Nitric oxide (NO) is a free radical endogenously produced by nitric oxide synthase. This molecule possesses many important functions in the mammalian organism. The role of NO in regulating cell death and proliferation is now widely recognized. In cultured primary hepatocytes both proapoptotic and antiapoptotic NO effects have been reported. However, most reports support its role in the inhibition of apoptosis. NO has been shown to suppress apoptosis in a model of inflammation and cholestasis, and inhibits spontaneous apoptosis. NO antiapoptotic function was exerted via inhibition of both activity and activation of caspases either directly by nitrosylation, or indirectly via an cGMP-dependent pathway. Both spontaneous and induced hepatocyte apoptosis can be determined by biochemical and morphological methods, which cover various aspects of the apoptotic process, and have a different specificity for detection of apoptotic cell death.
cell proliferation; NO donor; caspase-3; hepatotoxicity; TNF-alpha
Alam MS, Akaike T, Okamoto S, Kubota T, Yoshitake J, Sawa T, Miyamoto Y, Tamura F, Maeda H: Role of nitric oxide in host defense in murine salmonellosis as a function of its antibacterial and antiapoptotic activities. Infect Immun 70:3130-3142, 2002.
Albina J, Cui S, Mateo R, Reichner J: Nitric oxide-mediated apoptosis in murine peritoneal macrophages. J Immunol 150:5080-5085, 1993.
Billiar TR: Nitric oxide: Novel biology with clinical relevance. Ann Surg 221:339-349, 1995.
Bredt DS, Snyder SH: Nitric oxide, a novel neuronal messenger. Neuron 8:3-11, 1992.
Cascales M, Alvarez A, Gasco P, Fernandez-Simon L, Sanz N, Bosca L: Cocaine-induced liver injury in mice elicits specific changes in DNA ploidy and induces programmed death of hepatocytes. Hepatology 20:992-1001, 1994.
Cheng W, Li B, Kajstura J, Li P, Wolin MS, Sonnenblick EH, Hintze TH, Olivetti G, Anversa P: Stretch-induced programmed myocyte cell death. J Clin Invest 96:2247-2259, 1995.
Chun SJ, Eisenhauer KM, Kubo M, Hsueh AJW: Interleukin-1beta suppresses apoptosis in rat ovarian follicles by increasing nitric oxide production. Endocrinology 136:3120-3127, 1995.
Court FG, Wemyss-Holden SA, Dennison AR, Maddern GJ: The mystery of liver regeneration. Br J Surg 89:1089-1095, 2002.
Dimmeler S, Haendeler J, Nehls M, Zeiher AM: Suppression of apoptosis by nitric oxide via inhibition of interleukin-1beta-converting enzyme (ICE)-like and cysteine protease protein (CPP)- 32-like proteases. J Exp Med 185:601-608, 1997.
Farghali H, Canova N, Kucera T, Martinek J, Masek K: Nitric oxide synthase inhibitors modulate lipopolysaccharide-induced hepatocyte injury: dissociation between in vivo and in vitro effects. Int Immunopharmacol 3:1627-1638, 2003.
Fehsel K, Kroncke KD, Meyer KL, Huber H, Wahn V, Kolb-Bachofen V: Nitric oxide induces apoptosis in mouse thymocytes. J Immunol 155:2858-2865, 1995.
Garcia-Trevijano ER, Martinez-Chantar ML, Latasa MU, Mato JM, Avila MA: NO sensitizes rat hepatocytes to proliferation by modifying S-Adenosylmethionine levels. Gastroenterology 122:1355-1363, 2002.
Geller DA, Nussler AK, Di Silvio M, Lowenstein CJ, Shapiro RA, Wang SC, Simmons RL, Billiar TR: Cytokines, endotoxin, and glucocorticoids regulate the expression of inducible nitric oxide synthase in hepatocytes. Proc Natl Acad Sci USA 90:522-526, 1993.
Genaro AM, Hortelano S, Alvarez A, Martinez C, Bosca L: Splenic B lymphocyte programmed cell death is prevented by nitric oxide release through mechanisms involving sustained Bcl-2 levels. J Clin Invest 95:1884-1890, 1995.
Goldin RD, Hunt NC, Clark J, Wickrmasinghe SN: Apoptotic bodies in a murine model of alcoholic liver disease: reversibility of ethanol-induced changes. J Pathol 171:73-76, 1993.
Green SJ, Meltzer MS, Hibbs JB Jr., Nacy CA: Activated macrophages destroy intracellular Leishmania major amastigotes by an L-arginine-dependent killing mechanism. J Immunol 144:278-283, 1990.
Gumpricht E, Dahl R, Yerushalmi B, Devereaux MW, Sokol RJ: Nitric oxide ameliorates hydrophobic bile acid-induced apoptosis in isolated rat hepatocytes by non-mitochondrial pathways. J Biol Chem 277:25823-25830, 2002.
Helyar L, Bundschuh DS, Laskin JD, Laskin DL: Induction of hepatic Ito cell nitric oxide production after acute endotoxemia. Hepatology 20:1509-1515, 1994.
Hierholzer C, Harbrecht B, Menezes JM, Kane J, MacMicking J, Nathan CF, Peitzman AB, Billiar TR, Tweardy DJ: Essential role of induced nitric oxide in the initiation of the inflammatory response after hemorrhagic shock. J Exp Med 187:917-928, 1998.
Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G: Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci USA 84:9265-9269, 1987.
Ishida A, Sasaguri T, Kosaka C, Nojima H, Ogata J: Induction of the cyclin-dependent kinase inhibitor p21Sdi1/Cip1/Waf1 by nitric oxide-generating vasodilator in vascular smooth muscle cells. J Biol Chem 272:10050-10057, 1997.
Ito Y, Takeda T, Umeshita K, Sakon M, Wakasa K, Matsuura N, Monden M: Fas antigen expression in hepatocellular carcinoma tissues. Oncol Rep 1:41-44, 1998.
Joshi MS, Ponthier JL, Lancaster JR Jr.: Cellular antioxidant and pro-oxidant actions of nitric oxide. Free Radic Biol Med 27:1357-1366, 1999.
Kaneto H, Fujii J, Seo HG, Suzuki K, Matsuoka T, Nakamura M, Tatsumi H, Yamasaki Y, Kamada T, Taniguchi N: Apoptotic cell death triggered by nitric oxide in pancreatic beta-cells. Diabetes 44:733-738, 1995.
Kibbe MR, Li J, Nie S, Watkins SC, Lizonova A, Kovesdi I, Simmons RL, Billiar TR, Tzeng E: Inducible nitric oxide synthase (iNOS) expression upregulates p21 and inhibits vascular smooth muscle cell proliferation through p42/44 mitogen - activated protein kinase activation and independent of p53 and cyclic guanosine monophosphate. J Vasc Surg 31:1214-1228, 2000.
Kilbourn RG, Jubran A, Gross SS, Griffith OW, Levi R, Adams J, Lodato RF: Reversal of endotoxin-mediated shock by NG-methyl-L-arginine, an inhibitor of nitric oxide synthesis. Biochem. Biophys Res Commun 172:1132-1138, 1991.
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 272:1402-1411, 1997a.
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 272:31138-31148, 1997b.
Lee NPY, Cheng CY: Regulation of Sertoli cell tight junction dynamics in the rat testis via the nitric oxide synthase/soluble guanylate cyclase/3',5'-cyclic guanosine monophosphate/ protein kinase G signaling pathway: An in vitro study. Endocrinology 144:3114-3129, 2003.
Li J, Billiar TR: Nitric Oxide IV. Determinants of nitric oxide protection and toxicity in liver. Am J Physiol 276:G1069-G1073, 1999.
Li J, Bombeck CA, Yang S, Kim YM, Billiar TR: Nitric oxide suppresses apoptosis via interrupting caspase activation and mitochondrial dysfunction in cultured hepatocytes. J Biol Chem 274:17325-17333, 1999.
Liu J, Saavedra JE, Lu T, Song JG, Clark J, Waalkes MP, Keefer LK: O2-Vinyl 1-(pyrrolidin-1-yl) diazen-1-ium-1, 2-diolate protection against D-galactosamine/endotoxin-induced hepatotoxicity in mice: Genomic analysis using microarrays. J Pharmacol Exp Ther 300:18-25, 2002.
Liu Z, Martin LJ: Motor neurons rapidly accumulate DNA single-strand breaks after in vitro exposure to nitric oxide and peroxynitrite and in vivo axotomy. J Comp Neurol 432:35-60, 2001.
Mannick JB, Asano K, Izumi K, Kieff E, Stamler JS: Nitric oxide produced by human B lymphocytes inhibits apoptosis and Epstein-Barr virus reactivation. Cell 79:1137-46, 1994.
Muriel P: Nitric oxide protection of rat liver from lipid peroxidation, collagen accumulation, and liver damage induced by carbon tetrachloride. Biochem Pharmacol 56:773-779, 1998.
Murphy MP: Nitric oxide and cell death. Biochim Biophys Acta 1178:153-175, 1993.
Muscara MN, Wallace JL: Nitric Oxide V. Therapeutic potential of nitric oxide donors and inhibitors. Am J Physiol 276:G1313-G1316, 1999.
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 1:404-416, 1997.
Palluy O, Rigaud M: Nitric oxide induces cultured cortical neuron apoptosis. Neurosci Lett 208:1-4, 1996.
Patel T, Bronk SF, Gores GJ: Increases of intracellular magnesium promote glycodeoxycholate - induced apoptosis in rat hepatocytes. J Clin Invest 94:2183-2192, 1994.
Rai RM, Lee FYJ, Rosen A, Yang SQ, Lin HZ, Koteish A, Liew FY, Zaragoza C, Lowenstein C, Diehl AM: Impaired liver regeneration in inducible nitric oxide synthase-deficient mice. Proc Natl Acad Sci USA 95:13829-13834, 1998.
Saavedra JE, Billiar TR, Williams DL, Kim YM, Watkins SC, Keefer LK: Targeting nitric oxide (NO) delivery in vivo. Design of a liver-selective NO donor prodrug that blocks tumor necrosis factor-alpha-induced apoptosis and toxicity in the liver. J Med Chem 40:1947-54, 1997.
Sarih M, Souvannavong V, Adam A: Nitric oxide synthase induces macrophage death by apoptosis. Biochem Biophys Res Commun 191:503-508, 1993.
Schoemaker MH, Ros JE, Homan M, Trautwein C, Liston P, Poelstra K, van Goor H, Jansen PLM, Moshage H: Cytokine regulation of pro- and anti-apoptotic genes in rat hepatocytes: NF-kappaB-regulated inhibitor of apoptosis protein 2 (cIAP2) prevents apoptosis. J Hepatol 36:742-750, 2002.
Spitzer JA: Cytokine stimulation of nitric oxide formation and differential regulation in hepatocytes and nonparenchymal cells of endotoxemic rats. Hepatology 19:217-228, 1994.
Strand S, Hofmann WJ, Grambihler A, Hug H, Volkmann M, Otto G, Wesch H, Mariani SM, Hack V, Stremmel W, Krammer PH, Galle PR: Hepatic failure and liver cell damage in acute Wilson's disease involve CD95 (APO-1/Fas) mediated apoptosis. Nature Med. 4(5):588-593, 1998.
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 116:2845-2851, 1995.
Tzeng E, Billiar TR, Williams DL, Li J, Lizonova A, Kovesdi I, Kim YM: Adenovirus - mediated inducible nitric oxide synthase gene transfer inhibits hepatocyte apoptosis. Surgery 124:278-283, 1998.
Wang JH, Redmond HP, Wu QD, Bouchier-Hayes D: Nitric oxide mediates hepatocyte injury. Am J Physiol 275:G1117-G1126, 1998.
Wiest R, Groszmann RJ: The paradox of nitric oxide in cirrhosis and portal hypertension: too much, not enough. Hepatology 35:478-491, 2002.