Role Of Tissue Renin-Angiotensin System In The Pathogenesis Of Acute Pancreatitis And The Prophylactic And Therapeutic Treatments With Losartan

Part I The Induction of Rat Models of Acute Edema Pancreatitis and Necrotic Pancreatitis.Objective To induce rat models of acute edema pancreatitis(AEP) and acute necrotic pancreatitis(ANP). To provide rat models for the second and the third parts of this study. Methods Thirty Sprague-Dawley rats were randomly divided into three groups, control group, AEP group and ANP group. AEP model was induced by intraperitoneal injection of cerulein and ANP model was induced by intraperitoneal injection of L-arginine while the control group received same volume injections of 0.9% saline solution. Amylase in blood plasma, pancreas/body weight ratio were evaluated and pancreatic pathology was recorded. Results The amylases and the pancreas/body weight ratio increased significantly in both AEP and ANP groups and higher in ANP group. The pathology of pancreas in AEP group showed interstitial edema, inflammatory cells infiltration and acini swelling while in ANP group, the histological changes were more severe include acinar cell necrosis and bleeding. Conclusions Intraperitoneal injection of cerulein and L-arginine can induce AEP and ANP.Part II Role of Tissue Renin-Angiotensin System in the Pathogenesis of Acute Pancreatitis.Objective To study the role of tissue renin-angiotensin system in the pathogenesis of acute pancreatitis. Methods Thirty Sprague-Dawley rats were randomly divided into three groups, control group, AEP group and ANP group. AEP model was induced by intraperitoneal injection of cerulein and ANP model was induced by intraperitoneal injection of L-arginine while the control group received same volume injections of 0.9% saline solution. Amylase, angiotensinⅡ, renin, TNF-αand IL-1βin blood plasma and pancreas/body weight ratio were evaluated and pancreatic pathology was recorded. Angiotensinogen and angiotensinⅡreceptor AT1 were detected in pancreas by immunohistochemistry. The gene expression of angiotensinogen , renin and angiotensinⅡreceptor AT1 were investigated by RT-PCR. Results The amylases, angiotensinⅡ, renin, TNF-αand IL-1βincreased significantly in both AEP and ANP groups and higher in ANP group. The mRNA of angiotensinogen, renin and AT1 were also increased markedly in both pancreatitis groups compared to control group and higher in ANP group. The increase of TNF-αand IL-1βwas correlated with angiotensinⅡ, and these three substances'increases correlated with the severitity of pancreatitis. Angiotensinogen and angiotensinⅡreceptor AT1 localized to epithelia and endothelia of pancreatic ducts and blood vesels. Conclusions The data support the notion of an intrisinc RAS in the rat pancreas and the RAS was activated in acute pancreatitis. The local RAS may activate other cellular factors and play a role in the pathogenesis of acute pancreatitis.Part III Prophylactic and Therapeutic Treatments with Losartan Ameliorate Acute Pancreatitis and Pancreatitis-Associated Pulmonary Injury.Objective To prove the protective effects of losartan on acute pancreatitis and pancreatitis-associated pulmonary injury. Method Forty Sprague-Dawley rats were randomly divided into four groups, control group, ANP group, prophylactic treatment group and therapeutic treatment group. In the pancreatitis group, rats were given two intraperitoneal injections of L-arginine while the controls received same volume injections of 0.9% saline solution. For the prophylactic treatment groups, rats were injected intravenously with losartan two times at an hour interval 90min prior to the induction of pancreatitis. For the therapeutic treatment groups, animals were injected with losartan two times at an hour interval 30min after the induction of pancreatitis. Amylase, angiotensinⅡ, renin, TNF-αand IL-1βin blood plasma, lung myeloperoxidase, pancreas/body weight ratio and lung wet/dry weight ratio were evaluated. Pancreatic and pulmonary pathology were observed. The gene expression of angiotensinogen , renin and angiotensinⅡreceptor AT1 were investigated by RT-PCR. Results Both prophylactic and therapeutic treatments with losartan could ameliorate pancreatic and pulmanory injury induced by L-arginine, as observed by biochemical and histopathological study. The protective action of losartan was linked to inhibitions of TNF-αand IL-1βincreases, but not affect the angiotensinⅡand renin levels in plasma and the mRNA levels of angiotensinogen, renin and AT1 in pancreas. Conclusions Losartan ameliorates acute pancreatitis and pancreatitis-associated pulmonary injury in both prophylactic and therapeutic uses. This protective action may come from the inhibition of AT1 receptor and thus the decreases of other cellular factors.