The goal of this research project is to define the role of peroxynitrite in chemical-induced liver injury. Many hepatotoxicants are damaging due to their ability to increase oxidative stress within the liver. Recently, Kupffer cells have been shown to be involved in the initiation and/or progression of liver injury by a number of hepatotoxicants. After exposure of these hepatotoxicants, the Kupffer cells become activated, and release a number of mediators, many of which have been reported to be toxic. These include cytokines, eicosanoids and reactive oxygen species, such nitric oxide, superoxide anion and peroxynitrite. Peroxynitrite, which is formed by the energetically favorable reaction of superoxide anion and nitric oxide, is a novel, potent oxidizing agent. It is a highly reactive molecule known to react with proteins and inhibit vital cellular processes. Other cell types can also generate peroxynitrite. Consequently, peroxynitrite has been implicated in a number of diseases including stroke, atherosclerosis and pulmonary edema. However, no studies to date have examined its role in liver injury. This proposal will examine the formation of peroxynitrite in liver after exposure to model hepatotoxicants and determine the susceptibility of the hepatocyte towards this mediator. It is our hypothesis that peroxynitrite is directly involved in the progression of chemical-induced liver injury. These studies will give further insight of the mechanisms of chemical- induced liver injury and may ultimately lead to treatment of individuals exposed to hepatotoxicants.
