METALLOPROTEINASE INHIBITOR PREVENTS HEPATIC-INJURY IN ENDOTOXEMIC MICE

This study was conducted to examine of [4-(N-hydroxyamino)-2 3S-(pheny lthiomethyl)-succinyl]-L-phenylalanine-N- methylamide (GI 129471), a m atrix metalloproteinase inhibitor, for its effects on increase of seru m pro-inflammatory cytokine levels as well as hepatic injury in D-gala ctosamine plus lipopolysaccharide-injected mice. In vitro experiments showed that GI 129471 was able to inhibit the elevation of tumor necro sis factor-alpha (TNF-alpha) in LPS-stimulated human and mouse whole b lood with IC50 values of 370 nM and 260 nM, respectively. When adminis trated i.p. at 40 mg/kg, GI 129471 significantly reduced serum TNF-alp ha level but not other pro-inflammatory cytokines in D-galactosamine p lus lipopolysaccharide injected mice. Treatment of mice with GI 129471 also reduced biochemical indices of hepatic injury to the normal leve l. Histopathological findings indicated that GI 129471 treatment can p revent severe centrilobular necrosis in liver. These results suggest t hat release of TNF-alpha from lipopolysaccharide-stimulated cells is t he critical step leading to hepatic injury in endotoxemia and that a m atrix metalloproteinase inhibitor with an inhibitory action on this st ep may be a promising drug for the clinical treatment of endotoxemia a ccompanied by hepatic injury. (C) 1998 Elsevier Science B.V.