Transforming growth factor β promotes development of fibrosis after repeated courses of acute pancreatitis in mice

Abstract

Background and Aims: Transforming growth factor β (TGF-β) is a putative mediator of fibrosis in several chronic diseases. Recently, chronic pancreatitis was suggested to be related to acute pancreatitis in the so- called necrosis-fibrosis sequence hypothesis. The present study investigated whether TGF-β is able to promote chronic fibrosis after repeated courses of necrotizing acute pancreatitis induced by cerulein in mice. Methods: Six episodes of acute pancreatitis were repeatedly induced at weekly intervals in mice receiving either recombinant TGF-β (4 μg in 4 days) or excipient alone at each induction. One week after the last induction, pancreatic lesions and collagen deposition were histologically assessed. Expression of pancreatic fibronectin messenger RNA was also examined in both groups. Results: TGF-β had no influence on a single course of acute pancreatitis. After six courses of acute pancreatitis, only mild inflammatory changes were observed in the control group. In contrast, important areas of perilobular and intralobular fibrosis were observed adjacent to inflammatory and necrotic loci in the TGF- β group. Fibronectin messenger RNA expression was significantly higher in this group. Conclusions: TGF-β promotes development of pancreatic fibrosis after recurrent episodes of acute pancreatitis. This model of pancreatic fibrosis could be used as a model of chronic pancreatitis consistent with the necrosis-fibrosis sequence hypothesis.