Free Radical Biology

Edited by: Karen Young Kreeger H. Rubbo, R. Radi, M. Trujillo, R. Telleri, B. Kalyanaraman, S. Barnes, M. Kirk, B.A. Freeman, "Nitric oxide regulation of superoxide and peroxynitrite-dependent lipid peroxidation," Journal of Biological Chemistry, 269:26066-75, 1994. (Cited in more than 70 publications as of August 1996) Comments by Bruce Freeman, University of Alabama, Birmingham Understanding the chemical actions of nitric oxide (NO)-- a free radical species that acts as a mediator of signal transduction -- has been a hot topic of research since the late 1980s. Nitric oxide, because of its unpaired electron, is classified as a free radical and displays important reactivities with certain types of proteins and other free radicals. Researchers first observed nitric oxide's role in mediating blood vessel dilation, the killing of invading pathogens by macrophages, and the normal functioning of platelets and neurotransmission. During these early NO studies, investigators believed the chemical to be "inactivated" by the superoxide, another oxygen free radical, remarks Bruce Freeman, a professor of anesthesiology at the University of Alabama, Birmingham. This reaction, he says, was actually found to yield the more potent oxidant, peroxynitrite (J.S. Beckman et al., Proceedings of the National Academy of Sciences, 87:1620-4, 1990). Peroxynitrite is now recognized by researchers as the culprit in many toxic reactions that were previously ascribed to its chemical precursors, superoxide and nitric oxide. "In the study [discussed here], we investigated model reactions using lipids and cellular membranes exposed to both superoxide and nitric oxide because we were frequently observing an unexpected and confounding protective action of nitric oxide in lung cell cultures exposed to a source of superoxide that also yielded peroxynitrite [H. Gutierrez et al., Free Radical Biology and Medicine, 21:43-52, 1996]," explains Freeman. "At the same time, we were seeing from our colleagues and the literature that nitric oxide would both increase and limit oxygen radical-related damage to not only chemical reaction systems, but also cell and animal models." DOUBLE IDENTITY: Studies led by, from left, coauthors Rafael Radi, Bruce Freeman, and Homero Rubbo, showed that NO can stimulate and inhibit tissue injury. From the lipid studies, Freeman and colleagues learned that nitric oxide can both stimulate and inhibit superoxide-mediated tissue injury, depending on the relative concentrations of different radical species. "Stimulation of injury was mediated by the formation of peroxynitrite, but when nitric oxide is in excess of superoxide, damage was limited, and at the same time, yielded novel nitric oxide-containing oxidized lipid species," notes Freeman. "Nitric oxide can have Jekyll and Hyde-like qualities in many pathologic processes," he says. "The persona being revealed depends on the oxidative milieu of nitric oxide's surroundings." He attributes the paper's frequent citation to researchers' interests in the double identity of nitric oxide; its potential action as an antioxidant; and the description of a new class of oxidized lipid species. Freeman also suggests that this observation eventually will have a significant impact on clinical issues. "The nitric oxide-containing lipid oxidation products described in the 1994 paper are reactive and can serve as mediators of events including redox regulation of gene expression and vascular or inflammatory cell function," he predicts. "This is becoming a provocative issue, especially since we have recently observed that nitric oxide-containing lipids accumulate in high concentrations in athero-sclerotic human vessels [H. Rubbo et al., J. Biol. Chem., in press]." The growing evidence of nitric oxide- and peroxynitrite- mediated reactions with proteins and carbohydrates, as well as lipids, is leading investigators to better understand the critical role that NO has in the pathologic process of many diseases and disorders. Freeman notes some of the clinical areas in which these reactions are significant: stroke, heart attack, and organ transplantation; atherogenesis; arthritis; and respiratory distress syndrome. "Decreasing inflammation, avoiding free radical injury, and improving vascular function plays a big part in all of these applications," notes Freeman. "It is especially important to learn the conditions where nitric oxide reveals its dark side, in contrast to its protective actions, because new treatments for vascular dysfunction are being tested or are on the horizon. These include applications in new and established intravenously administered drugs, as well as gene therapies using nitric oxide synthases."

Free Radical Biology

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