Abstract

whether Hpa is involved in the pathogenesis of cerulein-induced AP in mice. Material and Methods: Heparanase over-expressing transgenic mice (hpa-TG) and their wild-type (WT) BALB/c mice, and Hpa knockout mice (hpa-KO) and their WT C57BL mice were intraperitoneally injected with either Cerulein (50 mg/kg, 5 times, at 1 hour apart) or vehicle. Pancreatic Hpa activity, edema, and inflammation along blood amylase and lipase levels, were determined 24 hours following pancreatitis induction. Results: Cerulein-induced pancreatitis in wild type mice was associated with significant rises in the serum levels of amylase and lipase. These increases were characterized by enhancement of Hpa activity and pancreatic inflammation. The elevation in amylase and lipase as well as pancreatic edema/inflammation responses to administration of cerulein were profoundly exaggerated in hpa-TG mice. In contrast, when cerulein was injected to hpa-KO mice, the severity of pancreatitis was attenuated as compared with their wild type controls. Importantly, pretreatment with Hpa inhibitor (PG545) reduced significantly the inflammatory response of acute pancreatitis by ameliorating pancreatic edema, amylase, and lipase serum levels. Conclusions: The hpa-TG mice are more susceptible to acute pancreatitis than their WT controls, indicating a role for Hpa in the pathogenesis of this disease state. The pancreatic-protective effects of Hpa inhibition provide a rational basis for therapeutic application of Hpa inhibitors.

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