Mechanisms of enhanced allyl alcohol hepatotoxicity by endotoxin.

摘要

Lipopolysaccharide (LPS) causes enhancement of toxicity from a number of xenobiotics including allyl alcohol. The mechanism by which LPS enhances the hepatotoxicity of allyl alcohol was investigated. Kupffer cells are critical for the enhancement of allyl alcohol hepatotoxicity by LPS. Stimulation of Kupffer cells with LPS in either Kupffer cell-hepatocyte cocultures or isolated, perfused livers from naive rats did not induce the enhancement of allyl alcohol hepatotoxicity. These data indicate that Kupffer cells require the participation of other factors not present in the medium-perfused liver. Extrahepatic factors critical to large dose LPS-induced liver injury include neutrophils and thrombin. A role for each of these factors in the potentiation of allyl alcohol-induced liver injury by LPS was investigated. Neutrophils were previously known to play a critical role in this potentiation model. Allyl alcohol is well known to rapidly deplete glutathione stores in hepatocytes. Therefore, it was hypothesized that neutrophils enhance the toxicity of allyl alcohol through the release of reactive oxygen species onto hepatocytes depleted of their glutathione. While neutrophil-derived reactive oxygen species caused a slight enhancement of allyl alcohol-induced cytotoxicity in vitro, in vivo administration of the antioxidants superoxide dismutase and catalase or apocynin did not afford protection from the potentiation of allyl alcohol toxicity by LPS. These data indicate that neutrophil-derived reactive oxygen species do not play a critical role in this potentiation model. To begin to investigate the role of thrombin rats were pretreated with the anticoagulants heparin or warfarin. Both of these anticoagulants protected against LPS enhancement of allyl alcohol-induced liver injury. These results suggested that thrombin might play a critical role in this potentiation model. To determine whether thrombin was acting through a receptor mediated mechanism to enhance the toxicity of allyl alcohol, isolated, perfused livers from LPS-treated rats were perfused with medium containing allyl alcohol in the absence or presence of thrombin. In these experiments thrombin did not enhance the toxicity of allyl alcohol indicating that the role of thrombin in this potentiation model may be dependent on other coagulation factors or other components of the blood. In conclusion, LPS enhances the hepatotoxicity of allyl alcohol through a complex mechanism in which the roles of Kupffer cells, neutrophils and thrombin are interdependent.