The Effects of Sirolimus on Pancreatic Fibrosis and Apoptosis in Experimental Chronic Pancreatit Model

Abstract

Purpose: Sirolimus reduces hepatic fibrosis by inhibiting hepatic stellat cells. We aimed to show the similar effect by inhibiting the pancreatic stellat cells in experimental chronic pancreatitis. Methods: In our study 55 male, Sprague-Dawley rats weighing between 200 and 400 grams randomized into four groups. Chronic pancreatitis is induced by injection of 0,4 ml, 2% trinitrobenzene sulfanic acid (TNBS) into major pancreatic duct. Group A (n=15): chronic pancreatitis + sirolimus; TNBS induction, 4 weeks later, 2 mg/kg/day oral sirolimus for 2 weeks; Group B (n=15): Chronic pancreatitis + placebo; TNBS induction, 4 weeks later 2 ml/kg/day oral water for 2 weeks. Group C (n=15): Chronic pancreatitis; TNBS induction, 4 weeks later sacrified. Group D (n=10): Pancreatic cannulation + sirolimus; 0,4 ml, % 0,9 NaCl injection into pancreatic duct, 4 weeks later 2 mg/kg/day oral sirolimus for 2 weeks. At the end of the ninth week in group of A, B and D all rats have been sacrifi ced, and rat pancreatic tissues, oxidative stress markers and progression of fibrosis and apoptsosis have been examined Results: Tissue and blood malondialdehyde (MDA) levels has been found significantly lower in sirolimus group compared to placebo group (p<0,001) and superoxide dismutase (SOD) and glutation peroxidase (GSH-Px) activities have been significantly higher. (Respectively p<0,001 and p<0,001). Tissue and blood MDA, SOD, GSH Px levels was no different significantly in the sirolimus group compared to the pancreatic cannulation group (p>0,05) (Table 1). Histopathological analysis of the tissues revealed that score of sirolimus group was significantly higher at respect to other groups (p<0,05). The levels of apoptotic cell of sirolimus group was higher at respect to placebo group, but this was not statistically significant (Table 2).Table: Table. Levels of oxidative stress markers in tissue and bloodTable: Table. Histopathological FindingsConclusion: Administration of sirolimus decreases oxidative stress in experimental chronic pancreatitis, but hasn't beneficial effects on fibrosis and apoptosis.