Characterization of a lipopolysaccharide mediated neutrophilic hepatitis model in Sprague Dawley rats

Several studies have investigated the role of neutrophils during endotoxin-mediated liver injury, yet the precise mechanism for endotoxin-mediated hepatic neutrophil transmigration is unknown. The primary objective of this study was to establish a reliable lipopolysaccharide (LPS)-mediated necro-hepatitis model to investigate the mechanisms of hepatic neutrophil infiltration following LPS administration. Male Sprague Dawley rats were administered a single (5 or 10 mg kg(-1), i.v.) or repeated injection of LPS (10 mg kg(-1), i.v., 24 h apart) with appropriate controls (i.v. saline) and were killed at various time points following LPS injection. Significant hematologic changes included neutrophilia, elevation of the neutrophil to lymphocyte ratio and toxic changes in neutrophils. Biochemical changes were observed in several liver (aspartate aminotransferase AST, gamma glutamyl transferase GGT) and kidney (blood urea nitrogen BUN) associated parameters generally at the earliest time points. Histopathology revealed a time-dependent neutrophil and mononuclear infiltration around the periportal areas in the single dose study and multifocal midzonal coagulative necrosis in the repeated dose study. The neutrophil adhesion molecule, CD 11b was up-regulated in single and repeat dose studies. Based on these studies, a reliable LPS-mediated hepatitis model with necrosis was developed by intravenous administration of LPS in a repeat dose fashion. Midzonal hepatic necrosis, peripheral neutrophilia, hepatic neutrophil infiltration and up-regulation of CD11b were the most significant and consistent markers of LPS mediated effects in this model.