Histamine restores biliary mass following carbon tetrachloride-induced damage in a cholestatic rat model.

Abstract

BACKGROUND: Bile duct ligation coupled with carbon tetrachloride induces apoptosis of large but not small cholangiocytes. Histidine decarboxylase regulates histamine synthesis. We have shown that: (i) cholangiocytes express histidine decarboxylase and secrete histamine and (ii) histamine stimulates biliary growth. AIMS: To demonstrate that histidine decarboxylase/histamine regulates cholangiocyte homeostasis after carbon tetrachloride treatment. METHODS: In vivo, normal and bile duct ligated rats were treated with saline or histamine (0.5mg/kg body weight) and given carbon tetrachloride by gavage 2 days before sacrifice. Serum, liver blocks and large cholangiocytes were obtained. Histidine decarboxylase, bile duct mass and proliferation were measured in liver sections and in cholangiocytes. Apoptosis was measured by immunohistochemistry and gene expression. Histamine levels were evaluated in serum. In vitro, large cholangiocytes were treated with carbon tetrachloride in the absence/presence of histamine before evaluating proliferation. RESULTS: After bile duct ligation there was enhanced ductal mass, histidine decarboxylase expression and serum histamine levels. Carbon tetrachloride treatment enhanced biliary apoptosis, and decreased histidine decarboxylase and serum histamine levels and biliary proliferation, changes that were restored by histamine. In vitro, cholangiocytes treated with carbon tetrachloride had a lower proliferative capacity that was reversed when cells were pre-treated with histamine. CONCLUSION: Histidine decarboxylase may be a key regulator of cholangiocyte homeostasis during biliary injury.