Connective tissue growth factor is a regulator for fibrosis in human chronic pancreatitis

Objective To evaluate the parameters that mediate fibrogenesis in chronic pancreatiti s (CP). Background Connective tissue growth factor (CTGF), which is regulated by transforming growth factor beta (TGF-beta), has recently been implicated in skin fibrosi s and atherosclerosis. in the present study, the authors analyzed the conco mitant presence of TGF-beta 1 and its signaling receptors-TGF-beta receptor I, subtype ALK5 (T beta R-I-ALK5), and TGF-beta receptor II (T beta R-II)- as well as CTGF and collagen type I in the pancreatic tissue of patients un dergoing surgery for chronic pancreatitis. Patients and Methods CP tissue samples were obtained from 40 patients (8 women, 32 men) undergoi ng pancreatic resection. Tissue samples of 25 previously healthy organ dono rs (12 women, 13 men) served as controls. The expression of TGF-beta 1, T b eta R-I-ALK5, T beta R-II, CTGF, and collagen type I was studied by Norther n blot analysis. By in situ hybridization and immunohistochemistry, the res pective mRNA moieties and proteins were localized in the tissue samples. Results Northern blot analysis showed that CP tissue samples exhibited concomitant enhanced mRNA expression of TGF-beta 1 (38-fold), T beta R-II (5-fold), CTG F (25-fold), and collagen type I (24-fold) compared with normal controls. I n addition, T beta R-I-ALK5 mRNA was increased in 50% of CP tissue samples (1.8-fold). By in situ hybridization, TGF-beta 1, T beta R-I-ALK5, and T be ta R-II mRNA were often seen to be colocalized, especially in the ductal ce lls and in metaplastic areas where atrophic acinar cells appeared to dediff erentiate into ductal structures. In contrast, CTGF was located in degenera ting acinar cells and principally in fibroblasts surrounding these areas; M oreover, CTGF mRNA expression levels correlated positively with the degree of fibrosis in CP tissues. Conclusion The concomitant overexpression of CTGF, collagen type I, TGF-beta 1, and it s signaling receptors in CP suggests that these proteins contribute to enha nced extracellular matrix synthesis and accumulation, resulting finally in the fibrogenesis observed in CP.