Oxidative Stress and the Pathogenesis of Cholestasis

ABSTRACT

Cholestasis is a reduction in bile flow that occurs from a variety of causes in humans. This produces hepatocellular injury and fibrosis. Considering that there are limited therapies for this disease, there has been interest in understanding the mechanism by which cholestasis produces injury. Studies have demonstrated that oxidative stress occurs in livers of humans with cholestasis. In vitro studies have demonstrated that bile acids kill hepatocytes by a mechanism that depends upon reactive oxygen species (ROS). Further studies, however, have demonstrated that this mechanism is of limited importance in vivo. Cholestasis also initiates an inflammatory response resulting in accumulation of neutrophils in the liver. Inhibition of neutrophil function reduces oxidative stress and liver injury suggesting that neutrophils are an important source of damaging ROS in vivo. Furthermore, inhibition of ROS during cholestasis reduces fibrosis. Collectively, these studies suggest that ROS are important for pathologic changes that occur during cholestasis.

KEYWORDS

Oxidative stress - hepatocytes - inflammation - fibrosis - bile acids - cholestasis

REFERENCES

• 1 Qureshi W A. Intrahepatic cholestatic syndromes: pathogenesis, clinical features and management.  Dig Dis. 1999;  17(1) 49-59
• 2 Kim W R, Ludwig J, Lindor K D. Variant forms of cholestatic diseases involving small bile ducts in adults.  Am J Gastroenterol. 2000;  95(5) 1130-1138
• 3 Poupon R, Chazouillères O, Poupon R E. Chronic cholestatic diseases.  J Hepatol. 2000;  32(1, Suppl) 129-140
• 4 Murphy M P. How mitochondria produce reactive oxygen species.  Biochem J. 2009;  417(1) 1-13
• 5 Schrader M, Fahimi H D. Peroxisomes and oxidative stress.  Biochim Biophys Acta. 2006;  1763(12) 1755-1766
• 6 Bedard K, Krause K H. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology.  Physiol Rev. 2007;  87(1) 245-313
• 7 Jaeschke H. Cellular antioxidant defense mechanisms. In: Roth RA, Ganey P Comprehensive Toxicology, Volume IX: Hepatic Toxicology. Oxford, UK; Elsevier 2010 In press
• 8 Jaeschke H, Knight T R, Bajt M L. The role of oxidant stress and reactive nitrogen species in acetaminophen hepatotoxicity.  Toxicol Lett. 2003;  144(3) 279-288
• 9 Li Y, Huang T T, Carlson E J et al.. Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase.  Nat Genet. 1995;  11(4) 376-381
• 10 Mathews W R, Guido D M, Fisher M A, Jaeschke H. Lipid peroxidation as molecular mechanism of liver cell injury during reperfusion after ischemia.  Free Radic Biol Med. 1994;  16(6) 763-770
• 11 Hong J Y, Lebofsky M, Farhood A, Jaeschke H. Oxidant stress-induced liver injury in vivo: role of apoptosis, oncotic necrosis, and c-Jun NH2-terminal kinase activation.  Am J Physiol Gastrointest Liver Physiol. 2009;  296(3) G572-G581
• 12 Nieminen A L, Saylor A K, Tesfai S A, Herman B, Lemasters J J. Contribution of the mitochondrial permeability transition to lethal injury after exposure of hepatocytes to t-butylhydroperoxide.  Biochem J. 1995;  307(Pt 1) 99-106
• 13 Sokol R J, Devereaux M, Khandwala R A. Effect of dietary lipid and vitamin E on mitochondrial lipid peroxidation and hepatic injury in the bile duct-ligated rat.  J Lipid Res. 1991;  32(8) 1349-1357
• 14 Parola M, Leonarduzzi G, Robino G, Albano E, Poli G, Dianzani M U. On the role of lipid peroxidation in the pathogenesis of liver damage induced by long-standing cholestasis.  Free Radic Biol Med. 1996;  20(3) 351-359
• 15 Singh S, Shackleton G, Ah-Sing E, Chakraborty J, Bailey M E. Antioxidant defenses in the bile duct-ligated rat.  Gastroenterology. 1992;  103(5) 1625-1629
• 16 Pastor A, Collado P S, Almar M, González-Gallego J. Antioxidant enzyme status in biliary obstructed rats: effects of N-acetylcysteine.  J Hepatol. 1997;  27(2) 363-370
• 17 Lemonnier F, Cresteil D, Fénéant M, Couturier M, Bernard O, Alagille D. Plasma lipid peroxides in cholestatic children.  Acta Paediatr Scand. 1987;  76(6) 928-934
• 18 Tazawa Y, Nakagawa M, Yamada M et al.. Serum vitamin E levels in children with corrected biliary atresia.  Am J Clin Nutr. 1984;  40(2) 246-250
• 19 Weinberger B, Watorek K, Strauss R, Witz G, Hiatt M, Hegyi T. Association of lipid peroxidation with hepatocellular injury in preterm infants.  Crit Care. 2002;  6(6) 521-525
• 20 Belli D C, Fournier L A, Lepage G et al.. Total parenteral nutrition-associated cholestasis in rats: comparison of different amino acid mixtures.  JPEN J Parenter Enteral Nutr. 1987;  11(1) 67-73
• 21 Kitada T, Seki S, Iwai S, Yamada T, Sakaguchi H, Wakasa K. In situ detection of oxidative DNA damage, 8-hydroxydeoxyguanosine, in chronic human liver disease.  J Hepatol. 2001;  35(5) 613-618
• 22 Aboutwerat A, Pemberton P W, Smith A et al.. Oxidant stress is a significant feature of primary biliary cirrhosis.  Biochim Biophys Acta. 2003;  1637(2) 142-150
• 23 Vendemiale G, Grattagliano I, Lupo L, Memeo V, Altomare E. Hepatic oxidative alterations in patients with extra-hepatic cholestasis. Effect of surgical drainage.  J Hepatol. 2002;  37(5) 601-605
• 24 Klaassen C D, Reisman S A. Nrf2 the Rescue: Effects of the antioxidative/electrophilic response on the liver.  Toxicol Appl Pharmacol. 2010;  244(1) 57-65
• 25 Maher J M, Cheng X, Slitt A L, Dieter M Z, Klaassen C D. Induction of the multidrug resistance-associated protein family of transporters by chemical activators of receptor-mediated pathways in mouse liver.  Drug Metab Dispos. 2005;  33(7) 956-962
• 26 Maher J M, Dieter M Z, Aleksunes L M et al.. Oxidative and electrophilic stress induces multidrug resistance-associated protein transporters via the nuclear factor-E2-related factor-2 transcriptional pathway.  Hepatology. 2007;  46(5) 1597-1610
• 27 Reisman S A, Csanaky I L, Aleksunes L M, Klaassen C D. Altered disposition of acetaminophen in Nrf2-null and Keap1-knockdown mice.  Toxicol Sci. 2009;  109(1) 31-40
• 28 Cheng X, Buckley D, Klaassen C D. Regulation of hepatic bile acid transporters Ntcp and Bsep expression.  Biochem Pharmacol. 2007;  74(11) 1665-1676
• 29 Weerachayaphorn J, Cai S Y, Soroka C J, Boyer J L. Nuclear factor erythroid 2-related factor 2 is a positive regulator of human bile salt export pump expression.  Hepatology. 2009;  50(5) 1588-1596
• 30 Sokol R J, Devereaux M, Khandwala R, O'Brien K. Evidence for involvement of oxygen free radicals in bile acid toxicity to isolated rat hepatocytes.  Hepatology. 1993;  17(5) 869-881
• 31 Sokol R J, Winklhofer-Roob B M, Devereaux M W, McKim Jr J M. Generation of hydroperoxides in isolated rat hepatocytes and hepatic mitochondria exposed to hydrophobic bile acids.  Gastroenterology. 1995;  109(4) 1249-1256
• 32 Fang Y, Han S I, Mitchell C et al.. Bile acids induce mitochondrial ROS, which promote activation of receptor tyrosine kinases and signaling pathways in rat hepatocytes.  Hepatology. 2004;  40(4) 961-971
• 33 Graf D, Kurz A K, Fischer R, Reinehr R, Häussinger D. Taurolithocholic acid-3 sulfate induces CD95 trafficking and apoptosis in a c-Jun N-terminal kinase-dependent manner.  Gastroenterology. 2002;  122(5) 1411-1427
• 34 Patel T, Bronk S F, Gores G J. Increases of intracellular magnesium promote glycodeoxycholate-induced apoptosis in rat hepatocytes.  J Clin Invest. 1994;  94(6) 2183-2192
• 35 Miyoshi H, Rust C, Roberts P J, Burgart L J, Gores G J. Hepatocyte apoptosis after bile duct ligation in the mouse involves Fas.  Gastroenterology. 1999;  117(3) 669-677
• 36 Fickert P, Trauner M, Fuchsbichler A et al.. Oncosis represents the main type of cell death in mouse models of cholestasis.  J Hepatol. 2005;  42(3) 378-385
• 37 Gujral J S, Liu J, Farhood A, Jaeschke H. Reduced oncotic necrosis in Fas receptor-deficient C57BL/6J-lpr mice after bile duct ligation.  Hepatology. 2004;  40(4) 998-1007
• 38 Schoemaker M H, Gommans W M, Conde de la Rosa L et al.. Resistance of rat hepatocytes against bile acid-induced apoptosis in cholestatic liver injury is due to nuclear factor-kappa B activation.  J Hepatol. 2003;  39(2) 153-161
• 39 Nalapareddy P, Schüngel S, Hong J Y, Manns M P, Jaeschke H, Vogel A. The BH3-only protein bid does not mediate death-receptor-induced liver injury in obstructive cholestasis.  Am J Pathol. 2009;  175(3) 1077-1085
• 40 Reinehr R, Graf D, Häussinger D. Bile salt-induced hepatocyte apoptosis involves epidermal growth factor receptor-dependent CD95 tyrosine phosphorylation.  Gastroenterology. 2003;  125(3) 839-853
• 41 Allen K, Kim N D, Copple B L. Bile acids increase proinflammatory gene expression in hepatocytes by early growth response factor-1-dependent and independent mechanisms (abstract).  Toxicol Sci. 2010;  114(Suppl. 1) 344
• 42 Saito J M, Maher J J. Bile duct ligation in rats induces biliary expression of cytokine-induced neutrophil chemoattractant.  Gastroenterology. 2000;  118(6) 1157-1168
• 43 Gujral J S, Farhood A, Bajt M L, Jaeschke H. Neutrophils aggravate acute liver injury during obstructive cholestasis in bile duct-ligated mice.  Hepatology. 2003;  38(2) 355-363
• 44 Gujral J S, Liu J, Farhood A, Hinson J A, Jaeschke H. Functional importance of ICAM-1 in the mechanism of neutrophil-induced liver injury in bile duct-ligated mice.  Am J Physiol Gastrointest Liver Physiol. 2004;  286(3) G499-G507
• 45 Georgiev P, Jochum W, Heinrich S et al.. Characterization of time-related changes after experimental bile duct ligation.  Br J Surg. 2008;  95(5) 646-656
• 46 Kennedy J A, Lewis H, Clements W D et al.. Kupffer cell blockade, tumour necrosis factor secretion and survival following endotoxin challenge in experimental biliary obstruction.  Br J Surg. 1999;  86(11) 1410-1414
• 47 Ito Y, Bethea N W, Baker G L, McCuskey M K, Urbaschek R, McCuskey R S. Hepatic microcirculatory dysfunction during cholestatic liver injury in rats.  Microcirculation. 2003;  10(5) 421-432
• 48 Gehring S, Dickson E M, San Martin M E et al.. Kupffer cells abrogate cholestatic liver injury in mice.  Gastroenterology. 2006;  130(3) 810-822
• 49 Jaeschke H, Farhood A. Neutrophil and Kupffer cell-induced oxidant stress and ischemia-reperfusion injury in rat liver.  Am J Physiol. 1991;  260(3 Pt 1) G355-G362
• 50 Melgert B N, Olinga P, Van Der Laan J M et al.. Targeting dexamethasone to Kupffer cells: effects on liver inflammation and fibrosis in rats.  Hepatology. 2001;  34(4 Pt 1) 719-728
• 51 Canbay A, Feldstein A E, Higuchi H et al.. Kupffer cell engulfment of apoptotic bodies stimulates death ligand and cytokine expression.  Hepatology. 2003;  38(5) 1188-1198
• 52 Minter R M, Fan M H, Sun J et al.. Altered Kupffer cell function in biliary obstruction.  Surgery. 2005;  138(2) 236-245
• 53 Kim N D, Moon J O, Slitt A L, Copple B L. Early growth response factor-1 is critical for cholestatic liver injury.  Toxicol Sci. 2006;  90(2) 586-595
• 54 Allen K, Kim N D, Moon J O, Copple B L. Upregulation of early growth response factor-1 by bile acids requires mitogen-activated protein kinase signaling.  Toxicol Appl Pharmacol. 2010;  243(1) 63-67
• 55 Jaeschke H. Enhanced sinusoidal glutathione efflux during endotoxin-induced oxidant stress in vivo.  Am J Physiol. 1992;  263(1 Pt 1) G60-G68
• 56 Bilzer M, Lauterburg B H. Effects of hypochlorous acid and chloramines on vascular resistance, cell integrity, and biliary glutathione disulfide in the perfused rat liver: modulation by glutathione.  J Hepatol. 1991;  13(1) 84-89
• 57 Gujral J S, Hinson J A, Farhood A, Jaeschke H. NADPH oxidase-derived oxidant stress is critical for neutrophil cytotoxicity during endotoxemia.  Am J Physiol Gastrointest Liver Physiol. 2004;  287(1) G243-G252
• 58 Hasegawa T, Malle E, Farhood A, Jaeschke H. Generation of hypochlorite-modified proteins by neutrophils during ischemia-reperfusion injury in rat liver: attenuation by ischemic preconditioning.  Am J Physiol Gastrointest Liver Physiol. 2005;  289(4) G760-G767
• 59 Lehnert M, Arteel G E, Smutney O M et al.. Dependence of liver injury after hemorrhage/resuscitation in mice on NADPH oxidase-derived superoxide.  Shock. 2003;  19(4) 345-351
• 60 Jaeschke H, Ho Y S, Fisher M A, Lawson J A, Farhood A. Glutathione peroxidase-deficient mice are more susceptible to neutrophil-mediated hepatic parenchymal cell injury during endotoxemia: importance of an intracellular oxidant stress.  Hepatology. 1999;  29(2) 443-450
• 61 Jaeschke H. Mechanisms of liver injury. II. Mechanisms of neutrophil-induced liver cell injury during hepatic ischemia-reperfusion and other acute inflammatory conditions.  Am J Physiol Gastrointest Liver Physiol. 2006;  290(6) G1083-G1088
• 62 Soylu A R, Aydogdu N, Basaran U N et al.. Antioxidants vitamin E and C attenuate hepatic fibrosis in biliary-obstructed rats.  World J Gastroenterol. 2006;  12(42) 6835-6841
• 63 Parola M, Pinzani M, Casini A et al.. Induction of procollagen type I gene expression and synthesis in human hepatic stellate cells by 4-hydroxy-2,3-nonenal and other 4-hydroxy-2,3-alkenals is related to their molecular structure.  Biochem Biophys Res Commun. 1996;  222(2) 261-264
• 64 Bataller R, Schwabe R F, Choi Y H et al.. NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis.  J Clin Invest. 2003;  112(9) 1383-1394
• 65 Barón V, Muriel P. Role of glutathione, lipid peroxidation and antioxidants on acute bile-duct obstruction in the rat.  Biochim Biophys Acta. 1999;  1472(1-2) 173-180
• 66 Sokol R J, Heubi J E, McGraw C, Balistreri W F. Correction of vitamin E deficiency in children with chronic cholestasis. II. Effect on gastrointestinal and hepatic function.  Hepatology. 1986;  6(6) 1263-1269
• 67 Yang Y Y, Lee K C, Huang Y T et al.. Effects of N-acetylcysteine administration in hepatic microcirculation of rats with biliary cirrhosis.  J Hepatol. 2008;  49(1) 25-33
• 68 Tahan G, Tarcin O, Tahan V et al.. The effects of N-acetylcysteine on bile duct ligation-induced liver fibrosis in rats.  Dig Dis Sci. 2007;  52(12) 3348-3354
• 69 Gonzalez-Correa J A, De La Cruz J P, Martin-Aurioles E, Lopez-Egea M A, Ortiz P, Sanchez de la Cuesta F. Effects of S-adenosyl-L-methionine on hepatic and renal oxidative stress in an experimental model of acute biliary obstruction in rats.  Hepatology. 1997;  26(1) 121-127
• 70 Yang H, Ramani K, Xia M et al.. Dysregulation of glutathione synthesis during cholestasis in mice: molecular mechanisms and therapeutic implications.  Hepatology. 2009;  49(6) 1982-1991
• 71 Zhong Z, Froh M, Lehnert M et al.. Polyphenols from Camellia sinenesis attenuate experimental cholestasis-induced liver fibrosis in rats.  Am J Physiol Gastrointest Liver Physiol. 2003;  285(5) G1004-G1013
• 72 Zhong Z, Froh M, Wheeler M D, Smutney O, Lehmann T G, Thurman R G. Viral gene delivery of superoxide dismutase attenuates experimental cholestasis-induced liver fibrosis in the rat.  Gene Ther. 2002;  9(3) 183-191
• 73 Jaeschke H. Mechanisms of oxidant stress-induced acute tissue injury.  Proc Soc Exp Biol Med. 1995;  209(2) 104-111
• 74 Jaeschke H. Reactive oxygen and mechanisms of inflammatory liver injury.  J Gastroenterol Hepatol. 2000;  15(7) 718-724
• 75 Rehman H, Ramshesh V K, Theruvath T P et al.. NIM811 (N-methyl-4-isoleucine cyclosporine), a mitochondrial permeability transition inhibitor, attenuates cholestatic liver injury but not fibrosis in mice.  J Pharmacol Exp Ther. 2008;  327(3) 699-706