Role of TGF-β1 in the development of pancreatic fibrosis in Otsuka Long-Evans Tokushima Fatty rats

Abstract

Recently established Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of naturally occurring obesity diabetes, exhibit progressive accumulation of connective tissue in the pancreas. The present study was designed to determine the pathogenic role of transforming growth factor-beta1 (TGF-beta1) in the development of pancreatic fibrosis in OLETF rats by investigating the serial changes in the expression of TGF-beta1 and extracellular matrix (ECM) in the pancreas. Progressive proliferation of connective tissue arose from the interstitial region surrounding islets at 20 wk of age and extended to the exocrine pancreas adjacent to the islets. TGF-beta1 mRNA levels in the pancreas increased at 20 wk of age and reached a peak value at 30 wk of age. Fibronectin (FN) and procollagen types I and III mRNAs peaked at 20 wk of age and remained at higher levels than those in the nondiabetic counterparts Long-Evans Tokushima Otsuka rats until 50 wk of age. Immunoreactivities for TGF-beta1 and FN were found in islets of OLETF rats at 20 wk of age and were seen in acinar and interstitial cells at 50 wk of age. Moreover, alpha-smooth muscle actin was located at interstitial region surrounding the islets. Proliferation of the connective tissue in the pancreas of OLETF rats closely correlated with expression of TGF-beta1 and ECM. Our results suggest that the development of pancreatic fibrosis in OLETF rats extends from endocrine to exocrine pancreas and that TGF-beta1 is involved in pancreatic fibrosis of OLETF rats.

Effect of emodin on pancreatic fibrosis in rats

“…The pathogenesis of chronic pancreatitis has not been completely understood. Nevertheless, it was reported that various factors such as TGF-β1, ECM, oxidative stress etc, are involved in the progression of pancreatic fibrosis [10,11] . Since pancreatic fibrosis is the characteristic feature of chronic pancreatitis, preventing and inverting pancreatic fibrosis is the key to therapy of chronic pancreatitis and amelioration of its prognosis.…”

Inhibition of transforming growth factor β decreases pancreatic fibrosis and protects the pancreas against chronic injury in mice

“…[2][3][4][5][6][7] Many studies have demonstrated the presence of TGF-b1 in the form of either protein or message, in the fibrotic tissues of human chronic pancreatitis and animal models. [8][9][10]23,32 Van Laethem et al 33 demonstrated that repeated injections of recombinant TGF-b into mice after recurrent episodes of acute pancreatitis led to pancreatic fibrosis. On the other hand, Menke et al 13 have demonstrated that inhibition of TGF-b1 by TGF-b1-neutralizing antibody causes partial reduction of the accumulation of ECM (collagen type I and III, and fibronectin) during regeneration from the cerulein-induced acute pancreatitis.…”

“…[19][20][21][22] Immunohistochemical staining of a-SMA was performed as described previously. 23 A DAKO EnVision system (Dako Cytomation) was used for collagen type I, fibronectin, and ssDNA immunostaining. Immunoreactivity of the Ki-67 antigen was visualized by the labeled streptavidinbiotin method (Dako Cytomation).…”

“…23 Five nonoverlapping fields per Azan-Mallory-stained pancreatic specimen (n ¼ 5) were randomly selected at  20 magnification by an investigator who was unaware of the sample identity. The rate of pancreatic fibrosis was indicated as a percentage of total pancreatic specimen.…”

The induction of insulinomas by X-irradiation to the gastric region in Otsuka Long-Evans Tokushima Fatty rats

“…At later than 40 weeks the rats become hypoinsulinemic, and exhibit defects in insulin secretion (9)(10)(11). Histologically, the OLETF rats also show progressive fibrosis in the pancreas (9,12). After 20 weeks, fibrosis and the enlargement of the islets clustered in connective tissue become prominent.…”