Effects of fibrogenic mediators on the development of pancreatic fibrosis in a TGF-beta 1 transgenic mouse model

The pancreas morphology of transgenic mice that overexpress transforming gr owth factor-beta1 (TGF-beta1) in the pancreas resembles partially morpholog ical features of chronic pancreatitis, such as progressive accumulation of extracellular matrix (ECM). Using this transgenic mouse model, we character ized the composition of pancreatic fibrosis and involved fibrogenic mediato rs. On day 14 after birth, fibrotic tissue was mainly composed of collagen type I and III. At this time, mRNA levels of TGF-beta1 were increased. On d ay 70, the ECM composition was expanded by increased deposition of fibronec tin, whereas connective tissue growth factor, fibroblast growth factor (FGF )-1, and FGF-2 mRNA expression levels were elevated in addition to TGF-beta 1. In parallel, the number of pancreatic stellate cells (PSC) increased ove r time. In vitro, TGF-beta1 stimulated collagen type I expression but not f ibronectin expression in PSC, in contrast to FGF-2, which stimulated both. This confirms that TGF-beta1 mediates pancreatic fibrosis through activatio n of PSC and deposition of collagen type I and III at early time points. Fu rthermore, this points to an indirect mechanism in which TGF-beta regulates pancreatic ECM assembly by induction of additional growth factors.