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Published on: December 21, 2011
Effect of endotoxin on release of reactive oxygen intermediates by rat hepatic macrophages
M J Arthur1, P Kowalski-Saunders, R Wright
1Department of Medicine II, Southampton General Hospital, United Kingdom.
Abstract:
Reactive oxygen intermediates released by activated hepatic macrophages have been implicated in the pathogenesis of a rat model of liver injury induced by sequential administration of Corynebacterium parvum and endotoxin. In this model, C. parvum causes extensive infiltration of the liver with activated macrophages, but severe liver injury occurs only after subsequent exposure to endotoxin. We have therefore investigated the effects of endotoxin on the release of reactive oxygen intermediates by C. parvum-activated hepatic macrophages. After in vitro exposure to zymosan, opsonized zymosan, or phorbol myristate acetate, hepatic macrophages isolated from C. parvum- and endotoxin-treated rats demonstrated significantly (1.5-2-fold) increased release of superoxide and oxidation of [1-14C]glucose via the hexose monophosphate shunt compared with hepatic macrophages isolated from C. parvum- and saline-treated control rats. These results indicate that endotoxin enhances the state of activation of hepatic macrophages already partially activated by C. parvum. We suggest that the increased release of reactive oxygen intermediates by these cells promotes liver injury in this model.
Insights
Endotoxin enhances the release of reactive oxygen intermediates by liver macrophages already activated by Corynebacterium parvum. This heightened release of reactive oxygen intermediates contributes to liver injury in a rat model.
Area of Science:
- Immunology
- Hepatology
- Toxicology
Background:
- Hepatic macrophages play a role in liver injury pathogenesis.
- Sequential administration of Corynebacterium parvum and endotoxin induces liver injury in rats.
- Corynebacterium parvum activates macrophages, but endotoxin is required for severe injury.
Purpose of the Study:
- To investigate the effect of endotoxin on reactive oxygen intermediate release from Corynebacterium parvum-activated hepatic macrophages.
- To understand the mechanism of endotoxin-induced potentiation of macrophage activation.
Main Methods:
- Isolation of hepatic macrophages from rats treated with Corynebacterium parvum and either endotoxin or saline.
- In vitro stimulation of macrophages with zymosan, opsonized zymosan, or phorbol myristate acetate.
- Measurement of superoxide release and hexose monophosphate shunt activity.
Main Results:
- Endotoxin treatment significantly increased superoxide release (1.5-2 fold) by activated hepatic macrophages.
- Hexose monophosphate shunt activity, indicative of reactive oxygen intermediate production, was also elevated.
- These effects were observed compared to control macrophages from rats treated with Corynebacterium parvum and saline.
Conclusions:
- Endotoxin enhances the activation state of hepatic macrophages primed by Corynebacterium parvum.
- Increased release of reactive oxygen intermediates by these hyperactivated macrophages likely contributes to liver injury.
- This study elucidates a key mechanism in endotoxin-mediated potentiation of inflammatory liver injury.
