Nitric Oxide: A Novel Mediator of Inflammation

Abstract

Nitric oxide (NO), first identified as an endothelium-derived relaxation factor, is now recognized to regulate the functions of many mammalian cells and tissues. Nitric oxide is synthesized via the oxidation of arginine by a family of nitric oxide synthases (NOS), which are either constitutive and calcium dependent (cNOS) or inducible and calcium independent (iNOS). The endogenous production of nitric oxide plays a vital role in the regulation of physiological processes (e.g., blood vessel tone, neurotransmission) as well as in host defense and immunity. There is increasing evidence that nitric oxide also plays a complex role in the modulation of the inflammatory response. The induction of nitric oxide synthase (iNOS) in tissues can lead to the sustained production of high concentrations of nitric oxide which may exert pro-inflammatory effects including vasodilation, edema, cytotoxicity, and the mediation of cytokine dependent processes. Conversely, the production of NO by endothelial cell cNOS may serve a protective, or anti-inflammatory, function by preventing the adhesion and release of oxidants by activated neutrophils in the microvasculature. In this review we describe the multifaceted role of nitric oxide in inflammation, particularly focusing on the regulation of inflammatory cells and the repertoire of molecular processes targeted by NO that control cellular functions. Nitric oxide is synthesized via L-arginine oxidation by a family of nitric oxide synthases (NOS). Isomeric forms of nitric oxide synthase, representing at least three distinct gene products, have been cloned in bovine, rat, mice, and human tissues (1-5) (Table I). The three isoforms of the enzyme vary in calcium dependence, kinetics, and regulation. However, all nitric oxide synthases are flavoproteins which require NADPH and tetrahydrobiopterin as co-factors. The amino acid sequences deduced from the cDNA of the endothelial and neuronal cNOSs and iNOS have been reported (1-3, 6).