Resolution of Liver Fibrosis: Basic Mechanisms and Clinical Relevance

 

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Abstract

With evidence from a large number of animal models and clinical trials, it is now beyond debate that liver fibrosis and even cirrhosis are potentially reversible if the underlying cause can be successfully eliminated. However, in a significant proportion of patients cure of the underlying disease may not result in fibrosis regression or a significant reduction of the risk for hepatocellular carcinoma development. Understanding of the mechanistic pathways and regulatory factors that characterize matrix remodeling and architectural repair during fibrosis regression may provide therapeutic approaches to induce or accelerate regression as well as novel diagnostic tools. Recent seminal observations have determined that in resolving liver fibrosis a significant proportion of hepatic stellate cell-myofibroblasts (HSC-MFs) can revert to a near quiescent phenotype. Hepatic macrophages derived from inflammatory monocytes may contribute to fibrosis resolution through an in situ phenotypic switch mediated by phagocytosis. Emerging therapeutic approaches include deletion or inactivation of HSC-MFs, modulation of macrophage activity and autologous cell infusion therapies. Novel noninvasive diagnostic tests such as serum and imaging markers responsive to extracellular matrix degradation are being developed to evaluate the clinical efficacy of antifibrotic interventions.

• References

• 1 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 (3) 538-549
  CrossrefPubMedGoogle Scholar
• 2 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 2001; 48 (4) 548-557
  CrossrefPubMedGoogle Scholar
• 3 Ellis EL, Mann DA. Clinical evidence for the regression of liver fibrosis. J Hepatol 2012; 56 (5) 1171-1180
  CrossrefPubMedGoogle Scholar
• 4 Kweon YO, Goodman ZD, Dienstag JL , et al. Decreasing fibrogenesis: an immunohistochemical study of paired liver biopsies following lamivudine therapy for chronic hepatitis B. J Hepatol 2001; 35 (6) 749-755
  CrossrefPubMedGoogle Scholar
• 5 Poynard T, McHutchison J, Manns M , et al. Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology 2002; 122 (5) 1303-1313
  CrossrefPubMedGoogle Scholar
• 6 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 (7) 1740-1749
  CrossrefPubMedGoogle Scholar
• 7 Niederau C, Fischer R, Pürschel A, Stremmel W, Häussinger D, Strohmeyer G. Long-term survival in patients with hereditary hemochromatosis. Gastroenterology 1996; 110 (4) 1107-1119
  CrossrefPubMedGoogle Scholar
• 8 Cope-Yokoyama S, Finegold MJ, Sturniolo GC , et al. Wilson disease: histopathological correlations with treatment on follow-up liver biopsies. World J Gastroenterol 2010; 16 (12) 1487-1494
  CrossrefPubMedGoogle Scholar
• 9 Czaja AJ, Carpenter HA. Decreased fibrosis during corticosteroid therapy of autoimmune hepatitis. J Hepatol 2004; 40 (4) 646-652
  CrossrefPubMedGoogle Scholar
• 10 Dixon JB, Bhathal PS, Hughes NR, O'Brien PE. Nonalcoholic fatty liver disease: Improvement in liver histological analysis with weight loss. Hepatology 2004; 39 (6) 1647-1654
  CrossrefPubMedGoogle Scholar
• 11 Muretto P, Angelucci E, Lucarelli G. Reversibility of cirrhosis in patients cured of thalassemia by bone marrow transplantation. Ann Intern Med 2002; 136 (9) 667-672
  CrossrefPubMedGoogle Scholar
• 12 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 (6) 418-423
  CrossrefPubMedGoogle Scholar
• 13 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 (9865) 468-475
  CrossrefPubMedGoogle Scholar
• 14 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 (3) 886-893
  CrossrefPubMedGoogle Scholar
• 15 Shiffman ML, Sterling RK, Contos M , et al. Long term changes in liver histology following treatment of chronic hepatitis C virus. Ann Hepatol 2014; 13 (4) 340-349
  PubMedGoogle Scholar
• 16 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 (6) 399-403
  CrossrefPubMedGoogle Scholar
• 17 Nagula S, Jain D, Groszmann RJ, Garcia-Tsao G. Histological-hemodynamic correlation in cirrhosis-a histological classification of the severity of cirrhosis. J Hepatol 2006; 44 (1) 111-117
  CrossrefPubMedGoogle Scholar
• 18 Sethasine S, Jain D, Groszmann RJ, Garcia-Tsao G. Quantitative histological-hemodynamic correlations in cirrhosis. Hepatology 2012; 55 (4) 1146-1153
  CrossrefPubMedGoogle Scholar
• 19 Calvaruso V, Burroughs AK, Standish R , et al. Computer-assisted image analysis of liver collagen: relationship to Ishak scoring and hepatic venous pressure gradient. Hepatology 2009; 49 (4) 1236-1244
  CrossrefPubMedGoogle Scholar
• 20 Poynard T, Moussalli J, Munteanu M , et al; FibroFrance-GHPS group. Slow regression of liver fibrosis presumed by repeated biomarkers after virological cure in patients with chronic hepatitis C. J Hepatol 2013; 59 (4) 675-683
  CrossrefPubMedGoogle Scholar
• 21 Puche JE, Saiman Y, Friedman SL. Hepatic stellate cells and liver fibrosis. Compr Physiol 2013; 3 (4) 1473-1492
  PubMedGoogle Scholar
• 22 Reeves HL, Friedman SL. Activation of hepatic stellate cells—a key issue in liver fibrosis. Front Biosci 2002; 7: d808-d826
  CrossrefPubMedGoogle Scholar
• 23 Friedman SL. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 2008; 88 (1) 125-172
  CrossrefPubMedGoogle Scholar
• 24 Puche JE, Lee YA, Jiao J , et al. A novel murine model to deplete hepatic stellate cells uncovers their role in amplifying liver damage in mice. Hepatology 2013; 57 (1) 339-350
  CrossrefPubMedGoogle Scholar
• 25 Hernandez-Gea V, Friedman SL. Pathogenesis of liver fibrosis. Annu Rev Pathol 2011; 6: 425-456
  CrossrefPubMedGoogle Scholar
• 26 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 1992; 90 (1) 282-287
  CrossrefPubMedGoogle Scholar
• 27 Iredale JP. Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ. J Clin Invest 2007; 117 (3) 539-548
  CrossrefPubMedGoogle Scholar
• 28 Iredale JP. Tissue inhibitors of metalloproteinases in liver fibrosis. Int J Biochem Cell Biol 1997; 29 (1) 43-54
  CrossrefPubMedGoogle Scholar
• 29 Iredale J. Defining therapeutic targets for liver fibrosis: exploiting the biology of inflammation and repair. Pharmacol Res 2008; 58 (2) 129-136
  CrossrefPubMedGoogle Scholar
• 30 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
  PubMedGoogle Scholar
• 31 Benyon RC, Arthur MJP. Extracellular matrix degradation and the role of hepatic stellate cells. Semin Liver Dis 2001; 21 (3) 373-384
  Article in Thieme ConnectPubMedGoogle Scholar
• 32 Iredale JP, Thompson A, Henderson NC. Extracellular matrix degradation in liver fibrosis: Biochemistry and regulation. Biochim Biophys Acta 2013; 1832 (7) 876-883
  CrossrefPubMedGoogle Scholar
• 33 Hemmann S, Graf J, Roderfeld M, Roeb E. Expression of MMPs and TIMPs in liver fibrosis - a systematic review with special emphasis on anti-fibrotic strategies. J Hepatol 2007; 46 (5) 955-975
  CrossrefPubMedGoogle Scholar
• 34 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
  CrossrefPubMedGoogle Scholar
• 35 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 (4 Pt 1) 850-860
  CrossrefPubMedGoogle Scholar
• 36 Elsharkawy AM, Oakley F, Mann DA. The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis. Apoptosis 2005; 10 (5) 927-939
  CrossrefPubMedGoogle Scholar
• 37 Watson MR, Wallace K, Gieling RG , et al. NF-kappaB is a critical regulator of the survival of rodent and human hepatic myofibroblasts. J Hepatol 2008; 48 (4) 589-597
  CrossrefPubMedGoogle Scholar
• 38 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 (13) 11069-11076
  CrossrefPubMedGoogle Scholar
• 39 Murphy F, Waung J, Collins J , et al. N-Cadherin cleavage during activated hepatic stellate cell apoptosis is inhibited by tissue inhibitor of metalloproteinase-1. Comp Hepatol 2004; 3 (Suppl. 01) S8
  CrossrefPubMedGoogle Scholar
• 40 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
  CrossrefPubMedGoogle Scholar
• 41 Issa R, Zhou X, Trim N , et al. Mutation in collagen-1 that confers resistance to the action of collagenase results in failure of recovery from CCl4-induced liver fibrosis, persistence of activated hepatic stellate cells, and diminished hepatocyte regeneration. FASEB J 2003; 17 (1) 47-49
  PubMedGoogle Scholar
• 42 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 (5) 1849-1858
  CrossrefPubMedGoogle Scholar
• 43 Trim N, Morgan S, Evans M , et al. Hepatic stellate cells express the low affinity nerve growth factor receptor p75 and undergo apoptosis in response to nerve growth factor stimulation. Am J Pathol 2000; 156 (4) 1235-1243
  CrossrefPubMedGoogle Scholar
• 44 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 2009; 49 (3) 901-910
  CrossrefPubMedGoogle Scholar
• 45 Fischer R, Cariers A, Reinehr R, Häussinger D. Caspase 9-dependent killing of hepatic stellate cells by activated Kupffer cells. Gastroenterology 2002; 123 (3) 845-861
  CrossrefPubMedGoogle Scholar
• 46 Krizhanovsky V, Yon M, Dickins RA , et al. Senescence of activated stellate cells limits liver fibrosis. Cell 2008; 134 (4) 657-667
  CrossrefPubMedGoogle Scholar
• 47 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 2014; 1843 (5) 902-914
  CrossrefPubMedGoogle Scholar
• 48 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 2013; 33 (10) 2078-2090
  CrossrefPubMedGoogle Scholar
• 49 Kong X, Feng D, Wang H , et al. Interleukin-22 induces hepatic stellate cell senescence and restricts liver fibrosis in mice. Hepatology 2012; 56 (3) 1150-1159
  CrossrefPubMedGoogle Scholar
• 50 Klein S, Klösel 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 2012; 92 (10) 1440-1450
  CrossrefPubMedGoogle Scholar
• 51 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 2015; 62 (1) 18-23
  CrossrefPubMedGoogle Scholar
• 52 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
  CrossrefPubMedGoogle Scholar
• 53 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
  CrossrefPubMedGoogle Scholar
• 54 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
  CrossrefPubMedGoogle Scholar
• 55 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 2007; 178 (8) 5288-5295
  CrossrefPubMedGoogle Scholar
• 56 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
  CrossrefPubMedGoogle Scholar
• 57 Ide M, Kuwamura M, Kotani T, Sawamoto O, Yamate J. Effects of gadolinium chloride (GdCl(3)) on the appearance of macrophage populations and fibrogenesis in thioacetamide-induced rat hepatic lesions. J Comp Pathol 2005; 133 (2-3) 92-102
  CrossrefPubMedGoogle Scholar
• 58 Sunami Y, Leithäuser F, Gul S , et al. Hepatic activation of IKK/NFκB signaling induces liver fibrosis via macrophage-mediated chronic inflammation. Hepatology 2012; 56 (3) 1117-1128
  CrossrefPubMedGoogle Scholar
• 59 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
  CrossrefPubMedGoogle Scholar
• 60 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
  CrossrefPubMedGoogle Scholar
• 61 Wynn TA, Barron L. Macrophages: master regulators of inflammation and fibrosis. Semin Liver Dis 2010; 30 (3) 245-257
  Article in Thieme ConnectPubMedGoogle Scholar
• 62 Henderson NC, Mackinnon AC, Farnworth SL , et al. Galectin-3 expression and secretion links macrophages to the promotion of renal fibrosis. Am J Pathol 2008; 172 (2) 288-298
  CrossrefPubMedGoogle Scholar
• 63 Henderson NC, Mackinnon AC, Farnworth SL , et al. Galectin-3 regulates myofibroblast activation and hepatic fibrosis. Proc Natl Acad Sci U S A 2006; 103 (13) 5060-5065
  CrossrefPubMedGoogle Scholar
• 64 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 (10) e75361
  CrossrefPubMedGoogle Scholar
• 65 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 2010; 5 (6) e11049
  CrossrefPubMedGoogle Scholar
• 66 Liaskou E, Zimmermann HW, Li KK , et al. Monocyte subsets in human liver disease show distinct phenotypic and functional characteristics. Hepatology 2013; 57 (1) 385-398
  CrossrefPubMedGoogle Scholar
• 67 Preisser L, Miot C, Le Guillou-Guillemette H , et al. IL-34 and macrophage colony-stimulating factor are overexpressed in hepatitis C virus fibrosis and induce profibrotic macrophages that promote collagen synthesis by hepatic stellate cells. Hepatology 2014; 60 (6) 1879-1890
  CrossrefPubMedGoogle Scholar
• 68 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
  CrossrefPubMedGoogle Scholar
• 69 Gibbons MA, MacKinnon AC, Ramachandran P , et al. Ly6Chi monocytes direct alternatively activated profibrotic macrophage regulation of lung fibrosis. Am J Respir Crit Care Med 2011; 184 (5) 569-581
  CrossrefPubMedGoogle Scholar
• 70 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
  CrossrefPubMedGoogle Scholar
• 71 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
  CrossrefPubMedGoogle Scholar
• 72 Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol 2008; 8 (12) 958-969
  CrossrefPubMedGoogle Scholar
• 73 Tacke F, Zimmermann HW. Macrophage heterogeneity in liver injury and fibrosis. J Hepatol 2014; 60 (5) 1090-1096
  PubMedGoogle Scholar
• 74 Holt MP, Cheng L, Ju C. Identification and characterization of infiltrating macrophages in acetaminophen-induced liver injury. J Leukoc Biol 2008; 84 (6) 1410-1421
  CrossrefPubMedGoogle Scholar
• 75 Zigmond E, Samia-Grinberg S, Pasmanik-Chor M , et al. Infiltrating monocyte-derived macrophages and resident kupffer cells display different ontogeny and functions in acute liver injury. J Immunol 2014; 193 (1) 344-353
  CrossrefPubMedGoogle Scholar
• 76 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
  CrossrefPubMedGoogle Scholar
• 77 Schulz C, Gomez Perdiguero E, Chorro L , et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 2012; 336 (6077) 86-90
  CrossrefPubMedGoogle Scholar
• 78 Hashimoto D, Chow A, Noizat C , et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 2013; 38 (4) 792-804
  CrossrefPubMedGoogle Scholar
• 79 Seki E, de Minicis S, Inokuchi S , et al. CCR2 promotes hepatic fibrosis in mice. Hepatology 2009; 50 (1) 185-197
  CrossrefPubMedGoogle Scholar
• 80 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 2009; 174 (5) 1766-1775
  CrossrefPubMedGoogle Scholar
• 81 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
  CrossrefPubMedGoogle Scholar
• 82 Aoyama T, Inokuchi S, Brenner DA, Seki E. CX3CL1-CX3CR1 interaction prevents carbon tetrachloride-induced liver inflammation and fibrosis in mice. Hepatology 2010; 52 (4) 1390-1400
  CrossrefPubMedGoogle Scholar
• 83 Karlmark KR, Zimmermann HW, Roderburg C , et al. The fractalkine receptor CX3CR1 protects against liver fibrosis by controlling differentiation and survival of infiltrating hepatic monocytes. Hepatology 2010; 52 (5) 1769-1782
  CrossrefPubMedGoogle Scholar
• 84 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
  CrossrefPubMedGoogle Scholar
• 85 Yoshiji H, Kuriyama S, Yoshii J , et al. Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic fibrogenesis. Gut 2003; 52 (9) 1347-1354
  CrossrefPubMedGoogle Scholar
• 86 Rosmorduc O. Antiangiogenic therapies in portal hypertension: a breakthrough in hepatology. Gastroenterol Clin Biol 2010; 34 (8-9) 446-449
  CrossrefPubMedGoogle Scholar
• 87 Sahin H, Borkham-Kamphorst E, Kuppe C , et al. Chemokine Cxcl9 attenuates liver fibrosis-associated angiogenesis in mice. Hepatology 2012; 55 (5) 1610-1619
  CrossrefPubMedGoogle Scholar
• 88 Iredale JP, Bataller R. Identifying molecular factors that contribute to resolution of liver fibrosis. Gastroenterology 2014; 146 (5) 1160-1164
  CrossrefPubMedGoogle Scholar
• 89 Jiao J, Sastre D, Fiel MI , et al. Dendritic cell regulation of carbon tetrachloride-induced murine liver fibrosis regression. Hepatology 2012; 55 (1) 244-255
  CrossrefPubMedGoogle Scholar
• 90 Hume DA. Macrophages as APC and the dendritic cell myth. J Immunol 2008; 181 (9) 5829-5835
  CrossrefPubMedGoogle Scholar
• 91 Kubes P, Mehal WZ. Sterile inflammation in the liver. Gastroenterology 2012; 143 (5) 1158-1172
  CrossrefPubMedGoogle Scholar
• 92 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
  CrossrefPubMedGoogle Scholar
• 93 Harty MW, Muratore CS, Papa EF , et al. Neutrophil depletion blocks early collagen degradation in repairing cholestatic rat livers. Am J Pathol 2010; 176 (3) 1271-1281
  CrossrefPubMedGoogle Scholar
• 94 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
  CrossrefPubMedGoogle Scholar
• 95 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 (1) 60-71
  CrossrefPubMedGoogle Scholar
• 96 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 (1) 248-258
  CrossrefPubMedGoogle Scholar
• 97 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 2011; 53 (4) 1342-1351
  CrossrefPubMedGoogle Scholar
• 98 Glässner A, Eisenhardt M, Krämer B , et al. NK cells from HCV-infected patients effectively induce apoptosis of activated primary human hepatic stellate cells in a TRAIL-, FasL- and NKG2D-dependent manner. Lab Invest 2012; 92 (7) 967-977
  CrossrefPubMedGoogle Scholar
• 99 Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol 2008; 214 (2) 199-210
  CrossrefPubMedGoogle Scholar
• 100 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
  CrossrefPubMedGoogle Scholar
• 101 Katz SC, Ryan K, Ahmed N , et al. Obstructive jaundice expands intrahepatic regulatory T cells, which impair liver T lymphocyte function but modulate liver cholestasis and fibrosis. J Immunol 2011; 187 (3) 1150-1156
  CrossrefPubMedGoogle Scholar
• 102 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 2010; 52 (3) 315-321
  CrossrefPubMedGoogle Scholar
• 103 Hammerich L, Bangen JM, Govaere O , et al. Chemokine receptor CCR6-dependent accumulation of γδ T cells in injured liver restricts hepatic inflammation and fibrosis. Hepatology 2014; 59 (2) 630-642
  CrossrefPubMedGoogle Scholar
• 104 Desmet VJ, Roskams T. Cirrhosis reversal: a duel between dogma and myth. J Hepatol 2004; 40 (5) 860-867
  CrossrefPubMedGoogle Scholar
• 105 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
  CrossrefPubMedGoogle Scholar
• 106 Wanless IR, Nakashima E, Sherman M. Regression of human cirrhosis. Morphologic features and the genesis of incomplete septal cirrhosis. Arch Pathol Lab Med 2000; 124 (11) 1599-1607
  PubMedGoogle Scholar
• 107 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
  CrossrefPubMedGoogle Scholar
• 108 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
  CrossrefPubMedGoogle Scholar
• 109 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
  CrossrefPubMedGoogle Scholar
• 110 Fernández M, Semela D, Bruix J, Colle I, Pinzani M, Bosch J. Angiogenesis in liver disease. J Hepatol 2009; 50 (3) 604-620
  CrossrefPubMedGoogle Scholar
• 111 Hall A, Germani G, Isgrò G, Burroughs AK, Dhillon AP. Fibrosis distribution in explanted cirrhotic livers. Histopathology 2012; 60 (2) 270-277
  CrossrefPubMedGoogle Scholar
• 112 Marshall A, Rushbrook S, Davies SE , et al. Relation between hepatocyte G1 arrest, impaired hepatic regeneration, and fibrosis in chronic hepatitis C virus infection. Gastroenterology 2005; 128 (1) 33-42
  CrossrefPubMedGoogle Scholar
• 113 Lorenzini S, Bird TG, Boulter L , et al. Characterisation of a stereotypical cellular and extracellular adult liver progenitor cell niche in rodents and diseased human liver. Gut 2010; 59 (5) 645-654
  CrossrefPubMedGoogle Scholar
• 114 Kallis YN, Robson AJ, Fallowfield JA , et al. Remodelling of extracellular matrix is a requirement for the hepatic progenitor cell response. Gut 2011; 60 (4) 525-533
  CrossrefPubMedGoogle Scholar
• 115 Boulter L, Govaere O, Bird TG , et al. Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nat Med 2012; 18 (4) 572-579
  CrossrefPubMedGoogle Scholar
• 116 Bird TG, Lu WY, Boulter L , et al. Bone marrow injection stimulates hepatic ductular reactions in the absence of injury via macrophage-mediated TWEAK signaling. Proc Natl Acad Sci U S A 2013; 110 (16) 6542-6547
  CrossrefPubMedGoogle Scholar
• 117 Kundu AK, Nagaoka M, Chowdhury EH, Hirose S, Sasagawa T, Akaike T. IGF-1 induces growth, survival and morphological change of primary hepatocytes on a galactose-bared polymer through both MAPK and beta-catenin pathways. Cell Struct Funct 2003; 28 (4) 255-263
  CrossrefPubMedGoogle Scholar
• 118 Desbois-Mouthon C, Wendum D, Cadoret A , et al. Hepatocyte proliferation during liver regeneration is impaired in mice with liver-specific IGF-1R knockout. FASEB J 2006; 20 (6) 773-775
  PubMedGoogle Scholar
• 119 Ebrahimkhani MR, Oakley F, Murphy LB , et al. Stimulating healthy tissue regeneration by targeting the 5-HT₂B receptor in chronic liver disease. Nat Med 2011; 17 (12) 1668-1673
  CrossrefPubMedGoogle Scholar
• 120 Kim JK, Ma DW, Lee KS, Paik YH. Assessment of hepatic fibrosis regression by transient elastography in patients with chronic hepatitis B treated with oral antiviral agents. J Korean Med Sci 2014; 29 (4) 570-575
  CrossrefPubMedGoogle Scholar
• 121 Leeming DJ, Byrjalsen I, Jiménez W, Christiansen C, Karsdal MA. Protein fingerprinting of the extracellular matrix remodelling in a rat model of liver fibrosis—a serological evaluation. Liver Int 2013; 33 (3) 439-447
  CrossrefPubMedGoogle Scholar
• 122 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 2013; 38 (9) 1086-1096
  CrossrefPubMedGoogle Scholar
• 123 Fuchs BC, Wang H, Yang Y , et al. Molecular MRI of collagen to diagnose and stage liver fibrosis. J Hepatol 2013; 59 (5) 992-998
  CrossrefPubMedGoogle Scholar
• 124 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 2013; 48 (1) 46-54
  CrossrefPubMedGoogle Scholar
• 125 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
  CrossrefPubMedGoogle Scholar
• 126 Ruddell RG, Oakley F, Hussain Z , et al. A role for serotonin (5-HT) in hepatic stellate cell function and liver fibrosis. Am J Pathol 2006; 169 (3) 861-876
  CrossrefPubMedGoogle Scholar
• 127 Forbes SJ, Newsome PN. New horizons for stem cell therapy in liver disease. J Hepatol 2012; 56 (2) 496-499
  CrossrefPubMedGoogle Scholar
• 128 Thomas JA, Pope C, Wojtacha D , et al. Macrophage therapy for murine liver fibrosis recruits host effector cells improving fibrosis, regeneration, and function. Hepatology 2011; 53 (6) 2003-2015
  CrossrefPubMedGoogle Scholar
• 129 Ratziu V, Bedossa P, Francque SM , et al. Lack of efficacy of an inhibitor of PDE4 in phase 1 and 2 trials of patients with nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2014; 12 (10) 1724-30.e5
  CrossrefPubMedGoogle Scholar
• 130 Habens F, Srinivasan N, Oakley F, Mann DA, Ganesan A, Packham G. Novel sulfasalazine analogues with enhanced NF-kB inhibitory and apoptosis promoting activity. Apoptosis 2005; 10 (3) 481-491
  CrossrefPubMedGoogle Scholar
• 131 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 (6) 671-676
  CrossrefPubMedGoogle Scholar
• 132 Cong M, Liu T, Wang P , et al. Antifibrotic effects of a recombinant adeno-associated virus carrying small interfering RNA targeting TIMP-1 in rat liver fibrosis. Am J Pathol 2013; 182 (5) 1607-1616
  CrossrefPubMedGoogle Scholar
• 133 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 (5) 1106-1115
  CrossrefPubMedGoogle Scholar
• 134 Roderfeld M, Weiskirchen R, Wagner S , et al. Inhibition of hepatic fibrogenesis by matrix metalloproteinase-9 mutants in mice. FASEB J 2006; 20 (3) 444-454
  CrossrefPubMedGoogle Scholar
• 135 Roeb E, Behrmann I, Grötzinger J, Breuer B, Matern S. An MMP-9 mutant without gelatinolytic activity as a novel TIMP-1-antagonist. FASEB J 2000; 14 (12) 1671-1673
  PubMedGoogle Scholar
• 136 Arabpour M, Poelstra K, Helfrich W, Bremer E, Haisma HJ. Targeted elimination of activated hepatic stellate cells by an anti-epidermal growth factor-receptor single chain fragment variable antibody-tumor necrosis factor-related apoptosis-inducing ligand (scFv425-sTRAIL). J Gene Med 2014; 16 (9-10) 281-290
  PubMedGoogle Scholar
• 137 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 (4) 431-442
  CrossrefPubMedGoogle Scholar
• 138 Douglass A, Wallace K, Parr R , et al. Antibody-targeted myofibroblast apoptosis reduces fibrosis during sustained liver injury. J Hepatol 2008; 49 (1) 88-98
  CrossrefPubMedGoogle Scholar
• 139 Yang MD, Chiang YM, Higashiyama R , et al. Rosmarinic acid and baicalin epigenetically derepress peroxisomal proliferator-activated receptor γ in hepatic stellate cells for their antifibrotic effect. Hepatology 2012; 55 (4) 1271-1281
  CrossrefPubMedGoogle Scholar
• 140 Zhang S, Wang J, Liu Q, Harnish DC. Farnesoid X receptor agonist WAY-362450 attenuates liver inflammation and fibrosis in murine model of non-alcoholic steatohepatitis. J Hepatol 2009; 51 (2) 380-388
  CrossrefPubMedGoogle Scholar
• 141 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 (2) 584-595
  CrossrefPubMedGoogle Scholar
• 142 Kim EJ, Cho HJ, Park D , et al. Antifibrotic effect of MMP13-encoding plasmid DNA delivered using polyethylenimine shielded with hyaluronic acid. Mol Ther 2011; 19 (2) 355-361
  CrossrefPubMedGoogle Scholar
• 143 Siller-López F, Sandoval A, Salgado S , et al. Treatment with human metalloproteinase-8 gene delivery ameliorates experimental rat liver cirrhosis. Gastroenterology 2004; 126 (4) 1122-1133 , discussion 949
  CrossrefPubMedGoogle Scholar
• 144 Popov Y, Patsenker E, Bauer M, Niedobitek E, Schulze-Krebs A, Schuppan D. Halofuginone induces matrix metalloproteinases in rat hepatic stellate cells via activation of p38 and NFkappaB. J Biol Chem 2006; 281 (22) 15090-15098
  CrossrefPubMedGoogle Scholar
• 145 Fürst G, Schulte am Esch J, Poll LW , et al. Portal vein embolization and autologous CD133+ bone marrow stem cells for liver regeneration: initial experience. Radiology 2007; 243 (1) 171-179
  CrossrefPubMedGoogle Scholar
• 146 Wang J, Zhou X, Cui L , et al. The significance of CD14+ monocytes in peripheral blood stem cells for the treatment of rat liver cirrhosis. Cytotherapy 2010; 12 (8) 1022-1034
  CrossrefPubMedGoogle Scholar
• 147 Wasmuth HE, Lammert F, Zaldivar MM , et al. Antifibrotic effects of CXCL9 and its receptor CXCR3 in livers of mice and humans. Gastroenterology 2009; 137 (1) 309-319 , 319.e1–319.e3
  CrossrefPubMedGoogle Scholar