Metalloproteinase inhibitor prevents hepatic injury in endotoxemic mice.

This study was conducted to examine of [4-(N-hydroxyamino)-2R-isobutyl-3S-(phenylthiomethyl)-succinyl]-L- phenylalanine-N-methylamide (GI 129471), a matrix metalloproteinase inhibitor, for its effects on increase of serum pro-inflammatory cytokine levels as well as hepatic injury in D-galactosamine plus lipopolysaccharide-injected mice. In vitro experiments showed that GI 129471 was able to inhibit the elevation of tumor necrosis factor-alpha (TNF-alpha) in LPS-stimulated human and mouse whole blood with IC50 values of 370 nM and 260 nM, respectively. When administrated i.p. at 40 mg/kg, GI 129471 significantly reduced serum TNF-alpha level but not other pro-inflammatory cytokines in D-galactosamine plus lipopolysaccharide-injected mice. Treatment of mice with GI 129471 also reduced biochemical indices of hepatic injury to the normal level. Histopathological findings indicated that GI 129471 treatment can prevent severe centrilobular necrosis in liver. These results suggest that release of TNF-alpha from lipopolysaccharide-stimulated cells is the critical step leading to hepatic injury in endotoxemia and that a matrix metalloproteinase inhibitor with an inhibitory action on this step may be a promising drug for the clinical treatment of endotoxemia accompanied by hepatic injury.