ABSTRACT
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.
Subject(s)
Pancreatitis, Chronic/pathology , Smad6 Protein/metabolism , Animals , Ceruletide/toxicity , Disease Progression , Fibrosis , Male , Mice , Mice, Transgenic , Pancreatitis, Chronic/chemically induced , Pancreatitis, Chronic/metabolism , Smad6 Protein/genetics , Transforming Growth Factor beta/analysis , Transforming Growth Factor beta/metabolism , Trypsin/analysis , Trypsin/metabolismABSTRACT
OBJECTIVES: To elucidate the role of transforming growth factor (TGF) beta1 and extracellular matrix (ECM) after acute necrotizing pancreatitis, we studied the regulation of TGF-beta1 and ECM after induction of pancreatitis. METHODS: We examined the serial changes of levels of plasma TGF-beta1 by enzyme-linked immunoassay and expression of TGF-beta1 and ECM by Northern and Western blot analyses, respectively, in the pancreas after induction of sodium taurocholate-induced acute pancreatitis. RESULTS: Plasma total (active and inactive) TGF-beta1 levels at 3 hours after induction of pancreatitis were significantly increased compared with baseline values. The levels of TGF-beta1 messenger RNA (mRNA) were unaltered by day 2. Levels of fibronectin mRNA at 3 hours after induction of pancreatitis were already higher than the baseline values. Latency-associated peptide-TGF-beta1 showed a peak on day 7. Thus, the expression of ECM mRNA increased earlier than that of TGF-beta1 mRNA. CONCLUSIONS: These results suggest that the increase in plasma TGF-beta1 concentration probably results from the elevated secretion of TGF-beta1 from several cells and/or the redistribution of TGF-beta1 protein and that the increase in expression of ECM probably is associated with the activation of TGF-beta1. It is conceivable that both increased plasma concentration and focal activation of TGF-beta1 play an important role in ECM production during the early stage of acute pancreatitis.
