Apoptotic cell death of hepatocytes in rat experimental severe acute pancreatitis

BACKGROUND: Apoptosis of hepatocytes has been reported to be involved in liver failure complicated with systemic manifestations such as endotoxemia. We hypothesized that hepatocyte apoptosis occurs in severe acute pancreatitis. METHODS: Induction of apoptosis was evaluated in the liver from rats with necrotizing pancreatitis. Apoptosis-inducing activity of the pancreatitis-associated ascitic fluid on hepatocytes was evaluated in vivo by intraperitoneal injection of the ascitic fluid and in vitro using rat primary hepatocyte culture. RESULTS: Apoptosis was detected in hepatocytes in the rats both with severe acute pancreatitis and with the intraperitoneal injection of the ascitic fluid by in situ nick-end labeling and DNA fragmentation. Apoptotic change and hepatic injury were ameliorated by administration of an interleukin-1 beta-converting enzyme inhibitor. The ascitic fluid exhibited cytocidal activity in rat primary hepatocyte culture via apoptosis, which was confirmed by DNA fragmentation, by cell cycle analysis, and by nuclear fragmentation. The neutralizing antibody for transforming growth factor-beta 1 partially blocked the apoptosis induction but the antibody to tumor necrosis factor-alpha had no effect. CONCLUSIONS: Apoptotic cell death occurs in hepatocytes in severe acute pancreatitis partially via transforming growth factor-beta 1 in the pancreatitis-associated ascitic fluid.