Enhanced Expression of TGF-βs and Their Receptors in Human Acute Pancreatitis

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Abstract
To determine which mechanisms are involved in pancreatic remodeling, repair, and fibrosis after acute necrotizing pancreatitis (NP) in humans. Transforming growth factor betas (TGF-βs) are multifunctional polypeptides that have been implicated in the regulation and formation of extracellular matrix and fibrosis. They exert their functions by binding to specific receptors. In this study, we analyze the expression of TGF-β1, TGF-β2, and TGF-β3 and their receptors type I (Tβ-RI [ALK5]), type II (Tβ-RII), and type III (Tβ-RIII) in NP. Pancreatic tissue samples were obtained from 6 female and 8 male patients with a median age of 65 years (range, 37 to 77 years) undergoing surgery for NP. The median Ranson score of the patients was 6 (range, 2 to 9). The operation was performed a median 5.5 days (range, 4 to 17 days) after the onset of acute pancreatitis. Pancreatic tissue obtained from 12 previously healthy organ donors (6 male, 6 female; median age of 43 years) served as controls. The expression of TGF-β1, TGF-β2, TGF-β3, Tβ-RI (ALK5), Tβ-RII, Tβ-RIII, and collagen type I mRNA was analyzed by Northern blot analysis. In addition, immunohistochemical analysis using polyclonal antibodies was performed to detect TGF-β1, TGF-β2, TGF-β3, Tβ-RI (ALK5), and Tβ-RII. Northern blot analysis showed an increase in TGF-βs and their receptors in NP tissue samples compared with samples from normal controls. The increase was 3.5-fold for TGF-β1 (p < 0.05), 2.7-fold for TGF-β2 (p < 0.05), 3.5-fold for TGF-β3 (p < 0.05), 10-fold for Tβ-RI (ALK5) (p < 0.05), 5.7-fold for Tβ-RII (p < 0.05), and 1.4-fold for Tβ-RIII (not significant). Collagen type I mRNA was also markedly increased in NP samples and correlated with the level of TGF-βs. Immunohistochemical analysis demonstrated intense TGF-β1, TGF-β2, TGF-β3, Tβ-RI (ALK5), and Tβ-RII immunoreactivity in the remaining acinar and ductal cells in most NP samples; in the normal control pancreas, there was weak to moderate immunoreactivity for these factors only in some acinar cells and a few ductal cells. The marked increase in expression of TGF-βs and their signaling receptors Tβ-RI (ALK5) and Tβ-RII suggests a role for TGF-βs in the repair process after the onset of NP in humans and raises the possibility that TGF-βs might be involved in tissue remodeling and the fibrotic reaction that occurs in the pancreas after necrosis.