TGF beta and the extracellular matrix in pancreatitis

Regeneration from cerulein-induced pancreatitis is accompanied by a transie nt synthesis and deposition of extracellular matrix components in the rat p ancreas. To study the involvement of transforming growth factor beta 1 (TGF beta 1), 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 mu gkg(-1)h(-1)). TGF beta 1 protein increased twofold afte r 24 hours and 48 hours and returned to control values 7 days after inducti on of pancreatitis, while TGF beta 1-mRNA reached maximal values (3-fold ov er controls) after 2 days. The largest amount of TGF beta 1 mRNA was found in pancreatic acinar cells and in stromal cells. To verify the functional i mplication of TGF beta overexpression in regulating extracellular matrix re modeling during regeneration from acute pancreatitis, rats were treated wit h 3 injections of neutralizing antibody against TGF beta 1 given 30min befo re, and 24 hours and 48 hours after the start of infusion. In rats treated with maximal doses of cerulein and TGF beta antibodies, pancreatic hydroxyp roline content and expression of collagens I and III and of TGF beta 1 were significantly reduced. These results provide evidence that transforming gr owth factor beta 1 among other cytokines is involved in the regulation of e xtracellular 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 TGF beta after recurrent episod es of acute cerulein-induced pancreatitis promotes pancreatic fibrosis (3). Thus, TGF beta is a regulator of extracellular matrix remodeling in the pa ncreas, and may be an important promoting factor in the pathogenesis of chr onic pancreatitis. This hypothesis is supported by data in the literature s howing enhanced TGF beta expression in human chronic pancreatitis (2) and d evelopment of fibrosis and inflammation in pancreata of transgenic mice ove rexpressing TGF beta 1 (3).