Overexpression of Smad6 exacerbates pancreatic fibrosis in murine caerulein-induced chronic pancreatic injuries.

Objectives: We examined the effect of the overexpression of Smad6 on pancreatic fibrosis after chronic pancreatic injury.

Methods: Chronic pancreatic injury was induced in transgenic mice overexpressing Smad6 (Tg mice) in acini and wild-type (Wt) mice by 3 episodes of acute pancreatitis per week for 1 to 4 consecutive weeks. Acute pancreatitis was elicited by 6 intraperitoneal injections of caerulein (Cn) at 50 microg/kg of body weight at hourly intervals. Pancreatic fibrosis was evaluated by histological examination and hydroxyproline content before and 1, 2, 3, and 4 weeks of repetitive episodes of Cn-induced acute pancreatitis. We further determined transforming growth factor beta1 (TGF-beta1) messenger RNA expression and trypsin activity in the pancreas.

Results: After repetitive episodes of acute pancreatitis, pancreatic fibrosis in Tg mice was significantly severer than that in Wt mice at all time points (weeks 1-4). The expression of TGF-beta1 messenger RNA and the activity of trypsin in the pancreas in the Tg mice were significantly high compared with those in the Wt mice at all corresponding time points after repetitive episodes of acute pancreatitis.

Conclusions: These results demonstrated that overexpression of Smad6 in acini enhanced the development of pancreatic fibrosis after chronic pancreatic injury.