title: Evolving therapies for liver fibrosis.
abstract: Fibrosis is an intrinsic response to chronic injury, maintaining organ integrity when extensive necrosis or apoptosis occurs. With protracted damage, fibrosis can progress toward excessive scarring and organ failure, as in liver cirrhosis. To date, antifibrotic treatment of fibrosis represents an unconquered area for drug development, with enormous potential but also high risks. Preclinical research has yielded numerous targets for antifibrotic agents, some of which have entered early-phase clinical studies, but progress has been hampered due to the relative lack of sensitive and specific biomarkers to measure fibrosis progression or reversal. Here we focus on antifibrotic approaches for liver that address specific cell types and functional units that orchestrate fibrotic wound healing responses and have a sound preclinical database or antifibrotic activity in early clinical trials. We also touch upon relevant clinical study endpoints, optimal study design, and developments in fibrosis imaging and biomarkers.
authors: Institute of Molecular and Translational Medicine and Department of Medicine I, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany. detlef.schuppan@unimedizin-mainz.de
authors: Detlef
authors: D
authors: Schuppan
authors: Yong Ook
authors: YO
authors: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D018450:Disease Progression; D005355:Fibrosis; D055166:Hepatic Stellate Cells / Q000166:cytology; D022781:Hepatocytes / Q000166:cytology; D006801:Humans; D007249:Inflammation; D008099:Liver / Q000293:injuries; D008103:Liver Cirrhosis / Q000473:pathology* / Q000628:therapy*; D008107:Liver Diseases; D008264:Macrophages / Q000166:cytology; D051379:Mice; D009000:Monocytes / Q000166:cytology; D058628:Myofibroblasts / Q000166:cytology; D013234:Stem Cells / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology; D014945:Wound Healing
chemical_list: D015415:Biomarkers
references: Lancet. 2008 Mar 8;371(9615):838-51
references: 18328931
references: Hepatology. 2010 Apr;51(4):1345-53
references: 20162727
references: Am J Physiol Gastrointest Liver Physiol. 2011 May;300(5):G709-15
references: 21233278
references: Hepatology. 2011 Oct;54(4):1454-62
references: 21725995
references: Nat Med. 2010 Sep;16(9):1009-17
references: 20818376
references: Gastroenterology. 2008 May;134(5):1532-43
references: 18471524
references: Gastroenterology. 2011 Nov;141(5):1572-85
references: 21920463
references: J Hepatol. 2010 Nov;53(5):976-80
references: 20800926
references: Gastroenterology. 2009 Jul;137(1):309-19, 319.e1-3
references: 19344719
references: J Hepatol. 2011 May;54(5):1011-9
references: 21145828
references: Connect Tissue Res. 2012;53(3):187-96
references: 22329637
references: Physiol Rev. 2006 Apr;86(2):515-81
references: 16601268
references: Nat Biotechnol. 2008 Apr;26(4):431-42
references: 18376398
references: Hepatology. 2003 Oct;38(4):859-68
references: 14512873
references: J Hepatol. 2001 Dec;35(6):749-55
references: 11738102
references: J Clin Gastroenterol. 2005 Apr;39(4 Suppl 2):S158-61
references: 15758652
references: Front Physiol. 2012 May 22;3:138
references: 22661952
references: Gastroenterology. 2007 Jul;133(1):80-90
references: 17631134
references: Nature. 1995 Aug 17;376(6541):594-6
references: 7637808
references: Hepatol Res. 2010 Nov;40(11):1128-41
references: 20880061
references: Lung. 2012 Oct;190(5):523-7
references: 22810758
references: N Engl J Med. 2008 Dec 4;359(23):2429-41
references: 19052125
references: N Engl J Med. 2005 Nov 24;353(21):2229-42
references: 16306520
references: Semin Liver Dis. 2010 Aug;30(3):215-25
references: 20665374
references: Gastroenterology. 2008 May;134(6):1655-69
references: 18471545
references: Hepatology. 2009 Oct;50(4):1294-306
references: 19711424
references: World J Gastroenterol. 2002 Aug;8(4):679-85
references: 12174378
references: Am J Pathol. 2012 Apr;180(4):1340-55
references: 22387320
references: Hepatology. 2007 Dec;46(6):1919-26
references: 17935226
references: Curr Drug Targets. 2006 May;7(5):567-77
references: 16719767
references: Gut. 2010 Oct;59(10):1401-9
references: 20675691
references: Am J Physiol Gastrointest Liver Physiol. 2011 Apr;300(4):G516-25
references: 21252049
references: Semin Liver Dis. 2001 Aug;21(3):351-72
references: 11586465
references: Hepatology. 2009 Jul;50(1):261-74
references: 19554540
references: Gastroenterology. 2012 Sep;143(3):765-776.e3
references: 22687286
references: Hepatology. 2008 Nov;48(5):1549-57
references: 18846542
references: Hepatology. 2006 Feb;43(2 Suppl 1):S82-8
references: 16447275
references: Hepatology. 2009 May;49(5):1683-94
references: 19205035
references: Recent Pat Anticancer Drug Discov. 2012 Sep;7(3):251-64
references: 22376154
references: Hepatology. 2010 Nov;52(5):1769-82
references: 21038415
references: J Hepatol. 2006 Mar;44(3):462-74
references: 16427156
references: Hepatology. 2007 Aug;46(2):297-306
references: 17461418
references: J Hepatol. 2012 May;56(5):1171-1180
references: 22245903
references: J Hepatol. 2012 Nov;57(5):1144-6
references: 22878465
references: Biochim Biophys Acta. 2013 Jul;1832(7):1061-9
references: 23022478
references: Immunity. 2012 Sep 21;37(3):574-87
references: 22981538
references: J Immunother. 2011 Nov-Dec;34(9):611-28
references: 21989410
references: J Hepatol. 2013 Jun;58(6):1252-3
references: 23336979
references: J Transl Med. 2011 Jan 27;9 Suppl 1:S9
references: 21284908
references: Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9448-53
references: 22566629
references: Mucosal Immunol. 2009 Mar;2(2):103-21
references: 19129758
references: Gut. 2012 Sep;61(9):1323-9
references: 22427237
references: Gastroenterology. 2012 Jun;142(7):1431-43
references: 22504185
references: Hepatology. 2010 Nov;52(5):1836-46
references: 21038418
references: Nat Rev Immunol. 2009 Mar;9(3):162-74
references: 19197294
references: N Engl J Med. 2006 Nov 30;355(22):2297-307
references: 17135584
references: PLoS One. 2011;6(9):e23943
references: 21912653
references: Semin Liver Dis. 2010 Aug;30(3):226-31
references: 20665375
references: Hepatogastroenterology. 2003 Nov-Dec;50(54):2017-21
references: 14696456
references: J Biol Chem. 2006 Jun 2;281(22):15090-8
references: 16489207
references: Am J Physiol Gastrointest Liver Physiol. 2011 May;300(5):G697-702
references: 21350183
references: J Hepatol. 2008 Mar;48(3):453-64
references: 18221819
references: Lancet. 2013 Feb 9;381(9865):468-75
references: 23234725
references: J Clin Invest. 2009 Jul;119(7):1858-70
references: 19603542
references: J Hepatol. 2012 Dec;57(6):1220-7
references: 22878469
references: Nat Rev Drug Discov. 2012 Oct;11(10):763-76
references: 23023676
references: Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4329-34
references: 20142499
references: J Hepatol. 2011 Sep;55(3):726-728
references: 21601600
references: J Pharmacol Exp Ther. 2004 Mar;308(3):1191-6
references: 14617689
references: Hepatology. 2013 Jan;57(1):339-50
references: 22961591
references: Gastroenterology. 2010 Oct;139(4):1375-84
references: 20685364
references: Hepatology. 2006 Apr;43(4):771-9
references: 16557547
references: Hepatology. 2007 Nov;46(5):1404-12
references: 17924447
references: Gastroenterology. 2010 Sep;139(3):722-5
references: 20682361
references: J Pharmacol Exp Ther. 2007 Jun;321(3):856-65
references: 17369283
references: Semin Liver Dis. 2010 Aug;30(3):245-57
references: 20665377
references: Biochem Biophys Res Commun. 2011 Aug 19;412(1):74-9
references: 21798245
references: Hepatology. 2011 Aug;54(2):573-85
references: 21567441
references: Hepatology. 2009 Nov;50(5):1501-11
references: 19725105
references: Gastroenterology. 2009 Oct;137(4):1478-1488.e8
references: 19577569
references: Trends Pharmacol Sci. 2012 Jul;33(7):405-12
references: 22633092
references: Nat Rev Gastroenterol Hepatol. 2010 Aug;7(8):425-36
references: 20585339
references: N Engl J Med. 2011 Sep 22;365(12):1079-87
references: 21992121
references: Am J Physiol Gastrointest Liver Physiol. 2009 Oct;297(4):G726-34
references: 19628656
references: J Clin Invest. 2010 Nov;120(11):4129-40
references: 20978355
references: J Hepatol. 2013 Jul;59(1):183-5
references: 23353868
references: Hepatology. 2012 May;55(5):1610-9
references: 22237831
references: Hepatology. 2000 Dec;32(6):1196-9
references: 11093724
references: J Cell Physiol. 2013 May;228(5):1108-19
references: 23065814
references: Eur Rev Med Pharmacol Sci. 2004 Jan-Feb;8(1):33-46
references: 15209153
references: Nat Rev Immunol. 2011 Oct 14;11(11):723-37
references: 21997792
references: Gastroenterology. 2012 May;142(6):1293-1302.e4
references: 22537436
references: Annu Rev Physiol. 2010;72:219-46
references: 20148674
references: Arthritis Res Ther. 2012 Oct 23;14(5):R229
references: 23092446
references: Gastroenterology. 2008 May;134(6):1670-81
references: 18471546
references: Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):1864-9
references: 20080679
references: Hepatology. 2011 Apr;53(4):1342-51
references: 21480338
references: Proc Natl Acad Sci U S A. 2008 Aug 19;105(33):11915-20
references: 18695239
references: Nat Biotechnol. 2013 Jan;31(1):63-70
references: 23242163
references: Am J Gastroenterol. 2005 Sep;100(9):1970-80
references: 16128941
references: J Exp Med. 2010 Mar 15;207(3):535-52
references: 20176803
references: Gut. 2010 May;59(5):655-65
references: 20427400
references: Immunity. 2010 May 28;32(5):593-604
references: 20510870
references: Hepatology. 2011 Aug;54(2):586-96
references: 21538439
references: J Clin Invest. 2008 Oct;118(10):3331-42
references: 18802480
references: Sci Transl Med. 2013 Jan 9;5(167):167sr1
references: 23303606
references: Liver Int. 2007 Mar;27(2):247-59
references: 17311621
references: N Engl J Med. 2010 May 6;362(18):1675-85
references: 20427778
references: Gastroenterology. 2008 Aug;135(2):660-70
references: 18538673
references: J Hepatol. 2012 Apr;56(4):965-72
references: 22173163
references: Gastroenterology. 2007 Aug;133(2):481-8
references: 17681169
references: J Investig Dermatol Symp Proc. 2006 Sep;11(1):66-72
references: 17069012
references: J Hepatol. 2012;56 Suppl 1:S66-74
references: 22300467
references: Am J Respir Crit Care Med. 2012 Jul 1;186(1):88-95
references: 22561965
references: Am J Gastroenterol. 2003 Nov;98(11):2485-90
references: 14638353
references: Semin Immunopathol. 2009 Sep;31(3):345-58
references: 19533130
references: Gut. 2010 Sep;59(9):1245-51
references: 20675693
references: Nat Med. 2007 Nov;13(11):1324-32
references: 17952090
references: Proc Natl Acad Sci U S A. 2012 Nov 13;109(46):E3186-95
references: 23100531
references: Am J Physiol Gastrointest Liver Physiol. 2011 May;300(5):G723-8
references: 21292997
references: J Hepatol. 2013 May;58(5):1028-41
references: 23262248
references: Hepatology. 2011 Nov;54(5):1610-9
references: 21748765
references: Gastroenterology. 2012 Oct;143(4):1073-83.e22
references: 22750464
references: Semin Liver Dis. 2008 Nov;28(4):360-9
references: 18956292
references: Ann Intern Med. 1997 Dec 1;127(11):981-5
references: 9412303
references: Lancet. 2011 May 21;377(9779):1760-9
references: 21571362
references: J Pediatr Gastroenterol Nutr. 2008 Jan;46(1):65-70
references: 18162836
references: Hepatology. 2012 Sep;56(3):1053-62
references: 22473911
references: N Engl J Med. 1991 May 30;324(22):1548-54
references: 1674105
references: Gastroenterology. 2002 May;122(5):1303-13
references: 11984517
references: Hepatology. 2012 Dec;56(6):2125-33
references: 22767302
references: Clin Liver Dis. 2012 Aug;16(3):549-65
references: 22824480
references: J Am Soc Nephrol. 2001 Jul;12(7):1448-1457
references: 11423573
references: PLoS One. 2011 Jan 24;6(1):e16081
references: 21283674
references: Eur Respir J. 2010 Apr;35(4):821-9
references: 19996196
references: Hepatology. 2010 Feb;51(2):445-53
references: 19877169
references: Hepatology. 2011 Jan;53(1):325-35
references: 21254180
references: Gastroenterology. 2011 Dec;141(6):2200-9
references: 21864478
references: Nat Med. 2011 Mar;17(3):383-8
references: 21336283
references: Drug News Perspect. 2010 Jun;23(5):305-15
references: 20603654
references: Cochrane Database Syst Rev. 2010 Jan 20;(1):CD007340
references: 20091629
references: Gastroenterology. 2011 May;140(5):1642-52
references: 21277850
references: J Clin Invest. 2003 Jul;112(2):152-9
references: 12865404
references: Gastroenterology. 2012 Sep;143(3):536-539
references: 22842060
references: Gastroenterology. 2004 Jun;126(7):1795-808
references: 15188175
references: Gastroenterology. 2008 Oct;135(4):1176-84
references: 18718471
references: J Hepatol. 2012 Feb;56(2):496-9
references: 21798218
references: Liver Int. 2012 Jul;32(6):977-87
references: 22364262
references: Gastroenterology. 2008 Jul;135(1):32-40
references: 18471441
references: J Hepatol. 2006 Jan;44(1):167-75
references: 16168515
references: J Hepatol. 2009 Jul;51(1):139-48
references: 19457567
references: Expert Rev Anti Infect Ther. 2011 May;9(5):507-20
references: 21609262
references: Am J Physiol Gastrointest Liver Physiol. 2010 Mar;298(3):G323-34
references: 20056896
references: Gastroenterology. 2010 Apr;138(4):1365-73, 1373.e1-2
references: 20004661
references: Connect Tissue Res. 2009;50(2):98-109
references: 19296301
references: Hepatology. 2010 Apr;51(4):1438-44
references: 20209607
references: Front Physiol. 2012 Jun 20;3:213
references: 22723782
references: Curr Pharm Des. 2009;15(12):1318-33
references: 19355971
references: Biochem Biophys Res Commun. 2008 Nov 14;376(2):271-6
references: 18760996
references: Am J Respir Crit Care Med. 2010 Mar 15;181(6):604-10
references: 20007927
references: Hepatology. 2011 Nov;54(5):1631-9
references: 21748770
references: J Exp Med. 2001 Sep 17;194(6):809-21
references: 11560996
references: Hepatology. 2007 Mar;45(3):569-78
references: 17326152
references: PLoS One. 2010 Jun 10;5(6):e11049
references: 20548789
references: Nat Med. 2012 Jul 06;18(7):1028-40
references: 22772564
references: Am J Physiol Gastrointest Liver Physiol. 2011 Sep;301(3):G425-34
references: 21659620
references: J Clin Invest. 2009 Mar;119(3):582-94
references: 19221436
references: Am J Respir Crit Care Med. 2008 Nov 1;178(9):948-55
references: 18669816