Relationship between tumor necrosis factor-α and neutrophils in endotoxin-induced liver injury

Tumor necrosis factor-α (TNF-α) and blood neutrophils (polymorphonuclear leukocytes; PMNs) have been implicated in the pathogenesis of endotoxin (lipopolysaccharide, LPS) hepatotoxicity. However, the mechanism by which these factors mediate liver injury during LPS exposure is uncertain. The objective of this study was to test the hypothesis that TNF-α contributes to LPS hepatotoxicity by an indirect, PMN-dependent mechanism. Pretreatment of rats with an antiserum to TNF-α afforded protection against liver injury 6 h after LPS exposure. Pretreatment with pentoxifylline (100 mg/kg iv), which attenuated the increase in circulating TNF-α concentration 1.5 h after administration of LPS, also afforded protection against liver injury. Neither antiserum to TNF-α nor pentoxifylline affected hepatic PMN accumulation 1.5 h after LPS exposure. Depletion of circulating PMNs, which protects against LPS hepatotoxicity, enhanced circulating TNF-α concentration compared with control rats 1.5 h after LPS exposure. These results suggest that TNF-α contributes to liver injury after LPS exposure, but in the absence of circulating PMNs it is insufficient for full manifestation of liver injury. TNF-α apparently contributes to the pathogenesis of LPS-induced liver injury by an indirect, PMN-dependent mechanism.