Inducible nitric oxide synthase in the liver: regulation and functions

摘要

The inducible nitric oxide synthase (iNOS) gene is expressed by hepatocytes in a number of physiologic and pathophysiologic conditions affecting the liver including septic and hemorrhagic shock, The molecular regulation of iNOS expression is complex and occurs at multiple levels in the gene expression pathway: The cytokines TNF-#alpha#, ILl-#beta# and INF-#gamma# synergistically activate iNOS expression in the liver, and the human iNOS gene was first cloned from cytokine-stimulated hepatocytes, iNOS expression requires the transcription factor NF #kappa#B and is down-regulated by steriods, TGF-#beta#, the heat shock response, p53, and nitric oxide (NO) itself. In vivo, hepatic iNOS induction is differentially regulated from the typical acute-phase reactants and is not expressed as a mandatory component of the acute phase response. Thus, numerous mechanisms have evolved to regulate iNOS expression during hepatocellular injury. Studies of the effects.of NO, in the liver, demonstrate that induced NO synthesis plays an important role in hepatocyte function and protects the liver during sepsis and ischemia repefusion. Its cytoprotective role is best exemplified in a rodent model of endotoxemia. Here the addition of the non-specific NOS inhibitors significantly increased hepatic damage. NO exerts a protective effect through its ability to prevent intravascular thrombosis by inhibiting platelet adhesion and neutralizing toxic oxygen radicals. NO also exerts aprotective effects both in vivo and in vitro by blocking TNF-#alpha#-induced apoptosis and hepatotoxicity, in part by a thioldependent inhibition of caspase-3-1ike protease activity. These studies demonstrate the cytoprotective effects of NO in the liver and suggest that hepatic iNOS expression functions as an adaptive response to minimize inflammatory injury. In addition, NO has anti-tumor effects as well as known mutagenic effects, is involved in the systemic vasodilatation of cirrhosis, and has potent antimicrobial properties.