TGFbeta and the extracellular matrix in pancreatitis

Abstract

Regeneration from cerulein-induced pancreatitis is accompanied by a transient synthesis and deposition of extracellular matrix components in the rat pancreas. To study the involvement of transforming growth factor beta1 (TGFbeta1), one of the most potent modulators of the extracellular matrix, in the process of pancreatic regeneration we examined the expression of this gene on the transcript and protein level in pancreata of rats sacrificed 0 hours, 24 hours, 2, 3, 5, 7 days after a 12 hour infusion of maximal doses of cerulein (10 microg kg(-1) h(-1)). TGFbeta1 protein increased twofold after 24 hours and 48 hours and returned to control values 7 days after induction of pancreatitis, while TGFbeta1-mRNA reached maximal values (3-fold over controls) after 2 days. The largest amount of TGFbeta1 mRNA was found in pancreatic acinar cells and in stromal cells. To verify the functional implication of TGFbeta overexpression in regulating extracellular matrix remodeling during regeneration from acute pancreatitis, rats were treated with 3 injections of neutralizing antibody against TGFbeta1 given 30 min before, and 24 hours and 48 hours after the start of infusion. In rats treated with maximal doses of cerulein and TGFbeta antibodies, pancreatic hydroxyproline content and expression of collagens I and III and of TGFbeta1 were significantly reduced. These results provide evidence that transforming growth factor beta1 among other cytokines is involved in the regulation of extracellular matrix remodeling in the rat pancreas during regeneration from cerulein-induced acute pancreatitis. In addition, there is evidence in the literature that application of recombinant TGFbeta after recurrent episodes of acute cerulein-induced pancreatitis promotes pancreatic fibrosis (3). Thus, TGFbeta is a regulator of extracellular matrix remodeling in the pancreas, and may be an important promoting factor in the pathogenesis of chronic pancreatitis. This hypothesis is supported by data in the literature showing enhanced TGFbeta expression in human chronic pancreatitis (2) and development of fibrosis and inflammation in pancreata of transgenic mice overexpressing TGFbeta1 (3).