K. Murakami et al., METALLOPROTEINASE INHIBITOR PREVENTS HEPATIC-INJURY IN ENDOTOXEMIC MICE, European journal of pharmacology, 341(1), 1998, pp. 105-110
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.