Metalloproteinase inhibitor prevents hepatic injury in endotoxemic mice
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K Murakami1, F Kobayashi, R Ikegawa
1Pharmacology Laboratories, Research Division, The Green Cross Corporation, Hirakata, Osaka, Japan. gcc39616@greencross.co.jp
Abstract:
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.
Insights
This study shows that GI 129471, a matrix metalloproteinase inhibitor, reduces liver injury and tumor necrosis factor-alpha (TNF-alpha) in mice. This suggests GI 129471 may treat endotoxemia with liver damage.
Area of Science:
- Pharmacology
- Hepatology
- Immunology
Background:
- Endotoxemia, often accompanied by hepatic injury, involves elevated pro-inflammatory cytokines.
- Matrix metalloproteinases (MMPs) play a role in inflammatory processes.
Purpose of the Study:
- To investigate the efficacy of GI 129471, an MMP inhibitor, in mitigating D-galactosamine/lipopolysaccharide-induced liver injury and cytokine elevation in mice.
- To explore the role of tumor necrosis factor-alpha (TNF-alpha) in endotoxemic liver damage.
Main Methods:
- In vitro inhibition of TNF-alpha by GI 129471 in LPS-stimulated whole blood.
- In vivo administration of GI 129471 to D-galactosamine/lipopolysaccharide-injected mice.
- Assessment of serum cytokine levels, liver injury biochemical markers, and liver histopathology.
Main Results:
- GI 129471 inhibited TNF-alpha elevation in vitro (IC50: 370 nM human, 260 nM mouse).
- In vivo, GI 129471 significantly reduced serum TNF-alpha levels and biochemical markers of hepatic injury.
- GI 129471 treatment prevented centrilobular necrosis in the liver.
Conclusions:
- TNF-alpha release is a critical factor in endotoxemia-induced hepatic injury.
- GI 129471 demonstrates potential as a therapeutic agent for endotoxemia with liver complications.
- MMP inhibition targeting TNF-alpha release may offer a novel treatment strategy.
