Antioxidant therapy: A new pharmacological approach in shock, inflammation, and ischemia/reperfusion injury

A vast amount of circumstantial evidence implicates oxygen-derived free rad icals (especially superoxide and hydroxyl radical) and high-energy oxidants (such as peroxynitrite) as mediators of inflammation, shock, and ischemia/ reperfusion injury. The aim of this review is to describe recent developmen ts in the field of oxidative stress research. The first part of the review focuses on the roles of reactive oxygen species (ROS) in shock, inflammatio n, and ischemia/reperfusion injury. The second part of the review deals wit h the novel findings using recently identified pharmacological tools (e.g., peroxynitrite decomposition catalysts and selective superoxide dismutase m imetics (SODm) in shock, ischemia/reperfusion, and inflammation. 1) The rol e of ROS consists of immunohistochemical and biochemical evidence that demo nstrates the production of ROS in shock, inflammation, and ischemia/reperfu sion injury. ROS can initiate a wide range of toxic oxidative reactions. Th ese include initiation of lipid peroxidation, direct inhibition of mitochon drial respiratory chain enzymes, inactivation of glyceraldehyde-3-phosphate dehydrogenase, inhibition of membrane sodium/potassium ATPase activity, in activation of membrane sodium channels, and other oxidative modifications o f proteins. All these toxicities are likely to play a role in the pathophys iology of shock, inflammation, and ischemia/reperfusion. 2) Treatment with either peroxynitrite decomposition catalysts, which selectively inhibit per oxynitrite, or with SODm, which selectively mimic the catalytic activity of the human superoxide dismutase enzymes, have been shown to prevent in vivo the delayed vascular decompensation and the cellular energetic failure ass ociated with shock, inflammation, and ischemia/reperfusion injury. ROS (e.g ., superoxide, peroxynitrite, hydroxyl radical, and hydrogen peroxide) are all potential reactants capable of initiating DNA single-strand breakage, w ith subsequent activation of the nuclear enzyme poly(ADP-ribose) synthetase , leading to eventual severe energy depletion of the cells and necrotic-typ e cell death. Antioxidant treatment inhibits the activation of poly(ADP-rib ose) synthetase and prevents the organ injury associated with shock, inflam mation, and ischemia/reperfusion.