Peroxynitrite and Peroxiredoxin in the Pathogenesis of Experimental Amebic Liver Abscess

Figure 1

Hypothetical model of the generation of ONOO⁻ in ALA. Under inflammatory conditions the two substrates of ONOO⁻, nitric oxide (NO) and the superoxide anion (O₂⁻), are produced simultaneously. This allows for the production of large quantities of ONOO⁻, which is a highly oxidizing agent. Indeed, the products of spontaneous decomposition of ONOO⁻, nitrate and nitrite, are found at higher than normal levels in inflamed tissue. The superoxide anion is produced by NADPH oxidase expressed in activated neutrophils, macrophages, and endothelial cells. NO is produced by NOS found in inflammatory cells or in the vascular endothelium. The protonated form of ONOO⁻ is disintegrated to form free nitrogen dioxide (^•NO₂) and the hydroxyl radical (^•OH). Under conditions of hepatic hypoxia, low concentrations of L-arginine and oxygen enhance arginase activity that hydrolyzes L-arginine, thus competing with the substrate for NOS enzymes. This leads to the uncoupling of NOS, simultaneously producing O₂⁻ and NO, and thus resulting in additional ONOO⁻ generation. ONOO⁻ reacts directly with thiol groups of host cells. High levels of ONOO⁻ lead to the development of ALA by inducing apoptosis and necrosis in hepatic cells.