BILIARY-SECRETION OF ENDOTOXIN AND PATHOGENESIS OF PRIMARY BILIARY-CIRRHOSIS

Previous studies suggested endotoxin, derived from the intestine throu gh the portal blood to the liver, was predominantly metabolized by Kup ffer cells. In the present study, fluorescent-labeled endotoxin inject ed into the rat portal vein was demonstrated not only in Kupffer cells but also in hepatocytes. Furthermore a great amount of labeled endoto xin was recovered in bile. In the livers of patients with primary bili ary cirrhosis (PBC), immunohistochemistry demonstrated significant ret ention of endotoxin in the biliary epithelial cells, and treatment wit h ursodeoxycholic acid significantly reduced the retention in those ce lls. The study for detection of apoptosis demonstrated increased rates of apoptosis in hepatocytes and biliary epithelial cells in PBC liver , and the rate of apoptosis in biliary epithelial cells was significan tly reduced after treatment with ursodeoxycholic acid. Immunohistochem istry in PBC liver demonstrated significant reduction of fluorescence intensity for a 7H6 antigen in biliary epithelial cells, indicating th e increased paracellular permeability of bile ducts, because cellular immunolocalization of that antigen has been shown to be inversely corr elated with the paracellular permeability of the tight junction. These results suggest that, in biliary epithelial cells, retention of endot oxin, increased apoptosis, and increased permeability of tight junctio ns may be involved in the pathogenesis of PBC.