Antifibrotics in chronic liver disease: tractable targets and translational challenges

The Lancet Gastroenterology and Hepatology

Volumn 1, Issue 4, 2016, Pages 328-340

  Ramachandran, Prakash ^a   Henderson, Neil C ^a  

^a UNIVERSITY OF EDINBURGH   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIFIBROTIC AGENT; ATORVASTATIN; BEZAFIBRATE; CANDESARTAN; CASPASE INHIBITOR; CD51 ANTIGEN; CENICRIVIROC; EXENDIN 4; INTERLEUKIN 10; IRBESARTAN; LOSARTAN; METADOXINE; METFORMIN; NERVE GROWTH FACTOR; OBETICHOLIC ACID; OLTIPRAZ; OMEGA 3 FATTY ACID; PENTOXIFYLLINE; PIOGLITAZONE; PIRFENIDONE; SIMTUZUMAB; TUMOR NECROSIS FACTOR; VITAMIN D; VOLIXIBAT; GASTROINTESTINAL AGENT;

APOPTOSIS; AUTOPHAGY; CELL DIFFERENTIATION; CELL PROLIFERATION; CHRONIC LIVER DISEASE; EPITHELIUM CELL; HEPATITIS C VIRUS; HYPERTENSION; IMMUNOCOMPETENT CELL; LIVER CELL CARCINOMA; LIVER FIBROSIS; MYOFIBROBLAST; PREVALENCE; PRIORITY JOURNAL; REVIEW; WOUND HEALING; CHRONIC DISEASE; DISEASE EXACERBATION; HUMAN; LIVER CIRRHOSIS; PATHOPHYSIOLOGY; TRANSLATIONAL RESEARCH; TREATMENT OUTCOME;

CHRONIC DISEASE; DISEASE PROGRESSION; GASTROINTESTINAL AGENTS; HUMANS; LIVER CIRRHOSIS; TRANSLATIONAL MEDICAL RESEARCH; TREATMENT OUTCOME;

EID: 84996538540     PISSN: 24681253     EISSN: None     Source Type: Journal    
DOI: 10.1016/S2468-1253(16)30110-8     Document Type: Review

References (119)

1. 1 Nagula, S, Jain, D, Groszmann, RJ, Garcia-Tsao, G, Histological-hemodynamic correlation in cirrhosis-a histological classification of the severity of cirrhosis. J Hepatol 44 (2006), 111–117.
2. 2 Sethasine, S, Jain, D, Groszmann, RJ, Garcia-Tsao, G, Quantitative histological-hemodynamic correlations in cirrhosis. Hepatology 55 (2012), 1146–1153.
3. 3 Tsochatzis, E, Bruno, S, Isgro, G, et al. Collagen proportionate area is superior to other histological methods for sub-classifying cirrhosis and determining prognosis. J Hepatol 60 (2014), 948–954.
4. 4 Huang, Y, de Boer, WB, Adams, LA, MacQuillan, G, Bulsara, MK, Jeffrey, GP, Image analysis of liver biopsy samples measures fibrosis and predicts clinical outcome. J Hepatol 61 (2014), 22–27.
5. 5 Ramachandran, P, Iredale, JP, Fallowfield, JA, Resolution of liver fibrosis: basic mechanisms and clinical relevance. Semin Liver Dis 35 (2015), 119–131.
6. 6 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 52 (2010), 886–893.
7. 7 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 381 (2013), 468–475.
8. 8 Shiffman, ML, Sterling, RK, Contos, M, et al. Long term changes in liver histology following treatment of chronic hepatitis C virus. Ann Hepatol 13 (2014), 340–349.
9. 9 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 149 (2008), 399–403.
10. 10 Poynard, T, Moussalli, J, Munteanu, M, et al. Slow regression of liver fibrosis presumed by repeated biomarkers after virological cure in patients with chronic hepatitis C. J Hepatol 59 (2013), 675–683.
11. 11 Petta, S, Di Marco, V, Bruno, S, et al. Impact of virus eradication in patients with compensated hepatitis C virus-related cirrhosis: competing risks and multistate model. Liver Int, 2016, 10.1111/liv.13156 published online May 10.
12. 12 Friedman, SL, Sheppard, D, Duffield, JS, Violette, S, Therapy for fibrotic diseases: nearing the starting line. Sci Transl Med, 5, 2013, 167sr1.
13. 13 Barreyro, FJ, Holod, S, Finocchietto, PV, et al. The pan-caspase inhibitor Emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis. Liver Int 35 (2015), 953–966.
14. 14 Bugianesi, E, Gentilcore, E, Manini, R, et al. A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol 100 (2005), 1082–1090.
15. 15 Armstrong, MJ, Gaunt, P, Aithal, GP, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 387 (2016), 679–690.
16. 16 Kim, SG, Kim, YM, Choi, JY, et al. Oltipraz therapy in patients with liver fibrosis or cirrhosis: a randomized, double-blind, placebo-controlled phase II trial. J Pharm Pharmacol 63 (2011), 627–635.
17. 17 Sanyal, AJ, Abdelmalek, MF, Suzuki, A, Cummings, OW, Chojkier, M, No significant effects of ethyl-eicosapentanoic acid on histologic features of nonalcoholic steatohepatitis in a phase 2 trial. Gastroenterology 147 (2014), 377–384.
18. 18 Argo, CK, Patrie, JT, Lackner, C, et al. Effects of n-3 fish oil on metabolic and histological parameters in NASH: a double-blind, randomized, placebo-controlled trial. J Hepatol 62 (2015), 190–197.
19. 19 Neuschwander-Tetri, BA, Loomba, R, Sanyal, AJ, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385 (2015), 956–965.
20. 20 Colmenero, J, Bataller, R, Sancho-Bru, P, et al. Effects of losartan on hepatic expression of nonphagocytic NADPH oxidase and fibrogenic genes in patients with chronic hepatitis C. Am J Physiol Gastrointest Liver Physiol 297 (2009), G726–G734.
21. 21 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 32 (2012), 977–987.
22. 22 McHutchison, J, Goodman, Z, Patel, K, et al. Farglitazar lacks antifibrotic activity in patients with chronic hepatitis C infection. Gastroenterology 138 (2010), 1365–1373 1373.
23. 23 Belfort, R, Harrison, SA, Brown, K, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 355 (2006), 2297–2307.
24. 24 Aithal, GP, Thomas, JA, Kaye, PV, et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology 135 (2008), 1176–1184.
25. 25 Sanyal, AJ, Chalasani, N, Kowdley, KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 362 (2010), 1675–1685.
26. 26 Ratziu, V, Charlotte, F, Bernhardt, C, et al. Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial. Hepatology 51 (2010), 445–453.
27. 27 Ratziu, V, Harrison, SA, Francque, S, et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology 150 (2016), 1147–1159.
28. 28 Zein, CO, Yerian, LM, Gogate, P, et al. Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology 54 (2011), 1610–1619.
29. 29 Nelson, DR, Tu, ZK, Soldevila-Pico, C, et al. Long-term interleukin 10 therapy in chronic hepatitis C patients has a proviral and anti-inflammatory effect. Hepatology 38 (2003), 859–868.
30. 30 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 45 (2007), 569–578.
31. 31 Muir, AJ, Sylvestre, PB, Rockey, DC, Interferon gamma-1b for the treatment of fibrosis in chronic hepatitis C infection. J Viral Hepat 13 (2006), 322–328.
32. 32 Weng, HL, Wang, BE, Jia, JD, et al. Effect of interferon-gamma on hepatic fibrosis in chronic hepatitis B virus infection: a randomized controlled study. Clin Gastroenterol Hepatol 3 (2005), 819–828.
33. 33 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 27 (2007), 247–259.
34. 34 Meissner, EG, McLaughlin, M, Matthews, L, et al. Simtuzumab treatment of advanced liver fibrosis in HIV and HCV-infected adults: results of a 6-month open-label safety trial. Liver Int, 2016, 10.1111/liv.13177 published online May 27.
35. 35 Schuppan, D, Kim, YO, Evolving therapies for liver fibrosis. J Clin Invest 123 (2013), 1887–1901.
36. 36 Yoon, YJ, Friedman, SL, Lee, YA, Antifibrotic therapies: where are we now?. Semin Liver Dis 36 (2016), 87–98.
37. 37 Shiffman, ML, Pockros, P, McHutchison, JG, Schiff, ER, Morris, M, Burgess, G, Clinical trial: the efficacy and safety of oral PF-03491390, a pancaspase inhibitor—a randomized placebo-controlled study in patients with chronic hepatitis C. Aliment Pharmacol Ther 31 (2010), 969–978.
38. 38 Canbay, A, Guicciardi, ME, Higuchi, H, et al. Cathepsin B inactivation attenuates hepatic injury and fibrosis during cholestasis. J Clin Invest 112 (2003), 152–159.
39. 39 Bochaton-Piallat, ML, Gabbiani, G, Hinz, B, The myofibroblast in wound healing and fibrosis: answered and unanswered questions. F1000Res, 5, 2016.
40. 40 Hinz, B, Phan, SH, Thannickal, VJ, et al. Recent developments in myofibroblast biology: paradigms for connective tissue remodeling. Am J Pathol 180 (2012), 1340–1355.
41. 41 Friedman, SL, Roll, FJ, Boyles, J, Bissell, DM, Hepatic lipocytes: the principal collagen-producing cells of normal rat liver. Proc Natl Acad Sci USA 82 (1985), 8681–8685.
42. 42 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, 4, 2013, 2823.
43. 43 Iwaisako, K, Jiang, C, Zhang, M, et al. Origin of myofibroblasts in the fibrotic liver in mice. Proc Natl Acad Sci USA 111 (2014), E3297–E3305.
44. 44 Lemoinne, S, Cadoret, A, El Mourabit, H, Thabut, D, Housset, C, Origins and functions of liver myofibroblasts. Biochim Biophys Acta 1832 (2013), 948–954.
45. 45 Friedman, SL, Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 88 (2008), 125–172.
46. 46 Iredale, JP, Murphy, G, Hembry, RM, Friedman, SL, Arthur, MJ, Human hepatic lipocytes synthesize tissue inhibitor of metalloproteinases-1. Implications for regulation of matrix degradation in liver. J Clin Invest 90 (1992), 282–287.
47. 47 Hernandez-Gea, V, Friedman, SL, Pathogenesis of liver fibrosis. Annu Rev Pathol 6 (2011), 425–456.
48. 48 Lee, YA, Wallace, MC, Friedman, SL, Pathobiology of liver fibrosis: a translational success story. Gut 64 (2015), 830–841.
49. 49 Trautwein, C, Friedman, SL, Schuppan, D, Pinzani, M, Hepatic fibrosis: concept to treatment. J Hepatol 62:suppl 1 (2015), S15–S24.
50. 50 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 102 (1998), 538–549.
51. 51 Issa, R, Williams, E, Trim, N, et al. Apoptosis of hepatic stellate cells: involvement in resolution of biliary fibrosis and regulation by soluble growth factors. Gut 48 (2001), 548–557.
52. 52 Krizhanovsky, V, Yon, M, Dickins, RA, et al. Senescence of activated stellate cells limits liver fibrosis. Cell 134 (2008), 657–667.
53. 53 Kisseleva, T, Cong, M, Paik, Y, et al. Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis. Proc Natl Acad Sci USA 109 (2012), 9448–9453.
54. 54 Troeger, JS, Mederacke, I, Gwak, GY, et al. Deactivation of hepatic stellate cells during liver fibrosis resolution in mice. Gastroenterology 143 (2012), 1073–1083.
55. 55 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. Hepatology 58 (2013), 1461–1473.
56. 56 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 277 (2002), 11069–11076.
57. 57 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 279 (2004), 23996–24006.
58. 58 Kendall, TJ, Hennedige, S, Aucott, RL, et al. p75 Neurotrophin receptor signaling regulates hepatic myofibroblast proliferation and apoptosis in recovery from rodent liver fibrosis. Hepatology 49 (2009), 901–910.
59. 59 Douglass, A, Wallace, K, Parr, R, et al. Antibody-targeted myofibroblast apoptosis reduces fibrosis during sustained liver injury. J Hepatol 49 (2008), 88–98.
60. 60 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 26 (2008), 431–442.
61. 61 Kim, KH, Chen, CC, Monzon, RI, Lau, LF, Matricellular protein CCN1 promotes regression of liver fibrosis through induction of cellular senescence in hepatic myofibroblasts. Mol Cell Biol 33 (2013), 2078–2090.
62. 62 Borkham-Kamphorst, E, Schaffrath, C, Van de Leur, E, et al. The anti-fibrotic effects of CCN1/CYR61 in primary portal myofibroblasts are mediated through induction of reactive oxygen species resulting in cellular senescence, apoptosis and attenuated TGF-β signaling. Biochim Biophys Acta 1843 (2014), 902–914.
63. 63 Kong, X, Feng, D, Wang, H, et al. Interleukin-22 induces hepatic stellate cell senescence and restricts liver fibrosis in mice. Hepatology 56 (2012), 1150–1159.
64. 64 Klein, S, Klosel, J, Schierwagen, R, et al. Atorvastatin inhibits proliferation and apoptosis, but induces senescence in hepatic myofibroblasts and thereby attenuates hepatic fibrosis in rats. Lab Invest 92 (2012), 1440–1450.
65. 65 Huang, YW, Lee, CL, Yang, SS, et al. Statins reduce the risk of cirrhosis and its decompensation in chronic hepatitis B patients: a nationwide cohort study. Am J Gastroenterol 111 (2016), 976–985.
66. 66 Simon, TG, King, LY, Zheng, H, Chung, RT, Statin use is associated with a reduced risk of fibrosis progression in chronic hepatitis C. J Hepatol 62 (2015), 18–23.
67. 67 Butt, AA, Yan, P, Bonilla, H, et al. Effect of addition of statins to antiviral therapy in hepatitis C virus-infected persons: results from ERCHIVES. Hepatology 62 (2015), 365–374.
68. 68 Song, G, Pacher, M, Balakrishnan, A, et al. Direct reprogramming of hepatic myofibroblasts into hepatocytes in vivo attenuates liver fibrosis. Cell Stem Cell 18 (2016), 797–808.
69. 69 Rezvani, M, Español-Suñer, R, Malato, Y, et al. In vivo hepatic reprogramming of myofibroblasts with AAV vectors as a therapeutic sstrategy for liver fibrosis. Cell Stem Cell 18 (2016), 809–816.
70. 70 Duffield, JS, Forbes, SJ, Constandinou, CM, et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest 115 (2005), 56–65.
71. 71 Fallowfield, JA, Mizuno, M, Kendall, TJ, et al. Scar-associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis. J Immunol 178 (2007), 5288–5295.
72. 72 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 USA 109 (2012), E3186–E3195.
73. 73 Karlmark, KR, Weiskirchen, R, Zimmermann, HW, et al. Hepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology 50 (2009), 261–274.
74. 74 Yang, L, Kwon, J, Popov, Y, et al. Vascular endothelial growth factor promotes fibrosis resolution and repair in mice. Gastroenterology 146 (2014), 1339–1350.
75. 75 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 55 (2012), 1965–1975.
76. 76 Fischer, R, Cariers, A, Reinehr, R, Haussinger, D, Caspase 9-dependent killing of hepatic stellate cells by activated Kupffer cells. Gastroenterology 123 (2002), 845–861.
77. 77 Mitchell, C, Couton, D, Couty, JP, et al. Dual role of CCR2 in the constitution and the resolution of liver fibrosis in mice. Am J Pathol 174 (2009), 1766–1775.
78. 78 Seki, E, de Minicis, S, Inokuchi, S, et al. CCR2 promotes hepatic fibrosis in mice. Hepatology 50 (2009), 185–197.
79. 3CR1 protects against liver fibrosis by controlling differentiation and survival of infiltrating hepatic monocytes. Hepatology 52 (2010), 1769–1851.
80. 80 Wynn, TA, Barron, L, Macrophages: master regulators of inflammation and fibrosis. Semin Liver Dis 30 (2010), 245–257.
81. 81 Liaskou, E, Zimmermann, HW, Li, KK, et al. Monocyte subsets in human liver disease show distinct phenotypic and functional characteristics. Hepatology 57 (2013), 385–398.
82. 82 Zimmermann, HW, Seidler, S, Nattermann, J, et al. Functional contribution of elevated circulating and hepatic non-classical CD14CD16 monocytes to inflammation and human liver fibrosis. PLoS One, 5, 2010, e11049.
83. 83 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 59 (2014), 1060–1072.
84. 84 Pellicoro, A, Ramachandran, P, Iredale, JP, Fallowfield, JA, Liver fibrosis and repair: immune regulation of wound healing in a solid organ. Nat Rev Immunol 14 (2014), 181–194.
85. 85 Jeong, WI, Park, O, Suh, YG, et al. Suppression of innate immunity (natural killer cell/interferon-γ) in the advanced stages of liver fibrosis in mice. Hepatology 53 (2011), 1342–1351.
86. 86 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 130 (2006), 435–452.
87. 87 Saito, JM, Bostick, MK, Campe, CB, Xu, J, Maher, JJ, Infiltrating neutrophils in bile duct-ligated livers do not promote hepatic fibrosis. Hepatol Res 25 (2003), 180–191.
88. 88 Harty, MW, Muratore, CS, Papa, EF, et al. Neutrophil depletion blocks early collagen degradation in repairing cholestatic rat livers. Am J Pathol 176 (2010), 1271–1281.
89. 89 Jiao, J, Sastre, D, Fiel, MI, et al. Dendritic cell regulation of carbon tetrachloride-induced murine liver fibrosis regression. Hepatology 55 (2012), 244–255.
90. 90 Wynn, TA, Cellular and molecular mechanisms of fibrosis. J Pathol 214 (2008), 199–210.
91. 91 Claassen, MA, de Knegt, RJ, Tilanus, HW, Janssen, HL, Boonstra, A, Abundant numbers of regulatory T cells localize to the liver of chronic hepatitis C infected patients and limit the extent of fibrosis. J Hepatol 52 (2010), 315–321.
92. 92 Meng, F, Wang, K, Aoyama, T, et al. Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice. Gastroenterology 143 (2012), 765–776.
93. 93 Williamson, KD, Chapman, RW, New therapeutic strategies for primary sclerosing cholangitis. Semin Liver Dis 36 (2016), 5–14.
94. 94 DeLeve, LD, Liver sinusoidal endothelial cells in hepatic fibrosis. Hepatology 61 (2015), 1740–1746.
95. 95 Ding, BS, Cao, Z, Lis, R, et al. Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis. Nature 505 (2014), 97–102.
96. 96 Sahin, H, Borkham-Kamphorst, E, Kuppe, C, et al. Chemokine Cxcl9 attenuates liver fibrosis-associated angiogenesis in mice. Hepatology 55 (2012), 1610–1619.
97. 97 Thabut, D, Shah, V, Intrahepatic angiogenesis and sinusoidal remodeling in chronic liver disease: new targets for the treatment of portal hypertension?. J Hepatol 53 (2010), 976–980.
98. 98 Greuter, T, Shah, VH, Hepatic sinusoids in liver injury, inflammation, and fibrosis: new pathophysiological insights. J Gastroenterol 51 (2016), 511–519.
99. 99 Bocca, C, Novo, E, Miglietta, A, Parola, M, Angiogenesis and fibrogenesis in chronic liver diseases. Cell Mol Gastroenterol Hepatol 1 (2015), 477–488.
100. 100 Kantari-Mimoun, C, Castells, M, Klose, R, et al. Resolution of liver fibrosis requires myeloid cell-driven sinusoidal angiogenesis. Hepatology 61 (2015), 2042–2055.
101. 101 Mehal, WZ, Iredale, J, Friedman, SL, Scraping fibrosis: expressway to the core of fibrosis. Nat Med 17 (2011), 552–553.
102. 102 King, TE Jr, Bradford, WZ, Castro-Bernardini, S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med 370 (2014), 2083–2092.
103. 103 Richeldi, L, du Bois, RM, Raghu, G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 370 (2014), 2071–2082.
104. 104 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 16 (2010), 1009–1017.
105. 105 Rosenbloom, J, Castro, SV, Jimenez, SA, Narrative review: fibrotic diseases: cellular and molecular mechanisms and novel therapies. Ann Intern Med 152 (2010), 159–166.
106. 106 Reed, NI, Jo, H, Chen, C, et al. The αvβ1 integrin plays a critical in vivo role in tissue fibrosis. Sci Transl Med, 7, 2015, 288ra79.
107. 107 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 19 (2013), 1617–1624.
108. 108 Conroy, KP, Kitto, LJ, Henderson, NC, αv integrins: key regulators of tissue fibrosis. Cell Tissue Res, 2016, 10.1007/s00441-016-2407-9 published online May 2.
109. 109 Desmet, VJ, Roskams, T, Cirrhosis reversal: a duel between dogma and myth. J Hepatol 40 (2004), 860–867.
110. 110 Grompe, M, Strom, S, Mice with human livers. Gastroenterology 145 (2013), 1209–1214.
111. 111 Huch, M, Gehart, H, van Boxtel, R, et al. Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell 160 (2015), 299–312.
112. 112 Olinga, P, Schuppan, D, Precision-cut liver slices: a tool to model the liver ex vivo. J Hepatol 58 (2013), 1252–1253.
113. 113 Westra, IM, Oosterhuis, D, Groothuis, GM, Olinga, P, Precision-cut liver slices as a model for the early onset of liver fibrosis to test antifibrotic drugs. Toxicol Appl Pharmacol 274 (2014), 328–338.
114. 114 Torok, NJ, Dranoff, JA, Schuppan, D, Friedman, SL, Strategies and endpoints of antifibrotic drug trials: summary and recommendations from the AASLD Emerging Trends Conference, Chicago, June 2014. Hepatology 62 (2015), 627–634.
115. 115 US Food and Drug Administration. Clinical outcome assessment qualification program. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/ucm284077.htm (accessed Sept 16, 2016).
116. 116 Ratziu, V, Charlotte, F, Heurtier, A, et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology 128 (2005), 1898–1906.
117. 117 Leeming, DJ, Karsdal, MA, Byrjalsen, I, et al. Novel serological neo-epitope markers of extracellular matrix proteins for the detection of portal hypertension. Aliment Pharmacol Ther 38 (2013), 1086–1096.
118. 118 Fuchs, BC, Wang, H, Yang, Y, et al. Molecular MRI of collagen to diagnose and stage liver fibrosis. J Hepatol 59 (2013), 992–998.
119. 119 Chow, AM, Tan, M, Gao, DS, et al. Molecular MRI of liver fibrosis by a peptide-targeted contrast agent in an experimental mouse model. Invest Radiol 48 (2013), 46–54.