Lipopolysaccharide precipitates hepatic encephalopathy and increases blood–brain barrier permeability in mice with acute liver failure

Background & Aims Acute liver failure ( ALF ) is frequently complicated by infection leading to precipitation of central nervous system complications such as hepatic encephalopathy ( HE ) and increased mortality. There is evidence to suggest that when infection occurs in ALF patients, the resulting pro‐inflammatory mechanisms may be amplified that could, in turn, have a major impact on blood–brain barrier ( BBB ) function. The aim of this study was to investigate the role of endotoxemia on the progression of encephalopathy in relation to BBB permeability during ALF . Methods Adult male C57‐ BL 6 mice with ALF resulting from azoxymethane‐induced toxic liver injury were administered trace amounts of the endotoxin component lipopolysaccharide ( LPS ). Effects on the magnitude of the systemic inflammatory response, liver pathology and BBB integrity were measured as a function of progression of HE , defined as time to loss of corneal reflex (coma). Results Lipopolysaccharide caused additional two‐ to seven‐fold ( P  < 0.001) increases in circulating pro‐inflammatory cytokines (TNF‐α, IL‐1β, IL‐6), worsening liver pathology and associated increases of circulating transaminases as well as increased hyperammonaemia consistent with a further loss of viable hepatocytes. LPS treatment of ALF mice led to a rapid precipitation of hepatic coma and the BBB became permeable to the 25‐kDa protein immunoglobulin G (IgG). This extravasation of IgG was accompanied by ignificant up‐regulation of matrix metalloproteinase‐9 (MMP‐9), an endopeptidase known to modulate opening of the BBB in a wide range of neurological disorders. Conclusions These findings represent the first direct evidence of inflammation‐related BBB permeability changes in ALF .