Endotoxemia in Transgenic Mice with Antioxidant Enzymes

C49 ENDOTOXEMIA IN TRANSGENIC MICE WITH ANTIOXIDANT ENZYMES 0. Mlrochni tchenko. U. Palnltkar and M. lnouye Rober t Wood J o h n s o n Med lca l School , Un lvers l ty of M e d l c l n e a n d D e n t i s t r y of New Je rsey , Plscataway, New Jersey, USA Reactive oxygen species (ROS) are known to be important mediators of cellular injury during inflammation, either by causing macromolecular damage or by interfering with extraand intracellular regulatory processes. We are using transgenic mice overexpressing human antioxidant enzymes: Cu,Zn superoxide dismutase (SOD) and two types of glutathione peroxidases (GP), intracellular (GPE) and extracellular (GPP), to investigate whether antioxidant enzymes can modulate host inflammatory response to lipopolysacharide (LPS). Groups of normal and transgenic mice were administered a large dose of LPS and mortality rates compared. Data obtained indicate that GP mice were more protected against LPS mediated toxicity. This effect was more profound in GPP mice, indicating the critical effect of GP production in the bloodstream. SOD transgenics exhibited a similar response as normal mice. Levels of TNFa and IL-1p in blood of normal and GP mice as well as level of ILlp mRNA in different tissues were measured. Our data show that GP transgenics produced an increased level of blood TNFa but a lower level of IL-Ip in comparison to the normal mice. Levels of lipid peroxide were significantly modulated in blood and tissues of GP transgenic mice. Since adherence of leukocytes to endothelium is a critical event in their migration to the inflammation foci, we determined the expression of integrins in GPP transgenic mice after LPS treatment. ICAM-1 mRNA and protein expression in different tissues of transgenic mice was reduced which in turn led to the lower migration of neutrophils into the tissues of transgenic mice as compared to normal animals. The results prove that ox-redox balance at the endothelium cell surface is a critical factor modulating adhesive interactions of these cells. These data provide new insights into the role of the antioxidant enzymes regulating levels of ROS during endotoxin-induced multiple organ failure.