Endotoxemia in Transgenic Mice With Antioxidant Enzymes

Abstract

Biochemical SocietyTransactions ( 1 996) 24 535s C49 ENDOTOXEMIA IN TRANSGENIC MICE WITH ANTIOXIDANT ENZYMES 0. Mlrochnitchenko. U. Palnltkar a n d M. lnouye R o b e r t Wood J o h n s o n M e d l c a l School, U n l v e r s l t y of M e d l c l n e a n d D e n t i s t r yof N e w J e r s e y , 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 IL-lp 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. LS2 9JTPhotodynamic Therapy (PDT) is a cancer therapy which uses reactive oxygen species produced by illuminating photosensitisers. localised in tumours. with light (Dolphin, 1994) Macrophages have been suggested t o play an important role in this therapy due to the high concentration o f photosensitising drug accumulated in these cells, in particular the tumour-associated population These cells may also play a part in inflammatory and immune responses which influence the outcome o f the treatment (Hamblin and Newman, 1994) This work demonstrates PDT o f a macrophage cell line, PuS18. using Polyhaematoporphyrin (PHP), one form o f the clinically approved drug, and a zinc pyridinium phthalocyanine (PPC). after illumination with a white light source, results in a rapid reduction o f cellular glutath...