Nitric oxide-derived oxidants. Basics and potential applications in inflammatory/infectious conditions

Abstract

The discovery that the free radical nitric oxide is enzymatically synthesized in mammals to exert major physiological functions has promoted paradigmatic changes in the field of free radical research, leading to the present view that free radicaIs and oxidants pIay a role in cell homeostasis, and not only in cell injury, as previously emphasized. In addition, the discovery of mammalian nitric oxide synthesis has brought into focus oxidants that were practically ignored in Biology up to the 90's such as peroxynitrite, nitrogen dioxide and carbonate radical anion (for a revision, Augusto et al, 2002, Free Radic. Biol. Med. 32, 841). A role for these nitric oxide-derived oxidants in plant pathophysiology has been recently supported by the characterization of a pathogen-induced nitric oxide synthase in plants (Chandock et ai, 2003, Cell 113, 469). In this context, in order to continue to contribute to the elucidation of the pathophysiological roles of free radicaIs, we will approach two general problems. The first, is the Biochemistry of nitric oxide-derived oxidants such as peroxynitrite, nitrogen dioxide and carbonate radical anion. We will focus on their biological sources and fates, particularly in their reactions with glutathione and proteins that are among their main cellular targets, as we have recently demonstrated. The second problem to be approached is the mechanism and the protection of cell injury in inflammatory and infectious conditions in animal models of leishmaniasis, hepatotoxicity, skin-flap necrosis, and others. As protectors, we will employ tempol and urate because we have recently demonstrated that they are efficient scavengers of nitric oxide-derived oxidants in vitro. In our view, these studies will provide relevant new information on: (i) the Biochemistry of nitric oxide-derived oxidants, the cellular defenses against them and their potential biomarkers; (ü) the oxida tive microbicidal mechanisms of phagocytic cells; and (üi) potential therapeutic approaches to reduce (eliminate) the tissue injury associated with int1ammatory and infectious conditions. (AU)