Study Of Losarton In Suppressing Pancreatic Fibrosis

The relationship between reno-angiotensin system(RAS) and pancreatic fibrosis has been paid much attention in recent years. It is well known that RAS whose final and bioactive product, angiotensin Ⅱ, plays an important endocrine role in the maintenance of blood pressure and electrolyte as well as fluid balance. In addition to this circulating RAS, there are an increasing number of studies to suggest the existence of a local angiotensin-generating system in several tissues. The so-called tissue RAS can act locally as a paracrine and/or autocrine factor in meeting specific needs for individual tissues and it can operate, in whole or in part, independently of the circulating counterpart. Recent studies on the expression and localization of key RAS components, particularly angiotensinogen and renin, have provided solid evidence for the existence of an intrinsic, angiotensin-generating system in the pancreas. The presence of angiotensin Ⅱ, angiotensinogen protein and angiotensinogen mRNA have been documented in the dog pancreas (Chappell 1991). Moderately high quantities of angiotensin Ⅱ, angiotensin Ⅲ and angiotensin Ⅱ levels were found. The concentrations of these peptides were several times higher than those measured in blood, indicating that local generation of angiotensin Ⅱ may occur in the canine pancreas. The notion for the existence of a tissue RAS in the rat pancreas has been consolidated based on the expression and localization of angiotensinogen, the mandatory component for anintrinsic RAS. In rat model of pancreatitis, mRNA level of angiotensinogen greatly increases while their relevant receptor in model seems no difference in contrast with mormal control. All above described shows RAS plays a important role in local pancrease and in the development of some pancreatic diseases.RAS can be activated by many diseases such as acute pancreatitis, chronic pancreatitis , pancreatic cystic fibrosis and pancreatic tumor, then its activation can lead to multiple effects through direct or indirect ways. RAS acts comlicated and extensively in pancreas and draws close relation with pancreatic inflammation, β-cell apoptosis and death as well as pancreatic fibrosis. As a result, RAS take great effect in the function or disease in pancreas. In caeruline-induced pancreatitis rats that are angiotensinⅡ AT1 receptor deficient, TGF-β (transforming growth factor-β) protein level is much more lower than normal control andECM(extracellular matrix) components deposition proves to be slighter as well. Additonal experiments using ACEI and/or ATII receptor antagonist demonstrated that inhibition of ATIIduring regeneration from cerulein-induced pancreatitis is associated with decreased levels of both TGF mRNA and ECM components especially Collagen type I, at same time the gross appearance of the pancreas in untreated models are more severely atrophic and contain more wide damages. All above suggest that RAS plays an important role in the regulation of extracellular matrix proteins during regeneration from pancreatitis via TGF. Through the immunohistochemistry we can see accompanied decrease of expression of a-SMAand desmin which are specific signs for activation of PSCs, it indicates that all the ongoing changes in pancreatic fibrosis is linked with the declination of pancreatic stellate cells(PSCs) activation affected by ATII inhibitors. On the whole, using drugs to inhibit RAS shed new light on the prevention or delaying the development of pancreatic fibrosis and they will do more favor to the pancteatitis, pancreatic cells apoptosis and consequent fibrosis.In this study ,we took on the pancreatitis rat as our animal model ,and utilized immunohistochemistry and RT-PCR as well as light microscopy to explore the changes under the affect of Losarton, a ATII receptor antagonist in order that we can have a view about the RAS and pancreatic fibrosis and finally present some new ideas to clinic method on fibrosis.The main results and conclusions are as follows:1. As shown in picture, pancreas in untreated and treated group were severely congestive and dropsical and it seems time parallel. Though we see no obvious diversity about the two group, we discerned more slight in congestion.2. All but sham ones had focal severe inflammation in their pancreas. Massive infiltration of neutrophils, lymphocytes, and plasma cell, disappearance of acinar cells and replacement with fibous tissue. There seems no obivious diversity naked eyes.3. a-SMA-positive cells that have the morphology of activated PSCs were localized in the peri-acinar fibrotic areas and vascular walls in the rat except sham animals. And ,the 120 h grout is much severe than 72 h timepoint. The collagen I indicates surrounding the PSCs in pancreas and shares the same character of time parallel. However, analysis of the photograph by Image Pro Plus showed no obvious diversity between treated and untreadedgroups too.4.RT-PCR revealed that TGF-P mRNA was overexpressed in the pancreas of pancreatitis rat except sham ones in SD rats. It peaked in 72 h and declined gradually at followed periods. However statistics showed it was more slightly decreased in treated rats than untreated ones. Disappointedly it didn't happen to collagen I mRNA. Further analysis to collagen I mRNA didn't find any diversity between the two groups. However different from the expression of TGF-(3 mRNA, collagen mRNA showed time parallel, the expression in 120h was more upregulated than 72 h, which somewhat refered the relationship between TGF-(3 and collagen I expression.