Abstract: HepatologyVolume 30, Issue 1 p. 1-5 Concise ReviewFree Access Nitric oxide in liver injury Mark G. Clemens 9201 University City Blvd., Corresponding Author Mark G. Clemens 9201 University City Blvd. [email protected] From the Department of Biology, University of North Carolina at Charlotte, Charlotte NCCharlotte, NC 28223===Search for more papers by this author Mark G. Clemens 9201 University City Blvd., Corresponding Author Mark G. Clemens 9201 University City Blvd. [email protected] From the Department of Biology, University of North Carolina at Charlotte, Charlotte NCCharlotte, NC 28223===Search for more papers by this author First published: 30 December 2003 https://doi.org/10.1002/hep.510300148Citations: 144AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL References 1 Knowles RG, Merrett M, Salter M, Moncada S. Differential induction of brain, lung and liver nitric oxide synthase by endotoxin in the rat. Biochem J 1990; 270: 833– 836. MEDLINE 2 Esteban FJ, Pedrosa JA, Jimenez A, Fernandez AP, Bentura ML, Martinez-Murillo R, Rodrigo J, et al. Distribution of neuronal nitric oxide synthase in the rat liver. Neurosci Lett 1997; 226: 99– 102. MEDLINE 3 Clemens MG. Does altered regulation of ecNOS in sinusoidal endothelial cells determine increased intrahepatic resistance leading to portal hypertension? Hepatology 1998; 27: 1745– 1747. MEDLINE 4 Rockey DC, Chung JJ. Reduced nitric oxide production by endothelial cells in cirrhotic rat liver: endothelial dysfunction in portal hypertension. Gastroenterology 1998; 114: 344– 351. MEDLINE 5 Shah V, Haddad FG, Garcia-Cardena G, Frangos JA, Mennone A, Groszmann RJ, Sessa WC. Liver sinusoidal endothelial cells are responsible for nitric oxide modulation of resistance in the hepatic sinusoids. J Clin Invest 1997; 100: 2923– 2930. MEDLINE 6 Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991; 43: 109– 142. MEDLINE 7 Lautt WW, Greenway CV. Conceptual review of the hepatic vascular bed. Hepatology 1987; 7: 952– 963. MEDLINE 8 Clemens MG, Bauer M, Pannen BH, Bauer I, Zhang JX. Remodeling of hepatic microvascular responsiveness after ischemia/reperfusion. Shock 1997; 8: 80– 85. MEDLINE 9 Rockey D. The cellular pathogenesis of portal hypertension: stellate cell contractility, endothelin, and nitric oxide. Hepatology 1997; 25: 2– 5. MEDLINE 10 Lowenstein CJ, Glatt CS, Bredt DS, Snyder SH. Cloned and expressed macrophage nitric oxide synthase contrasts with the brain enzyme. Proc Natl Acad Sci U S A 1992; 89: 6711– 6715. MEDLINE 11 Rockey DC, Chung JJ. Regulation of inducible nitric oxide synthase in hepatic sinusoidal endothelial cells. Am J Physiol 1996; 271: G260– G267. MEDLINE 12 Rockey DC, Chung JJ, McKee CM, Noble PW. Stimulation of inducible nitric oxide synthase in rat liver by hyaluronan fragments. Hepatology 1998; 27: 86– 92. MEDLINE 13 Curran RD, Billiar TR, Stuehr DJ, Ochoa JB, Harbrecht BG, Flint SG, Simmons RL. Multiple cytokines are required to induce hepatocyte nitric oxide production and inhibit total protein synthesis. Ann Surg 1990; 212: 462– 469. MEDLINE 14 Geller DA, Lowenstein CJ, Shapiro RA, Nussler AK, Di Silvio M, Wang SC, Nakayama DK, et al. Molecular cloning and expression of inducible nitric oxide synthase from human hepatocytes. Proc Natl Acad Sci U S A 1993; 90: 3491– 3495. MEDLINE 15 Helyar L, Bundschuh DS, Laskin JD, Laskin DL. Induction of hepatic Ito cell nitric oxide production after acute endotoxemia. Hepatology 1994; 20: 1509– 1515. MEDLINE 16 Rockey DC, Chung JJ. Inducible nitric oxide synthase in rat hepatic lipocytes and the effect of nitric oxide on lipocyte contractility. J Clin Invest 1995; 95: 1199– 1206. MEDLINE 17 Coccheri S, Nazzari M. Defibrotide as a possible anti-ischemic drug. Semin Thromb Hemost 1996; 22(Suppl 1): 9– 14. MEDLINE 18 Ayuse T, Brienza N, Revelly JP, Boitnott JK, Robotham JL. Role of nitric oxide in porcine liver circulation under normal and endotoxemic conditions. J Appl Physiol 1995; 78: 1319– 1329. MEDLINE 19 Mathie RT, Ralevic V, Alexander B, Burnstock G. Nitric oxide is the mediator of ATP-induced dilatation of the rabbit hepatic arterial vascular bed. Br J Pharmacol 1991; 103: 1602– 1606. MEDLINE 20 Pannen BH, Bauer M. Differential regulation of hepatic arterial and portal venous vascular resistance by nitric oxide and carbon monoxide in rats. Life Sci 1998; 62: 2025– 2033. MEDLINE 21 Mittal MK, Gupta TK, Lee FY, Sieber CC, Groszmann RJ. Nitric oxide modulates hepatic vascular tone in normal rat liver. Am J Physiol 1994; 267: G416– G422. MEDLINE 22 Zhang JX, Pegoli WJ, Clemens MG. Endothelin-1 induces direct constriction of hepatic sinusoids. Am J Physiol 1994; 266: G624– G632. MEDLINE 23 Shibayama Y, Nakata K. Role of septal fibrosis in development of hepatic circulatory disturbance in the presence of liver cell enlargement. Liver 1992; 12: 84– 89. MEDLINE 24 Harbrecht BG, Billiar TR, Stadler J, Demetris AJ, Ochoa J, Curran RD, Simmons RL. Inhibition of nitric oxide synthesis during endotoxemia promotes intrahepatic thrombosis and an oxygen radical-mediated hepatic injury. J Leukoc Biol 1992; 52: 390– 394. MEDLINE 25 Harbrecht BG, Wu B, Watkins SC, Marshall HPJ, Peitzman AB, Billiar TR. Inhibition of nitric oxide synthase during hemorrhagic shock increases hepatic injury. Shock 1995; 4: 332– 337. MEDLINE 26 Saetre T, Gundersen Y, Thiemermann C, Lilleaasen P, Aasen AO. Aminoethyl-isothiourea, a selective inhibitor of inducible nitric oxide synthase activity, improves liver circulation and oxygen metabolism in a porcine model of endotoxemia. Shock 1998; 9: 109– 115. MEDLINE 27 Thiemermann C, Ruetten H, Wu CC, Vane JR. The multiple organ dysfunction syndrome caused by endotoxin in the rat: attenuation of liver dysfunction by inhibitors of nitric oxide synthase. Br J Pharmacol 1995; 116: 2845– 2851. MEDLINE 28 Wray GM, Millar CG, Hinds CJ, Thiemermann C. Selective inhibition of the activity of inducible nitric oxide synthase prevents the circulatory failure, but not the organ injury/dysfunction, caused by endotoxin. Shock 1998; 9: 329– 335. MEDLINE 29 Ou J, Carlos TM, Watkins SC, Saavedra JE, Keefer LK, Kim YM, Harbrecht BG, Billiar TR. Differential effects of nonselective nitric oxide synthase (NOS) and selective inducible NOS inhibition on hepatic necrosis, apoptosis, ICAM- 1 expression, and neutrophil accumulation during endotoxemia. Nitric Oxide 1997; 1: 404– 416. MEDLINE 30 Higuchi H, Satoh T. Endothelin-1 induces vasoconstriction and nitric oxide release via endothelin ET(B) receptors in isolated perfused rat liver. Eur J Pharmacol 1997; 328: 175– 182. MEDLINE 31 Gandhi CR, Sproat LA, Subbotin VM. Increased hepatic endothelin-1 levels and endothelin receptor density in cirrhotic rats. Life Sci 1996; 58: 55– 62. MEDLINE 32 Sonin NV, Garcia-Pagan JC, Nakanishi K, Zhang JX, Clemens MG. Patterns of vasoregulatory gene expression in the liver response to ischemia / reperfusion and endotoxemia. Shock 1999; 11: 175– 179. MEDLINE 33 Shekhonin BV, Klochkov SA, Domogatskii SP, Potapova IN. [Collagen and fibronectin of the liver in children with congenital fibrosis, an extrahepatic portal circulation block and post-hepatitis cirrhosis (an immunohistochemical study)]Kollagen i fibronektinn v pecheni detei pri vrozhdennom fibroze, vnepechenochnoi blokade portal'nogo krovoobrashcheniia i postgepatitnom tsirroze (immunogistokhimicheskoe issledovanie). Arkh Patol 1989; 51: 35– 41. MEDLINE 34 Krant JD, Gauthier VJ, Mannik M. Deposition of immune complexes containing cationized antibodies in myocardial small blood vessels of mice. Clin Immunol Immunopathol 1989; 50: 241– 250. MEDLINE 35 Bouwens L, Jacobs R, Remels L, Wisse E. Natural cytotoxicity of rat hepatic natural killer cells and macrophages against a syngeneic colon adenocarcinoma. Cancer Immunol Immunother 1988; 27: 137– 141. MEDLINE 36 Bauer I, Wanner GA, Rensing H, Alte C, Miescher EA, Wolf B, Pannen BH, et al. Expression pattern of heme oxygenase isoenzymes 1 and 2 in normal and stress-exposed rat liver. Hepatology 1998; 27: 829– 838. MEDLINE 37 Pannen BH, Kohler N, Hole B, Bauer M, Clemens MG, Geiger KK. Protective role of endogenous carbon monoxide in hepatic microcirculatory dysfunction after hemorrhagic shock in rats. J Clin Invest 1998; 102: 1220– 1228. MEDLINE 38 Downard PJ, Wilson MA, Spain DA, Matheson PJ, Siow Y, Garrison RN. Heme oxygenase-dependent carbon monoxide production is a hepatic adaptive response to sepsis. J Surg Res 1997; 71: 7– 12. MEDLINE 39 Vallance P, Moncada S. Role of endogenous nitric oxide in septic shock. New Horiz 1993; 1: 77– 86. MEDLINE 40 Saarela J, Rehn M, Oikarinen A, Autio-Harmainen H, Pihlajaniemi T. The short and long forms of type XVIII collagen show clear tissue specificities in their expression and location in basement membrane zones in humans. Am J Pathol 1998; 153: 611– 626. MEDLINE 41 Winnock M, Lafon ME, Boulard A, Ferrer AM, Saric J, Dubuisson L, Bioulac-Sage P, et al. Characterization of liver-associated natural killer cells in patients with liver tumors. Hepatology 1991; 13: 676– 682. MEDLINE 42 Fukatsu K, Saito H, Han I, Furukawa S, Lin MT, Matsuda T, Ikeda S, Inoue T, Yasuhara H, Muto T. Nitric oxide donor decreases neutrophil adhesion in both lung and peritoneum during peritonitis. J Surg Res 1998; 74: 119– 124. MEDLINE 43 Harbrecht BG, Wu B, Watkins SC, Billiar TR, Peitzman AB. Inhibition of nitric oxide synthesis during severe shock but not after resuscitation increases hepatic injury and neutrophil accumulation in hemorrhaged rats. Shock 1997; 8: 415– 421. MEDLINE 44 Liu P, Yin K, Nagele R, Wong PY. Inhibition of nitric oxide synthase attenuates peroxynitrite generation, but augments neutrophil accumulation in hepatic ischemia—reperfusion in rats. J Pharmacol Exp Ther 1998; 284: 1139– 1146. MEDLINE 45 Liu P, Xu B, Hock CE, Nagele R, Sun FF, Wong PY. NO modulates P-selectin and ICAM-1 mRNA expression and hemodynamic alterations in hepatic I/R. Am J Physiol 1998; 275: H2191– H2198. MEDLINE 46 Inam S, Sidki K, al-Marshedy AR, Judzewitsch R. Addison's disease, hypertension, renal and hepatic microthrombosis in ‘primary’ antiphospholipid syndrome. Postgrad Med J 1991; 67: 385– 388. MEDLINE 47 Jaeschke H, Smith CW, Clemens MG, Ganey PE, Roth RA. Mechanisms of inflammatory liver injury: adhesion molecules and cytotoxicity of neutrophils. Toxicol Appl Pharmacol 1996; 139: 213– 226. MEDLINE 48 West MA, Keller GA, Hyland BJ, Cerra FB, Simmons RL. Hepatocyte function in sepsis: Kupffer cells mediate a biphasic protein synthesis response in hepatocytes after exposure to endotoxin or killed Escherichia coli. Surgery 1985; 98: 388– 395. MEDLINE 49 Billiar TR, Curran RD, Ferrari FK, Williams DL, Simmons RL. Kupffer cell:hepatocyte cocultures release nitric oxide in response to bacterial endotoxin. J Surg Res 1990; 48: 349– 353. MEDLINE 50 Chartrain NA, Geller DA, Koty PP, Sitrin NF, Nussler AK, Hoffman EP, Billiar TR, et al. Molecular cloning, structure, and chromosomal localization of the human inducible nitric oxide synthase gene. J Biol Chem 1994; 269: 6765– 6772. MEDLINE 51 Curran RD, Ferrari FK, Kispert PH, Stadler J, Stuehr DJ, Simmons RL, Billiar TR. Nitric oxide and nitric oxide-generating compounds inhibit hepatocyte protein synthesis. FASEB J 1991; 5: 2085– 2092. MEDLINE 52 Ou J, Molina L, Kim YM, Billiar TR. Excessive NO production dose not account for the inhibition of hepatic gluconeogenesis in endotoxemia. Am J Physiol 1996; 271: G621– G628. MEDLINE 53 Szabo C. Potential role of the peroxynitrate-poly(ADP-ribose) synthetase pathway in a rat model of severe hemorrhagic shock. Shock 1998; 9: 341– 344. MEDLINE 54 Wang K, Deutschman CS, Clemens MG, De Maio A. Reciprocal expression of phosphoenolpyruvate carboxykinase and acute phase genes during acute inflammation. Shock 1995; 3: 204– 209. MEDLINE 55 Fisch C, Robin MA, Letteron P, Fromenty B, Berson A, Renault S, Chachaty C, et al. Cell-generated nitric oxide inactivates rat hepatocyte mitochondria in vitro but reacts with hemoglobin in vivo. Gastroenterology 1996; 110: 210– 220. MEDLINE 56 Giulivi C. Functional implications of nitric oxide produced by mitochondria in mitochondrial metabolism. Biochem J 1998; 332: 673– 679. MEDLINE 57 Kantrow SP, Taylor DE, Carraway MS, Piantadosi CA. Oxidative metabolism in rat hepatocytes and mitochondria during sepsis. Arch Biochem Biophys 1997; 345: 278– 288. MEDLINE 58 Kurose I, Kato S, Ishii H, Fukumura D, Miura S, Suematsu M, Tsuchiya M. Nitric oxide mediates lipopolysaccharide-induced alteration of mitochondrial function in cultured hepatocytes and isolated perfused liver. Hepatology 1993; 18: 380– 388. MEDLINE 59 Szabo C, Thiemermann C. Invited opinion: role of nitric oxide in hemorrhagic, traumatic, and anaphylactic shock and thermal injury. Shock 1994; 2: 145– 155. MEDLINE 60 Gardner CR, Heck DE, Yang CS, Thomas PE, Zhang XJ, DeGeorge GL, Laskin JD, et al. Role of nitric oxide in acetaminophen-induced hepatotoxicity in the rat. Hepatology 1998; 27: 748– 754. MEDLINE 61 Hinson JA, Pike SL, Pumford NR, Mayeux PR. Nitrotyrosine-protein adducts in hepatic centrilobular areas following toxic doses of acetaminophen in mice. Chem Res Toxicol 1998; 11: 604– 607. MEDLINE 62 Costantini P, Petronilli V, Colonna R, Bernardi P. On the effects of paraquat on isolated mitochondria. Evidence that paraquat causes opening of the cyclosporin A-sensitive permeability transition pore synergistically with nitric oxide. Toxicology 1995; 99: 77– 88. MEDLINE 63 Jaeschke H, Schini VB, Farhood A. Role of nitric oxide in the oxidant stress during ischemia/reperfusion injury of the liver. Life Sci 1992; 50: 1797– 1804. MEDLINE 64 Ma TT, Ischiropoulos H, Brass CA. Endotoxin-stimulated nitric oxide production increases injury and reduces rat liver chemiluminescence during reperfusion [comments]. Gastroenterology 1995; 108: 463– 469. MEDLINE 65 Wang Y, Mathews WR, Guido DM, Farhood A, Jaeschke H. Inhibition of nitric oxide synthesis aggravates reperfusion injury after hepatic ischemia and endotoxemia. Shock 1995; 4: 282– 288. MEDLINE 66 Balakirev MY, Khramtsov VV, Zimmer G. Modulation of the mitochondrial permeability transition by nitric oxide. Eur J Biochem 1997; 246: 710– 718. MEDLINE 67 Hortelano S, Dallaporta B, Zamzami N, Hirsch T, Susin SA, Marzo I, Bosca L, et al. Nitric oxide induces apoptosis via triggering mitochondrial permeability transition. FEBS Lett 1997; 410: 373– 377. MEDLINE 68 Szabo C, Ohshima H. DNA damage induced by peroxynitrite: subsequent biological effects. Nitric Oxide 1997; 1: 373– 385. MEDLINE 69 Szabo C. DNA strand breakage and activation of poly-ADP ribosyltransferase: a cytotoxic pathway triggered by peroxynitrite. Free Radic Biol Med 1996; 21: 855– 869. MEDLINE 70 Packer MA, Murphy MP. Peroxynitrite causes calcium efflux from mitochondria which is prevented by Cyclosporin A. FEBS Lett 1994; 345: 237– 240. MEDLINE 71 Sewer MB, Morgan ET. Down-regulation of the expression of three major rat liver cytochrome P450S by endotoxin in vivo occurs independently of nitric oxide production. J Pharmacol Exp Ther 1998; 287: 352– 358. MEDLINE 72 Li JY, Wang L, Sun H, Zhang XJ. [Involvement of nitric oxide and cGMP in the protective effect of neurotensin on hepatocytes]. Sheng Li Hsueh Pao 1997; 49: 459– 462. MEDLINE 73 Sanchez-Rodriguez A, Criado M, Rodriguez-Lopez AM, Esteller A, Martin DA, Lopez-Novoa JM. Increased nitric oxide synthesis and inducible nitric oxide synthase expression in patients with alcoholic and non-alcoholic liver cirrhosis. Clin Sci (Colch) 1998; 94: 637– 643. MEDLINE 74 Rodriguez-Roisin R, Barbera JA. Hepatopulmonary syndrome: is NO the right answer? [editorial; comment]. Gastroenterology 1997; 113: 682– 684. MEDLINE 75 Moller S, Henriksen JH. Circulatory abnormalities in cirrhosis with focus on neurohumoral aspects. Semin Nephrol 1997; 17: 505– 519. MEDLINE 76 Kim YM, Talanian RV, Billiar TR. Nitric oxide inhibits apoptosis by preventing increases in caspase-3- like activity via two distinct mechanisms. J Biol Chem 1997; 272: 31138– 31148. MEDLINE 77 Kim YM, de Vera ME, Watkins SC, Billiar TR. Nitric oxide protects cultured rat hepatocytes from tumor necrosis factor-alpha-induced apoptosis by inducing heat shock protein 70 expression. J Biol Chem 1997; 272: 1402– 1411. MEDLINE 78 Li J, Billiar TR, Talanian RV, Kim YM. Nitric oxide reversibly inhibits seven members of the caspase family via S-nitrosylation. Biochem Biophys Res Commun 1997; 240: 419– 424. MEDLINE 79 Ruiz F, Corrales FJ, Miqueo C, Mato JM. Nitric oxide inactivates rat hepatic methionine adenosyltransferase in vivo by S-nitrosylation. Hepatology 1998; 28: 1051– 1057. MEDLINE 80 Jaeschke H, Fisher MA, Lawson JA, Simmons CA, Farhood A, Jones DA. Activation of caspase 3 (CPP32)-like proteases is essential for TNF-alpha-induced hepatic parenchymal cell apoptosis and neutrophil-mediated necrosis in a murine endotoxin shock model. J Immunol 1998; 160: 3480– 3486. MEDLINE 81 Ambs S, Ogunfusika MO, Merriam WG, Bennett WP, Billiar TR, Harris CC. Up-regulation of inducible nitric oxide synthase expression in cancer-prone p53 knockout mice. Proc Natl Acad Sci U S A 1998; 95: 8823– 8828. MEDLINE 82 Rai RM, Lee FY, Rosen A, Yang SQ, Lin HZ, Koteish A, Liew FY, et al. Impaired liver regeneration in inducible nitric oxide synthasedeficient mice. Proc Natl Acad Sci U S A 1998; 95: 13829– 13834. MEDLINE 83 Bartsch H, Ohshima H, Pignatelli B, Calmels S. Endogenously formed N-nitroso compounds and nitrosating agents in human cancer etiology. Pharmacogenetics 1992; 2: 272– 277. MEDLINE 84 Ohshima H, Bartsch H. Chronic infections and inflammatory processes as cancer risk factors: possible role of nitric oxide in carcinogenesis. Mutat Res 1994; 305: 253– 264. MEDLINE Citing Literature Volume30, Issue1July 1999Pages 1-5 ReferencesRelatedInformation