Role Of Tnf Converting Enzyme In Tnf Production, Neutrophil Activation And Liver Injury In Hepatotoxic Interaction Of Lipopolysaccharide And Ranitidine

In rats, cotreatment with nontoxic doses of lipopolysaccharide (LPS) and ranitidine (RAN) causes liver injury. Previous studies showed that RAN augmented serum TNF production and neutrophil (PMN) activation after LPS treatment, and both TNF and neutrophils are crucial for the liver pathogenesis. We tested the hypothesis that TNF converting enzyme (TACE) is necessary for augmentation by RAN of TNF production, PMN activation and subsequent liver injury. LPS/RAN cotreatment elevated serum TNF; production as compared to LPS/Veh treatment, whereas it had no effects on hepatic TNF mRNA level. This suggests that RAN augmented TNF production by a post‐transcriptional mode. Indeed, LPS/RAN treatment increased hepatic TACE activation compared to LPS/Veh treatment. A TACE inhibitor, BMS‐561392, administered just before RAN reduced serum TNF protein. The inhibitor also reduced liver injury caused by LPS/RAN cotreatment. Interestingly, the TACE inhibitor also reduced plasma active PAI‐1, which has been shown to be causally involved in the pathogenesis of LPS/RAN‐induced liver injury. In fact, a PAI‐1 inhibitor, WAY‐140312, reduced hepatocellular injury and hepatic PMN activation. In summary, RAN enhanced TNF production after LPS treatment through TACE activation, which in turns led to PAI‐1 production, PMN activation and subsequent liver injury. (Supported by NIH grant DK061315.)