Involvement of Heparanase in the Pathogenesis of Pancreatitis: Potential Therapeutic Target

Heparanase (Hpa) is the sole mammalian endoglycosidase that selectively degrades heparan sulphate. Extensively studied for its capacity to promote cancer progression, heparanase has been recently implicated as an important determinant in several inflammatory disorders as well. Present study examine whether Hpa is involved in the pathogenesis of cerulein-induced experimental acute pancreatitis (AP) in mice. AP is defined as an acute inflammatory process developing within the pancreatic gland with lesser or greater involvement of adjacent tissues and/or other organs.

Heparanase over-expressing transgenic mice (hpa-TG), their wild-type (wt) BALB/c mice and heparanase knockout mice (hpa-KO), their wt C57BL mice were intraperitoneally injected with Cerulein (50 mg/kg, 5 times, at 1 hour apart) or vehicle. Cerulein-induced pancreatitis in wt mice was associated with significant rise in serum levels of amylase and lipase, accompanied by enhanced heparanase activity and inflammation in the pancreas. The elevation in amylase and lipase levels as well as pancreatic edema/inflammation in response to cerulein, were profoundly exaggerated in hpa-TG vs. wt mice. In contrast severity of pancreatitis was attenuated in hpa-KO mice as compared with their wt controls. Heparanase over-expressing mice showed increased infiltration of neutrophils and increased expression of cathepsin L and phospho IκB in pancreas as compared to wt mice, after cerulein administration. Importantly, pretreatment with PG545 (400µg, 1-day prior to cerulein), a potent inhibitor of heparanase enzymatic activity, resulted in pronounced amelioration of inflammatory response. Altogether, results clearly demonstrate an important role of heparanase in the pathogenesis of AP. The protective effect of heparanase inhibition provides a rational basis for therapeutic application of heparanase inhibitors (i.e., PG545) in AP and possibly other inflammatory disorders.