title: Role of NADPH oxidases in liver fibrosis.
abstract: CONCLUSIONS
  Hepatic fibrosis is the common pathophysiologic process resulting from chronic liver injury, characterized by the accumulation of an excessive extracellular matrix. Multiple lines of evidence indicate that oxidative stress plays a pivotal role in the pathogenesis of liver fibrosis. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) is a multicomponent enzyme complex that generates reactive oxygen species (ROS) in response to a wide range of stimuli. In addition to phagocytic NOX2, there are six nonphagocytic NOX proteins.
  
  
  BACKGROUND
  In the liver, NOX is functionally expressed both in the phagocytic form and in the nonphagocytic form. NOX-derived ROS contributes to various kinds of liver disease caused by alcohol, hepatitis C virus, and toxic bile acids. Recent evidence indicates that both phagocytic NOX2 and nonphagocytic NOX isoforms, including NOX1 and NOX4, mediate distinct profibrogenic actions in hepatic stellate cells, the main fibrogenic cell type in the liver. The critical role of NOX in hepatic fibrogenesis provides a rationale to assess pharmacological NOX inhibitors that treat hepatic fibrosis in patients with chronic liver disease.
  
  
  RESULTS
  Although there is compelling evidence indicating a crucial role for NOX-mediated ROS generation in hepatic fibrogenesis, little is known about the expression, subcellular localization, regulation, and redox signaling of NOX isoforms in specific cell types in the liver. Moreover, the exact mechanism of NOX-mediated fibrogenic signaling is still largely unknown.
  
  
  CONCLUSIONS
  A better understanding through further research about NOX-mediated fibrogenic signaling may enable the development of novel anti-fibrotic therapy using NOX inhibition strategy. Antio
authors.affiliation: 1 Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine , Seoul, Korea.
authors.forename: Yong-Han
authors.initials: YH
authors.lastname: Paik
authors.forename: Jonghwa
authors.initials: J
authors.lastname: Kim
authors.forename: Tomonori
authors.initials: T
authors.lastname: Aoyama
authors.forename: Samuele
authors.initials: S
authors.lastname: De Minicis
authors.forename: Ramon
authors.initials: R
authors.lastname: Bataller
authors.forename: David A
authors.initials: DA
authors.lastname: Brenner
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008103:Liver Cirrhosis / Q000201:enzymology / Q000473:pathology*; D019255:NADPH Oxidases / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D017382:Reactive Oxygen Species; D000804:Angiotensin II; D019255:NADPH Oxidases
references.citation: Proc Am Thorac Soc. 2006 Jul;3(5):413-7
references.pmid: 16799084
references.citation: Liver Int. 2010 Aug;30(7):1049-58
references.pmid: 20492512
references.citation: Cell Mol Life Sci. 2012 Jul;69(14):2365-71
references.pmid: 22618245
references.citation: Gastroenterology. 1999 Sep;117(3):669-77
references.pmid: 10464144
references.citation: Oncogene. 2006 Oct 30;25(51):6731-48
references.pmid: 17072325
references.citation: Hepatology. 2012 Dec;56(6):2316-27
references.pmid: 22806357
references.citation: FEBS J. 2010 Jul;277(13):2830-7
references.pmid: 20528914
references.citation: J Neurol. 2011 May;258(5):762-9
references.pmid: 21108037
references.citation: World J Gastroenterol. 2005 Dec 28;11(48):7560-3
references.pmid: 16437678
references.citation: J Cell Biol. 2008 Jun 30;181(7):1129-39
references.pmid: 18573911
references.citation: Lab Invest. 2004 Feb;84(2):153-9
references.pmid: 14688800
references.citation: J Clin Invest. 2008 Feb;118(2):659-70
references.pmid: 18219391
references.citation: J Hepatol. 2001 Dec;35(6):749-55
references.pmid: 11738102
references.citation: Gastroenterology. 2007 Feb;132(2):687-97
references.pmid: 17258719
references.citation: Front Physiol. 2012 May 22;3:138
references.pmid: 22661952
references.citation: Int J Hepatol. 2012;2012:158547
references.pmid: 22973518
references.citation: Am J Physiol. 1996 Oct;271(4 Pt 2):H1626-34
references.pmid: 8897960
references.citation: Hepatology. 2001 Sep;34(3):548-56
references.pmid: 11526541
references.citation: Cancer Res. 2009 Oct 1;69(19):7595-602
references.pmid: 19773433
references.citation: Gastroenterology. 2008 May;134(6):1655-69
references.pmid: 18471545
references.citation: J Hepatol. 2010 Mar;52(3):389-97
references.pmid: 20133001
references.citation: J Biol Chem. 2005 Jul 22;280(29):27179-94
references.pmid: 15917250
references.citation: Antioxid Redox Signal. 2009 Oct;11(10):2535-52
references.pmid: 19309261
references.citation: J Biol Chem. 2008 Dec 12;283(50):35273-82
references.pmid: 18849343
references.citation: Free Radic Biol Med. 2012 Jul 15;53(2):289-96
references.pmid: 22618020
references.citation: Am J Physiol Renal Physiol. 2010 Dec;299(6):F1348-58
references.pmid: 20630933
references.citation: J Biol Chem. 2001 Jun 22;276(25):23077-83
references.pmid: 11304537
references.citation: Medicine (Baltimore). 2000 May;79(3):170-200
references.pmid: 10844936
references.citation: J Clin Invest. 2003 Nov;112(9):1383-94
references.pmid: 14597764
references.citation: Int J Oncol. 2010 Jun;36(6):1581-9
references.pmid: 20428783
references.citation: J Virol. 2009 Dec;83(24):12934-46
references.pmid: 19812163
references.citation: J Biol Chem. 2000 Jun 30;275(26):20136-45
references.pmid: 10770928
references.citation: J Clin Invest. 1995 Nov;96(5):2461-8
references.pmid: 7593635
references.citation: Circ Res. 2002 Mar 8;90(4):E58-65
references.pmid: 11884382
references.citation: Thorax. 2010 Aug;65(8):733-8
references.pmid: 20685750
references.citation: Gastroenterology. 2003 Mar;124(3):778-90
references.pmid: 12612915
references.citation: Mol Cell Biol. 2010 Feb;30(4):961-75
references.pmid: 19995913
references.citation: Circ Res. 2009 Jul 31;105(3):249-59
references.pmid: 19574552
references.citation: Hepatology. 2008 Jul;48(1):322-35
references.pmid: 18506843
references.citation: Am J Physiol. 1996 Nov;271(5 Pt 1):C1424-37
references.pmid: 8944624
references.citation: Antioxid Redox Signal. 2009 Jun;11(6):1289-99
references.pmid: 18999986
references.citation: Hepatology. 2002 Oct;36(4 Pt 1):1022
references.pmid: 12297856
references.citation: J Biol Chem. 2003 Feb 7;278(6):3510-3
references.pmid: 12473664
references.citation: Gastroenterology. 2000 Jun;118(6):1149-56
references.pmid: 10833490
references.citation: Gastroenterology. 2002 Feb;122(2):352-65
references.pmid: 11832450
references.citation: J Submicrosc Cytol Pathol. 1992 Apr;24(2):193-203
references.pmid: 1600511
references.citation: Free Radic Biol Med. 1997;22(1-2):287-305
references.pmid: 8958154
references.citation: Dig Dis Sci. 2011 Feb;56(2):564-8
references.pmid: 21136163
references.citation: J Immunol. 2002 Apr 15;168(8):3974-82
references.pmid: 11937554
references.citation: J Hepatol. 2001 Aug;35(2):297-306
references.pmid: 11580156
references.citation: Circ Res. 2001 May 11;88(9):888-94
references.pmid: 11348997
references.citation: Alcohol Clin Exp Res. 2003 Nov;27(11):1765-72
references.pmid: 14634492
references.citation: Gastroenterology. 2002 Nov;123(5):1667-76
references.pmid: 12404241
references.citation: Nat Immunol. 2010 May;11(5):411-8
references.pmid: 20351694
references.citation: Am J Pathol. 2011 Jul;179(1):189-98
references.pmid: 21703401
references.citation: Hepatology. 2012 Aug;56(2):769-75
references.pmid: 22378017
references.citation: Cell Death Differ. 2010 Sep;17(9):1474-85
references.pmid: 20224597
references.citation: Circ Res. 2005 Oct 28;97(9):900-7
references.pmid: 16179589
references.citation: Gastroenterology. 2007 Feb;132(2):654-66
references.pmid: 17258733
references.citation: Antioxid Redox Signal. 2009 Jun;11(6):1279-87
references.pmid: 19061439
references.citation: Gastroenterology. 2012 May;142(6):1264-1273.e1
references.pmid: 22537432
references.citation: J Hepatol. 2009 Dec;51(6):1037-45
references.pmid: 19716616
references.citation: Gastroenterology. 2005 Dec;129(6):2009-31
references.pmid: 16344068
references.citation: Science. 1992 Jun 5;256(5062):1459-62
references.pmid: 1318579
references.citation: Hepatology. 2004 Feb;39(2):333-42
references.pmid: 14767986
references.citation: J Hepatol. 1999 Jan;30(1):77-87
references.pmid: 9927153
references.citation: J Clin Invest. 2000 Oct;106(7):867-72
references.pmid: 11018074
references.citation: Circ Res. 2007 Sep 28;101(7):663-71
references.pmid: 17673675
references.citation: Arterioscler Thromb Vasc Biol. 2004 Apr;24(4):677-83
references.pmid: 14670934
references.citation: J Biol Chem. 1999 Nov 26;274(48):33881-7
references.pmid: 10567349
references.citation: Biochem Biophys Res Commun. 2009 Jun 26;384(2):149-54
references.pmid: 19409874
references.citation: Circ Res. 2012 Apr 27;110(9):1217-25
references.pmid: 22456182
references.citation: Circ Res. 2000 Mar 17;86(5):549-57
references.pmid: 10720417
references.citation: J Med Chem. 2010 Nov 11;53(21):7715-30
references.pmid: 20942471
references.citation: Liver Int. 2009 May;29(5):748-53
references.pmid: 19220742
references.citation: J Biol Chem. 2000 May 5;275(18):13986-93
references.pmid: 10788525
references.citation: Cardiovasc Res. 2006 Dec 1;72(3):447-55
references.pmid: 17064675
references.citation: Lancet. 2013 Feb 9;381(9865):468-75
references.pmid: 23234725
references.citation: J Biol Chem. 2003 Sep 19;278(38):36830-40
references.pmid: 12855698
references.citation: Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5408-12
references.pmid: 1608949
references.citation: Liver Int. 2009 Aug;29(7):997-1009
references.pmid: 19422482
references.citation: Semin Liver Dis. 2007 Nov;27(4):378-89
references.pmid: 17979074
references.citation: Biochem Biophys Res Commun. 2003 Aug 15;308(1):177-83
references.pmid: 12890498
references.citation: Gastroenterology. 2010 Oct;139(4):1375-84
references.pmid: 20685364
references.citation: Am J Pathol. 2009 Jul;175(1):3-16
references.pmid: 19497999
references.citation: Cancer Biol Ther. 2010 Aug 1;10(3):223-31
references.pmid: 20523116
references.citation: Liver Int. 2010 Feb;30(2):334-5
references.pmid: 19515217
references.citation: J Hepatol. 2005 Aug;43(2):317-23
references.pmid: 15964094
references.citation: Circ Res. 2002 Jun 14;90(11):1205-13
references.pmid: 12065324
references.citation: Physiol Rev. 2007 Jan;87(1):245-313
references.pmid: 17237347
references.citation: Antioxid Redox Signal. 2009 Apr;11(4):791-810
references.pmid: 18783313
references.citation: Am J Physiol Lung Cell Mol Physiol. 2006 Apr;290(4):L661-L673
references.pmid: 16227320
references.citation: Cell Mol Life Sci. 2012 Jul;69(14):2315-25
references.pmid: 22585059
references.citation: Hepatology. 2005 Feb;41(2):336-44
references.pmid: 15660387
references.citation: Am J Physiol Gastrointest Liver Physiol. 2001 May;280(5):G1005-12
references.pmid: 11292610
references.citation: Arterioscler Thromb Vasc Biol. 2005 Nov;25(11):2295-300
references.pmid: 16179592
references.citation: Am J Physiol Gastrointest Liver Physiol. 2000 Jun;278(6):G992-9
references.pmid: 10859230
references.citation: World J Gastroenterol. 2000 Aug;6(4):540-545
references.pmid: 11819643
references.citation: Am J Physiol Gastrointest Liver Physiol. 2009 Oct;297(4):G726-34
references.pmid: 19628656
references.citation: J Hepatol. 2008 Dec;49(6):965-76
references.pmid: 18845355
references.citation: J Immunol. 2004 Sep 15;173(6):3589-93
references.pmid: 15356101
references.citation: Biochem Biophys Res Commun. 2008 Sep 19;374(2):351-5
references.pmid: 18638447
references.citation: Free Radic Biol Med. 2001 Dec 15;31(12):1544-9
references.pmid: 11744328
references.citation: Hepatology. 2011 May;53(5):1730-41
references.pmid: 21384410
references.citation: Annu Rev Biochem. 1989;58:79-110
references.pmid: 2673022
references.citation: Gastroenterology. 2006 Jul;131(1):272-5
references.pmid: 16831609
references.citation: Lab Invest. 2003 Dec;83(12):1689-707
references.pmid: 14691287
references.citation: Biol Chem. 2007 Feb;388(2):185-96
references.pmid: 17261082
references.citation: Free Radic Biol Med. 2009 Nov 1;47(9):1239-53
references.pmid: 19628035
references.citation: Hepatology. 2009 Mar;49(3):960-8
references.pmid: 19085953
references.citation: Hypertension. 2002 Oct;40(4):511-5
references.pmid: 12364355
references.citation: J Clin Invest. 2005 Feb;115(2):209-18
references.pmid: 15690074
references.citation: Gut. 2006 Jan;55(1):90-7
references.pmid: 16041064
references.citation: Transplantation. 2004 Sep 15;78(5):686-91
references.pmid: 15371669
references.citation: Hepatology. 2010 Oct;52(4):1420-30
references.pmid: 20690191
references.citation: Nature. 1999 Sep 30;401(6752):480-5
references.pmid: 10519551
references.citation: J Biol Chem. 2009 Aug 14;284(33):22173-22183
references.pmid: 19553664
references.citation: J Hepatol. 2002 Dec;37(6):773-80
references.pmid: 12445418
references.citation: Gastroenterology. 2004 Feb;126(2):529-40
references.pmid: 14762790
references.citation: N Engl J Med. 2010 May 6;362(18):1675-85
references.pmid: 20427778
references.citation: Hepatology. 2003 May;37(5):1067-78
references.pmid: 12717387
references.citation: Hepatology. 2001 Oct;34(4 Pt 1):745-50
references.pmid: 11584371
references.citation: Biochimie. 2011 Mar;93(3):457-68
references.pmid: 21075166
references.citation: Am J Transplant. 2009 Jan;9(1):74-82
references.pmid: 18976289
references.citation: Circ Res. 2002 Sep 6;91(5):406-13
references.pmid: 12215489
references.citation: Essays Biochem. 1994;28:147-64
references.pmid: 7925317
references.citation: J Clin Invest. 1989 Dec;84(6):1786-93
references.pmid: 2592560
references.citation: Hepatology. 2006 Mar;43(3):435-43
references.pmid: 16496318
references.citation: Circulation. 2002 Jul 2;106(1):130-5
references.pmid: 12093782
references.citation: J Cell Biol. 2005 Dec 5;171(5):893-904
references.pmid: 16330715
references.citation: Biochem J. 2005 Mar 1;386(Pt 2):255-61
references.pmid: 15491278
references.citation: Alcohol Alcohol. 1994 Sep;29(5):605-10
references.pmid: 7811345
references.citation: Biochem J. 2008 May 1;411(3):531-41
references.pmid: 18397177
references.citation: Pancreatology. 2007;7(4):332-40
references.pmid: 17627098
references.citation: Antioxid Redox Signal. 2014 Jan 1;20(1):121-34
references.pmid: 23472786
references.citation: N Engl J Med. 2001 Feb 8;344(6):418-23
references.pmid: 11172178
references.citation: Hepatology. 2005 Jun;41(6):1272-81
references.pmid: 15915457
references.citation: PLoS One. 2012;7(9):e45285
references.pmid: 23049784
references.citation: J Am Coll Cardiol. 2003 Jun 18;41(12):2164-71
references.pmid: 12821241
references.citation: Nat Med. 2007 Nov;13(11):1324-32
references.pmid: 17952090
references.citation: Proc Natl Acad Sci U S A. 1985 Dec;82(24):8681-5
references.pmid: 3909149
references.citation: Hepatology. 2001 Jul;34(1):89-100
references.pmid: 11431738
references.citation: Gastroenterol Res Pract. 2010;2010:
references.pmid: 20706677
references.citation: J Biol Chem. 2000 Jan 28;275(4):2247-50
references.pmid: 10644669
references.citation: Mol Cell Biol. 2006 Jan;26(1):140-54
references.pmid: 16354686
references.citation: Antioxid Redox Signal. 2009 Jul;11(7):1569-86
references.pmid: 19187001
references.citation: Free Radic Biol Med. 1999 Aug;27(3-4):322-8
references.pmid: 10468205
references.citation: Antioxid Redox Signal. 2009 Oct;11(10):2467-80
references.pmid: 19309256
references.citation: Cardiovasc Res. 2006 Jul 15;71(2):226-35
references.pmid: 16781692
references.citation: Mol Cell Biol. 2010 Jul;30(14):3553-68
references.pmid: 20457808
references.citation: J Cell Physiol. 2006 May;207(2):322-30
references.pmid: 16331683
references.citation: Biochem Biophys Res Commun. 2005 Apr 1;329(1):32-9
references.pmid: 15721269
references.citation: J Biol Chem. 2009 Nov 27;284(48):33255-64
references.pmid: 19801678
references.citation: J Biol Chem. 2004 Oct 29;279(44):45935-41
references.pmid: 15322091
references.citation: Hepatology. 2004 Nov;40(5):1222-5
references.pmid: 15382153
references.citation: J Hepatol. 2006 Sep;45(3):429-38
references.pmid: 16846660
references.citation: Regul Pept. 2000 Jul 28;91(1-3):21-7
references.pmid: 10967199
references.citation: Ann Intern Med. 2005 Jan 4;142(1):37-46
references.pmid: 15537682
references.citation: J Exp Med. 2001 Nov 19;194(10):1395-406
references.pmid: 11714747
references.citation: Hepatology. 2010 Jul;52(1):47-59
references.pmid: 20578128
references.citation: Proc Nutr Soc. 2006 Aug;65(3):278-90
references.pmid: 16923312
references.citation: J Am Soc Nephrol. 2010 Jan;21(1):93-102
references.pmid: 19926889
references.citation: Hepatology. 2006 Nov;44(5):1267-77
references.pmid: 17058265
references.citation: J Hepatol. 2005 Oct;43(4):606-13
references.pmid: 16112247
references.citation: Gene. 2001 May 16;269(1-2):131-40
references.pmid: 11376945
references.citation: Arterioscler Thromb Vasc Biol. 2007 Jan;27(1):42-8
references.pmid: 17082491
references.citation: Antioxid Redox Signal. 2005 Sep-Oct;7(9-10):1346-55
references.pmid: 16115040
references.citation: Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):8010-4
references.pmid: 10869423
references.citation: Nat Rev Drug Discov. 2011 Jun;10(6):453-71
references.pmid: 21629295
references.citation: Hepatology. 2010 Sep;52(3):886-93
references.pmid: 20683932
references.citation: Circ Res. 2009 May 22;104(10):1169-77
references.pmid: 19390057
references.citation: Lab Invest. 2003 May;83(5):655-63
references.pmid: 12746475
references.citation: Gastroenterology. 2005 Apr;128(4):1042-55
references.pmid: 15825085
references.citation: Hepatology. 2009 Mar;49(3):911-9
references.pmid: 19072832
references.citation: Nat Immunol. 2002 Dec;3(12):1129-34
references.pmid: 12447370
references.citation: Annu Rev Pharmacol Toxicol. 1983;23:239-57
references.pmid: 6307121
references.citation: Nat Rev Immunol. 2004 Mar;4(3):181-9
references.pmid: 15039755
references.citation: Oncogene. 2007 Feb 15;26(7):970-81
references.pmid: 16909112
references.citation: Stem Cells Dev. 2012 Aug 10;21(12):2212-21
references.pmid: 22181007
references.citation: Semin Liver Dis. 2001 Aug;21(3):437-51
references.pmid: 11586471
references.citation: J Biol Chem. 2009 Oct 30;284(44):30097-104
references.pmid: 19758997
references.citation: Liver Int. 2012 Jul;32(6):977-87
references.pmid: 22364262
references.citation: Hepatology. 2008 Dec;48(6):2016-26
references.pmid: 19025999
references.citation: J Immunol. 2004 Feb 15;172(4):2522-9
references.pmid: 14764725
references.citation: J Biol Chem. 2008 Jun 20;283(25):16961-5
references.pmid: 18420576
references.citation: Biochem J. 2007 Aug 15;406(1):105-14
references.pmid: 17501721
references.citation: Hepatology. 2003 May;37(5):1043-55
references.pmid: 12717385
references.citation: Am J Respir Cell Mol Biol. 2012 Nov;47(5):718-26
references.pmid: 22904198
references.citation: Gastroenterology. 2002 Feb;122(2):366-75
references.pmid: 11832451
references.citation: J Hepatol. 2001 Sep;35(3):376-85
references.pmid: 11592599
references.citation: Am J Physiol. 1999 Dec;277(6):G1259-67
references.pmid: 10600824
references.citation: Lab Invest. 2006 Jul;86(7):676-86
references.pmid: 16619004
references.citation: Hepatology. 2011 Sep 2;54(3):949-58
references.pmid: 21618578
references.citation: Antioxid Redox Signal. 2010 Aug 15;13(4):467-87
references.pmid: 20001746
references.citation: Cell Signal. 2006 Jan;18(1):69-82
references.pmid: 15927447
references.citation: Nat Med. 2009 Sep;15(9):1077-81
references.pmid: 19701206
references.citation: Am J Physiol Gastrointest Liver Physiol. 2006 May;290(5):G847-51
references.pmid: 16603728
references.citation: Fibrogenesis Tissue Repair. 2012 Jun 06;5(Suppl 1):S17
references.pmid: 23259769
references.citation: Biochem J. 2005 Sep 15;390(Pt 3):761-7
references.pmid: 15913451
references.citation: Antioxid Redox Signal. 2009 Jun;11(6):1313-33
references.pmid: 19072143
references.citation: Hepatology. 2004 Mar;39(3):770-8
references.pmid: 14999696
references.citation: Arterioscler Thromb Vasc Biol. 2005 Sep;25(9):1824-30
references.pmid: 15976327
references.citation: Front Physiol. 2012 Nov 01;3:412
references.pmid: 23125837
references.citation: J Leukoc Biol. 2004 Dec;76(6):1180-6
references.pmid: 15371490
references.citation: Mol Cell Endocrinol. 2009 Apr 29;302(2):148-58
references.pmid: 19059306
references.citation: Mol Cells. 2011 Dec;32(6):491-509
references.pmid: 22207195