk of elevated serum alanine aminotransferase activity in the United States. Gastroenterology 2005; 128:24.
  29. Wang Q, Dai X, Yang W, et al. Caffeine protects against alcohol-induced liver fibrosis by dampening the cAMP/PKA/CREB pathway in rat hepatic stellate cells. Int Immunopharmacol 2015; 25:340.
  30. Khalaf N, White D, Kanwal F, et al. Coffee and Caffeine Are Associated With Decreased Risk of Advanced Hepatic Fibrosis Among Patients With Hepatitis C. Clin Gastroenterol Hepatol 2015; 13:1521.
  31. Hsu SJ, Lee FY, Wang SS, et al. Caffeine ameliorates hemodynamic derangements and portosystemic collaterals in cirrhotic rats. Hepatology 2015; 61:1672.
  32. Everson GT, Shiffman ML, Hoefs JC, et al. Quantitative liver function tests improve the prediction of clinical outcomes in chronic hepatitis C: results from the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis Trial. Hepatology 2012; 55:1019.
  33. Cronstein BN. Adenosine receptors and fibrosis: a translational review. F1000 Biol Rep 2011; 3:21.
  34. Chan ES, Montesinos MC, Fernandez P, et al. Adenosine A(2A) receptors play a role in the pathogenesis of hepatic cirrhosis. Br J Pharmacol 2006; 148:1144.
  35. Kershenobich D, Vargas F, Garcia-Tsao G, et al. Colchicine in the treatment of cirrhosis of the liver. N Engl J Med 1988; 318:1709.
  36. Rodríguez L, Cerbón-Ambriz J, Muñoz ML. Effects of colchicine and colchiceine in a biochemical model of liver injury and fibrosis. Arch Med Res 1998; 29:109.
  37. Rambaldi A, Gluud C. Colchicine for alcoholic and non-alcoholic liver fibrosis and cirrhosis. Cochrane Database Syst Rev 2001; :CD002148.
  38. Lee J, Belanger A, Doucette JT, et al. Transplantation trends in primary biliary cirrhosis. Clin Gastroenterol Hepatol 2007; 5:1313.
  39. Poupon RE, Lindor KD, Cauch-Dudek K, et al. Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology 1997; 113:884.
  40. Poo JL, Feldmann G, Erlinger S, et al. Ursodeoxycholic acid limits liver histologic alterations and portal hypertension induced by bile duct ligation in the rat. Gastroenterology 1992; 102:1752.
  41. Melhem A, Muhanna N, Bishara A, et al. Anti-fibrotic activity of NK cells in experimental liver injury through killing of activated HSC. J Hepatol 2006; 45:60.
  42. Radaeva S, Sun R, Jaruga B, et al. 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; 130:435.
  43. Maricic I, Sheng H, Marrero I, et al. Inhibition of type I natural killer T cells by retinoids or following sulfatide-mediated activation of type II natural killer T cells attenuates alcoholic liver disease in mice. Hepatology 2015; 61:1357.
  44. Yi HS, Lee YS, Byun JS, et al. Alcohol dehydrogenase III exacerbates liver fibrosis by enhancing stellate cell activation and suppressing natural killer cells in mice. Hepatology 2014; 60:1044.
  45. Inagaki Y, Nemoto T, Kushida M, et al. Interferon alfa down-regulates collagen gene transcription and suppresses experimental hepatic fibrosis in mice. Hepatology 2003; 38:890.
  46. Rockey DC, Chung JJ. Interferon gamma inhibits lipocyte activation and extracellular matrix mRNA expression during experimental liver injury: implications for treatment of hepatic fibrosis. J Investig Med 1994; 42:660.
  47. Jeong WI, Park O, Gao B. Abrogation of the antifibrotic effects of natural killer cells/interferon-gamma contributes to alcohol acceleration of liver fibrosis. Gastroenterology 2008; 134:248.
  48. Horani A, Muhanna N, Pappo O, et al. Beneficial effect of glatiramer acetate (Copaxone) on immune modulation of experimental hepatic fibrosis. Am J Physiol Gastrointest Liver Physiol 2007; 292:G628.
  49. Muhanna N, Abu Tair L, Doron S, et al. Amelioration of hepatic fibrosis by NK cell activation. Gut 2011; 60:90.
  50. Connolly MK, Bedrosian AS, Mallen-St Clair J, et al. In liver fibrosis, dendritic cells govern hepatic inflammation in mice via TNF-alpha. J Clin Invest 2009; 119:3213.
  51. Lu TT. Dendritic cells: novel players in fibrosis and scleroderma. Curr Rheumatol Rep 2012; 14:30.
  52. Kluwe J, Pradere JP, Gwak GY, et al. Modulation of hepatic fibrosis by c-Jun-N-terminal kinase inhibition. Gastroenterology 2010; 138:347.
  53. Castaño AP, Lin SL, Surowy T, et al. Serum amyloid P inhibits fibrosis through Fc gamma R-dependent monocyte-macrophage regulation in vivo. Sci Transl Med 2009; 1:5ra13.
  54. Traber PG, Chou H, Zomer E, et al. Regression of fibrosis and reversal of cirrhosis in rats by galectin inhibitors in thioacetamide-induced liver disease. PLoS One 2013; 8:e75361.
  55. Stutchfield BM, Antoine DJ, Mackinnon AC, et al. CSF1 Restores Innate Immunity After Liver Injury in Mice and Serum Levels Indicate Outcomes of Patients With Acute Liver Failure. Gastroenterology 2015; 149:1896.
  56. Tigyi G. Aiming drug discovery at lysophosphatidic acid targets. Br J Pharmacol 2010; 161:241.
  57. Swaney JS, Chapman C, Correa LD, et al. A novel, orally active LPA(1) receptor antagonist inhibits lung fibrosis in the mouse bleomycin model. Br J Pharmacol 2010; 160:1699.
  58. 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; 59:1060.
  59. Lefebvre E, Moyle G, Reshef R, et al. Antifibrotic Effects of the Dual CCR2/CCR5 Antagonist Cenicriviroc in Animal Models of Liver and Kidney Fibrosis. PLoS One 2016; 11:e0158156.
  60. Baeck C, Wehr A, Karlmark KR, et al. Pharmacological inhibition of the chemokine CCL2 (MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury. Gut 2012; 61:416.
  61. Friedman S, Sanyal A, Goodman Z, et al. Efficacy and safety study of cenicriviroc for the treatment of non-alcoholic steatohepatitis in adult subjects with liver fibrosis: CENTAUR Phase 2b study design. Contemp Clin Trials 2016; 47:356.
  62. Kim WH, Matsumoto K, Bessho K, Nakamura T. Growth inhibition and apoptosis in liver myofibroblasts promoted by hepatocyte growth factor leads to resolution from liver cirrhosis. Am J Pathol 2005; 166:1017.
  63. Ueki T, Kaneda Y, Tsutsui H, et al. Hepatocyte growth factor gene therapy of liver cirrhosis in rats. Nat Med 1999; 5:226.
  64. Masunaga H, Fujise N, Shiota A, et al. Preventive effects of the deleted form of hepatocyte growth factor against various liver injuries. Eur J Pharmacol 1998; 342:267.
  65. Sanz S, Pucilowska JB, Liu S, et al. Expression of insulin-like growth factor I by activated hepatic stellate cells reduces fibrogenesis and enhances regeneration after liver injury. Gut 2005; 54:134.
  66. Valentino KL, Gutierrez M, Sanchez R, et al. First clinical trial of a novel caspase inhibitor: anti-apoptotic caspase inhibitor, IDN-6556, improves liver enzymes. Int J Clin Pharmacol Ther 2003; 41:441.
  67. www.hivandhepatitis.com/2010_conference/easl/docs/0423_2010_b.html (Accessed on June 07, 2010).
  68. Matsuda Y, Matsumoto K, Ichida T, Nakamura T. Hepatocyte growth factor suppresses the onset of liver cirrhosis and abrogates lethal hepatic dysfunction in rats. J Biochem 1995; 118:643.
  69. Yasuda H, Imai E, Shiota A, et al. Antifibrogenic effect of a deletion variant of hepatocyte growth factor on liver fibrosis in rats. Hepatology 1996; 24:636.
  70. Narayan P, Duan B, Jiang K, et al. Late intervention with the small molecule BB3 mitigates postischemic kidney injury. Am J Physiol Renal Physiol 2016; 311:F352.
  71. Ozaki I, Zhao G, Mizuta T, et al. Hepatocyte growth factor induces collagenase (matrix metalloproteinase-1) via the transcription factor Ets-1 in human hepatic stellate cell line. J Hepatol 2002; 36:169.
  72. Inagaki Y, Higashi K, Kushida M, et al. Hepatocyte growth factor suppresses profibrogenic signal transduction via nuclear export of Smad3 with galectin-7. Gastroenterology 2008; 134:1180.
  73. Santoni-Rugiu E, Preisegger KH, Kiss A, et al. Inhibition of neoplastic development in the liver by hepatocyte growth factor in a transgenic mouse model. Proc Natl Acad Sci U S A 1996; 93:9577.
  74. Canbay A, Friedman S, Gores GJ. Apoptosis: the nexus of liver injury and fibrosis. Hepatology 2004; 39:273.
  75. Feldstein A, Gores GJ. Steatohepatitis and apoptosis: therapeutic implications. Am J Gastroenterol 2004; 99:1718.
  76. Feldstein AE, Canbay A, Angulo P, et al. Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology 2003; 125:437.
  77. Canbay A, Kip SN, Kahraman A, et al. Apoptosis and fibrosis in non-alcoholic fatty liver disease. Turk J Gastroenterol 2005; 16:1.
  78. Canbay A, Feldstein A, Baskin-Bey E, et al. The caspase inhibitor IDN-6556 attenuates hepatic injury and fibrosis in the bile duct ligated mouse. J Pharmacol Exp Ther 2004; 308:1191.
  79. Zhang Y, Edwards PA. FXR signaling in metabolic disease. FEBS Lett 2008; 582:10.
  80. Rader DJ. Liver X receptor and farnesoid X receptor as therapeutic targets. Am J Cardiol 2007; 100:n15.
  81. Fiorucci S, Antonelli E, Rizzo G, et al. The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis. Gastroenterology 2004; 127:1497.
  82. Li J, Kuruba R, Wilson A, et al. Inhibition of endothelin-1-mediated contraction of hepatic stellate cells by FXR ligand. PLoS One 2010; 5:e13955.
  83. 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; 145:574.
  84. Adorini L, Pruzanski M, Shapiro D. Farnesoid X receptor targeting to treat nonalcoholic steatohepatitis. Drug Discov Today 2012; 17:988.
  85. Fiorucci S, Rizzo G, Antonelli E, et al. A farnesoid x receptor-small heterodimer partner regulatory cascade modulates tissue metalloproteinase inhibitor-1 and matrix metalloprotease expression in hepatic stellate cells and promotes resolution of liver fibrosis. J Pharmacol Exp Ther 2005; 314:584.
  86. Fiorucci S, Rizzo G, Antonelli E, et al. Cross-talk between farnesoid-X-receptor (FXR) and peroxisome proliferator-activated receptor gamma contributes to the antifibrotic activity of FXR ligands in rodent models of liver cirrhosis. J Pharmacol Exp Ther 2005; 315:58.
  87. Di Bisceglie AM, Shiffman ML, Everson GT, et al. Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon. N Engl J Med 2008; 359:2429.
  88. 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; 45:569.
  89. Bansal R, Prakash J, Post E, et al. Novel engineered targeted interferon-gamma blocks hepatic fibrogenesis in mice. Hepatology 2011; 54:586.
  90. Teixeira-Clerc F, Julien B, Grenard P, et al. CB1 cannabinoid receptor antagonism: a new strategy for the treatment of liver fibrosis. Nat Med 2006; 12:671.
  91. Tam J, Vemuri VK, Liu J, et al. Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity. J Clin Invest 2010; 120:2953.
  92. Julien B, Grenard P, Teixeira-Clerc F, et al. Antifibrogenic role of the cannabinoid receptor CB2 in the liver. Gastroenterology 2005; 128:742.
  93. Siegmund SV, Uchinami H, Osawa Y, et al. Anandamide induces necrosis in primary hepatic stellate cells. Hepatology 2005; 41:1085.
  94. 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; 324:475.
  95. De Minicis S, Candelaresi C, Marzioni M, et al. Role of endogenous opioids in modulating HSC activity in vitro and liver fibrosis in vivo. Gut 2008; 57:352.
  96. Ebrahimkhani MR, Kiani S, Oakley F, et al. Naltrexone, an opioid receptor antagonist, attenuates liver fibrosis in bile duct ligated rats. Gut 2006; 55:1606.
  97. Houglum K, Venkataramani A, Lyche K, Chojkier M. A pilot study of the effects of d-alpha-tocopherol on hepatic stellate cell activation in chronic hepatitis C. Gastroenterology 1997; 113:1069.
  98. Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010; 362:1675.
  99. Lavine JE, Schwimmer JB, Van Natta ML, et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA 2011; 305:1659.
  100. Kawada N, Seki S, Inoue M, Kuroki T. Effect of antioxidants, resveratrol, quercetin, and N-acetylcysteine, on the functions of cultured rat hepatic stellate cells and Kupffer cells. Hepatology 1998; 27:1265.
  101. Ferenci P, Dragosics B, Dittrich H, et al. Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver. J Hepatol 1989; 9:105.
  102. Trappoliere M, Caligiuri A, Schmid M, et al. Silybin, a component of sylimarin, exerts anti-inflammatory and anti-fibrogenic effects on human hepatic stellate cells. J Hepatol 2009; 50:1102.
  103. Jacobs BP, Dennehy C, Ramirez G, et al. Milk thistle for the treatment of liver disease: a systematic review and meta-analysis. Am J Med 2002; 113:506.
  104. Bataller R, Schwabe RF, Choi YH, et al. NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis. J Clin Invest 2003; 112:1383.
  105. Bataller R, Sancho-Bru P, Ginès P, et al. Activated human hepatic stellate cells express the renin-angiotensin system and synthesize angiotensin II. Gastroenterology 2003; 125:117.
  106. Bataller R, Gäbele E, Schoonhoven R, et al. Prolonged infusion of angiotensin II into normal rats induces stellate cell activation and proinflammatory events in liver. Am J Physiol Gastrointest Liver Physiol 2003; 285:G642.
  107. Ramalho LN, Ramalho FS, Zucoloto S, et al. Effect of losartan, an angiotensin II antagonist, on secondary biliary cirrhosis. Hepatogastroenterology 2002; 49:1499.
  108. Yoshiji H, Yoshii J, Ikenaka Y, et al. Inhibition of renin-angiotensin system attenuates liver enzyme-altered preneoplastic lesions and fibrosis development in rats. J Hepatol 2002; 37:22.
  109. Kurikawa N, Suga M, Kuroda S, et al. An angiotensin II type 1 receptor antagonist, olmesartan medoxomil, improves experimental liver fibrosis by suppression of proliferation and collagen synthesis in activated hepatic stellate cells. Br J Pharmacol 2003; 139:1085.
  110. Kim SY, Cho BH, Kim UH. CD38-mediated Ca2+ signaling contributes to angiotensin II-induced activation of hepatic stellate cells: attenuation of hepatic fibrosis by CD38 ablation. J Biol Chem 2010; 285:576.
  111. Sancho-Bru P, Bataller R, Fernandez-Varo G, et al. Bradykinin attenuates hepatocellular damage and fibrosis in rats with chronic liver injury. Gastroenterology 2007; 133:2019.
  112. Bataller R, Sancho-Bru P, Ginès P, Brenner DA. Liver fibrogenesis: a new role for the renin-angiotensin system. Antioxid Redox Signal 2005; 7:1346.
  113. Moreno M, Gonzalo T, Kok RJ, et al. Reduction of advanced liver fibrosis by short-term targeted delivery of an angiotensin receptor blocker to hepatic stellate cells in rats. Hepatology 2010; 51:942.
  114. Friedman SL. Cytokines and fibrogenesis. Semin Liver Dis 1999; 19:129.
  115. George J, Roulot D, Koteliansky VE, Bissell DM. In vivo inhibition of rat stellate cell activation by soluble transforming growth factor beta type II receptor: a potential new therapy for hepatic fibrosis. Proc Natl Acad Sci U S A 1999; 96:12719.
  116. Friedman SL. Mechanisms of disease: Mechanisms of hepatic fibrosis and therapeutic implications. Nat Clin Pract Gastroenterol Hepatol 2004; 1:98.
  117. Okuno M, Akita K, Moriwaki H, et al. Prevention of rat hepatic fibrosis by the protease inhibitor, camostat mesilate, via reduced generation of active TGF-beta. Gastroenterology 2001; 120:1784.
  118. Zheng S, Chen A. Disruption of transforming growth factor-beta signaling by curcumin induces gene expression of peroxisome proliferator-activated receptor-gamma in rat hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol 2007; 292:G113.
  119. Leclercq IA, Farrell GC, Sempoux C, et al. Curcumin inhibits NF-kappaB activation and reduces the severity of experimental steatohepatitis in mice. J Hepatol 2004; 41:926.
  120. Dooley S, Hamzavi J, Breitkopf K, et al. Smad7 prevents activation of hepatic stellate cells and liver fibrosis in rats. Gastroenterology 2003; 125:178.
  121. Wang B, Dolinski BM, Kikuchi N, et al. Role of alphavbeta6 integrin in acute biliary fibrosis. Hepatology 2007; 46:1404.
  122. 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; 19:1617.
  123. Zhu J, Choi WS, McCoy JG, et al. Structure-guided design of a high-affinity platelet integrin αIIbβ3 receptor antagonist that disrupts Mg²⁺ binding to the MIDAS. Sci Transl Med 2012; 4:125ra32.
  124. Lüscher TF, Wenzel RR. Endothelin and endothelin antagonists: pharmacology and clinical implications. Agents Actions Suppl 1995; 45:237.
  125. Rockey DC, Chung JJ. Endothelin antagonism in experimental hepatic fibrosis. Implications for endothelin in the pathogenesis of wound healing. J Clin Invest 1996; 98:1381.
  126. Wiedmann MW, Caca K. Molecularly targeted therapy for gastrointestinal cancer. Curr Cancer Drug Targets 2005; 5:171.
  127. Yoshiji H, Kuriyama S, Noguchi R, et al. Amelioration of liver fibrogenesis by dual inhibition of PDGF and TGF-beta with a combination of imatinib mesylate and ACE inhibitor in rats. Int J Mol Med 2006; 17:899.
  128. Gonzalo T, Beljaars L, van de Bovenkamp M, et al. Local inhibition of liver fibrosis by specific delivery of a platelet-derived growth factor kinase inhibitor to hepatic stellate cells. J Pharmacol Exp Ther 2007; 321:856.
  129. 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; 46:1919.
  130. Caligiuri A, Bertolani C, Guerra CT, et al. Adenosine monophosphate-activated protein kinase modulates the activated phenotype of hepatic stellate cells. Hepatology 2008; 47:668.
  131. Benedetti A, Di Sario A, Casini A, et al. Inhibition of the NA(+)/H(+) exchanger reduces rat hepatic stellate cell activity and liver fibrosis: an in vitro and in vivo study. Gastroenterology 2001; 120:545.
  132. Hennenberg M, Trebicka J, Kohistani Z, et al. Hepatic and HSC-specific sorafenib effects in rats with established secondary biliary cirrhosis. Lab Invest 2011; 91:241.
  133. Wang Y, Gao J, Zhang D, et al. New insights into the antifibrotic effects of sorafenib on hepatic stellate cells and liver fibrosis. J Hepatol 2010; 53:132.
  134. Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002; 347:472.
  135. Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 2001; 344:1038.
  136. Yoshiji H, Noguchi R, Kuriyama S, et al. Imatinib mesylate (STI-571) attenuates liver fibrosis development in rats. Am J Physiol Gastrointest Liver Physiol 2005; 288:G907.
  137. Neef M, Ledermann M, Saegesser H, et al. Oral imatinib treatment reduces early fibrogenesis but does not prevent progression in the long term. J Hepatol 2006; 44:167.
  138. Mejias M, Garcia-Pras E, Tiani C, et al. Beneficial effects of sorafenib on splanchnic, intrahepatic, and portocollateral circulations in portal hypertensive and cirrhotic rats. Hepatology 2009; 49:1245.
  139. Tada S, Iwamoto H, Nakamuta M, et al. A selective ROCK inhibitor, Y27632, prevents dimethylnitrosamine-induced hepatic fibrosis in rats. J Hepatol 2001; 34:529.
  140. Borkham-Kamphorst E, Stoll D, Gressner AM, Weiskirchen R. Antisense strategy against PDGF B-chain proves effective in preventing experimental liver fibrogenesis. Biochem Biophys Res Commun 2004; 321:413.
  141. Ogawa S, Ochi T, Shimada H, et al. Anti-PDGF-B monoclonal antibody reduces liver fibrosis development. Hepatol Res 2010; 40:1128.
  142. Sato Y, Murase K, Kato J, et al. Resolution of liver cirrhosis using vitamin A-coupled liposomes to deliver siRNA against a collagen-specific chaperone. Nat Biotechnol 2008; 26:431.
  143. Stefanovic B, Schnabl B, Brenner DA. Inhibition of collagen alpha 1(I) expression by the 5' stem-loop as a molecular decoy. J Biol Chem 2002; 277:18229.
  144. Lindquist JN, Parsons CJ, Stefanovic B, Brenner DA. Regulation of alpha1(I) collagen messenger RNA decay by interactions with alphaCP at the 3'-untranslated region. J Biol Chem 2004; 279:23822.
  145. Stefanovic B, Stefanovic L, Schnabl B, et al. TRAM2 protein interacts with endoplasmic reticulum Ca2+ pump Serca2b and is necessary for collagen type I synthesis. Mol Cell Biol 2004; 24:1758.
  146. Stefanovic L, Stephens CE, Boykin D, Stefanovic B. Inhibitory effect of dicationic diphenylfurans on production of type I collagen by human fibroblasts and activated hepatic stellate cells. Life Sci 2005; 76:2011.
  147. Geerts A, Rogiers V. Sho-saiko-To: the right blend of traditional Oriental medicine and liver cell biology. Hepatology 1999; 29:282.
  148. Sakaida I, Matsumura Y, Akiyama S, et al. Herbal medicine Sho-saiko-to (TJ-9) prevents liver fibrosis and enzyme-altered lesions in rat liver cirrhosis induced by a choline-deficient L-amino acid-defined diet. J Hepatol 1998; 28:298.
  149. Shimizu I, Ma YR, Mizobuchi Y, et al. Effects of Sho-saiko-to, a Japanese herbal medicine, on hepatic fibrosis in rats. Hepatology 1999; 29:149.
  150. Wasser S, Ho JM, Ang HK, Tan CE. Salvia miltiorrhiza reduces experimentally-induced hepatic fibrosis in rats. J Hepatol 1998; 29:760.
  151. Mann DA, Mann J. Epigenetic regulation of hepatic stellate cell activation. J Gastroenterol Hepatol 2008; 23 Suppl 1:S108.
  152. Mann J, Chu DC, Maxwell A, et al. MeCP2 controls an epigenetic pathway that promotes myofibroblast transdifferentiation and fibrosis. Gastroenterology 2010; 138:705.
  153. Ordovás JM, Smith CE. Epigenetics and cardiovascular disease. Nat Rev Cardiol 2010; 7:510.
  154. Arthur MJ. Fibrosis and altered matrix degradation. Digestion 1998; 59:376.
  155. Parsons CJ, Bradford BU, Pan CQ, et al. Antifibrotic effects of a tissue inhibitor of metalloproteinase-1 antibody on established liver fibrosis in rats. Hepatology 2004; 40:1106.
  156. Iimuro Y, Nishio T, Morimoto T, et al. Delivery of matrix metalloproteinase-1 attenuates established liver fibrosis in the rat. Gastroenterology 2003; 124:445.
  157. Siller-López F, Sandoval A, Salgado S, et al. Treatment with human metalloproteinase-8 gene delivery ameliorates experimental rat liver cirrhosis. Gastroenterology 2004; 126:1122.
  158. 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:E3186.
  159. Ramachandran P, Iredale JP. Macrophages: central regulators of hepatic fibrogenesis and fibrosis resolution. J Hepatol 2012; 56:1417.
  160. Tacke F, Zimmermann HW. Macrophage heterogeneity in liver injury and fibrosis. J Hepatol 2014; 60:1090.
  161. 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; 16:1009.
  162. Weiskirchen R, Tacke F. Liver Fibrosis: From Pathogenesis to Novel Therapies. Dig Dis 2016; 34:410.
  163. Liu SB, Ikenaga N, Peng ZW, et al. Lysyl oxidase activity contributes to collagen stabilization during liver fibrosis progression and limits spontaneous fibrosis reversal in mice. FASEB J 2016; 30:1599.
  164. Iwasaki A, Sakai K, Moriya K, et al. Molecular Mechanism Responsible for Fibronectin-controlled Alterations in Matrix Stiffness in Advanced Chronic Liver Fibrogenesis. J Biol Chem 2016; 291:72.
  165. Yoshiji H, Kuriyama S, Yoshii J, et al. Tissue inhibitor of metalloproteinases-1 attenuates spontaneous liver fibrosis resolution in the transgenic mouse. Hepatology 2002; 36:850.
  166. Murphy FR, Issa R, Zhou X, et al. Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metalloproteinase-1 is mediated via effects on matrix metalloproteinase inhibition: implications for reversibility of liver fibrosis. J Biol Chem 2002; 277:11069.
  167. Roderfeld M, Weiskirchen R, Wagner S, et al. Inhibition of hepatic fibrogenesis by matrix metalloproteinase-9 mutants in mice. FASEB J 2006; 20:444.
  168. Troeger JS, Mederacke I, Gwak GY, et al. Deactivation of hepatic stellate cells during liver fibrosis resolution in mice. Gastroenterology 2012; 143:1073.
  169. 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; 109:9448.
  170. Gressner AM. The cell biology of liver fibrogenesis - an imbalance of proliferation, growth arrest and apoptosis of myofibroblasts. Cell Tissue Res 1998; 292:447.
  171. Pinzani M. Unraveling the spider web of hepatic stellate cell apoptosis. Gastroenterology 2009; 136:2061.
  172. Iwamoto H, Sakai H, Tada S, et al. Induction of apoptosis in rat hepatic stellate cells by disruption of integrin-mediated cell adhesion. J Lab Clin Med 1999; 134:83.
  173. Oh Y, Park O, Swierczewska M, et al. Systemic PEGylated TRAIL treatment ameliorates liver cirrhosis in rats by eliminating activated hepatic stellate cells. Hepatology 2016; 64:209.
  174. Iredale JP, Benyon RC, Pickering J, et al. Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J Clin Invest 1998; 102:538.
  175. Dekel R, Zvibel I, Brill S, et al. Gliotoxin ameliorates development of fibrosis and cirrhosis in a thioacetamide rat model. Dig Dis Sci 2003; 48:1642.
  176. Wright MC, Issa R, Smart DE, et al. Gliotoxin stimulates the apoptosis of human and rat hepatic stellate cells and enhances the resolution of liver fibrosis in rats. Gastroenterology 2001; 121:685.
  177. Oakley F, Meso M, Iredale JP, et al. Inhibition of inhibitor of kappaB kinases stimulates hepatic stellate cell apoptosis and accelerated recovery from rat liver fibrosis. Gastroenterology 2005; 128:108.
  178. Iwamoto H, Sakai H, Kotoh K, et al. Soluble Arg-Gly-Asp peptides reduce collagen accumulation in cultured rat hepatic stellate cells. Dig Dis Sci 1999; 44:1038.
  179. Taimr P, Higuchi H, Kocova E, et al. Activated stellate cells express the TRAIL receptor-2/death receptor-5 and undergo TRAIL-mediated apoptosis. Hepatology 2003; 37:87.
  180. Oakley F, Trim N, Constandinou CM, et al. Hepatocytes express nerve growth factor during liver injury: evidence for paracrine regulation of hepatic stellate cell apoptosis. Am J Pathol 2003; 163:1849.
  181. Fallowfield JA, Iredale JP. Targeted treatments for cirrhosis. Expert Opin Ther Targets 2004; 8:423.
  182. Trebicka J, Hennenberg M, Odenthal M, et al. Atorvastatin attenuates hepatic fibrosis in rats after bile duct ligation via decreased turnover of hepatic stellate cells. J Hepatol 2010; 53:702.
  183. Friedman SL. Targeting siRNA to arrest fibrosis. Nat Biotechnol 2008; 26:399.