INDUCIBLE NITRIC-OXIDE SYNTHASE IN THE LIVER - REGULATION AND FUNCTION

The inducible nitric oxide synthase (iNOS) gene is expressed by hepato cytes in a number of physiologic and pathophysiologic conditions affec ting the liver including septic and hemorrhagic shock. The molecular r egulation of iNOS expression is complex and occurs at multiple levels in the gene expression pathway. The cytokines TNF-alpha, IL-1 beta, an d INF-gamma synergistically activate iNOS expression in the liver, and the human iNOS gene was first cloned from cytokine-stimulated hepatoc ytes. INOS expression requires the transcription factor NF-kB and is d own-regulated by steroids, TGF-beta, the heat shock response, p53, and nitric oxide (NO) itself. III vivo, hepatic iNOS induction is differe ntially regulated from the typical acute-phase reactants and is not ex pressed as a mandatory component of the acute phase response. Thus, nu merous mechanisms have evolved to regulate iNOS expression during hepa tocellular injury. Studies of the effects of NO in the liver demonstra te that induced NO synthesis plays an important role in hepatocyte fun ction and protects the liver during sepsis and ischemia reperfusion. I ts cytoprotective role is best exemplified in a rodent model of endoto xemia. Here the addition of the nonspecific NOS inhibitors significant ly increased hepatic damage. NO exerts a protective effect through its ability to prevent intravascular thrombosis by inhibiting platelet ad hesion and neutralizing toxic oxygen radicals. NO also exerts a protec tive effects both in vivo and in vitro by blocking TNF-alpha-induced a poptosis and hepatotoxicity, in part by a thiol-dependent inhibition o f caspase-3-like protease activity. These studies demonstrate the cyto protective effects of NO in the liver and suggest hepatic iNOS express ion functions as an adaptive response to minimize inflammatory injury. In addition, NO has anti-tumor effects as well as known mutagenic eff ects, is involved in the systemic vasodilatation of cirrhosis, and has potent antimicrobial properties.