1 Scientific RepoRts | 7: 715 | DOI:10.1038/s41598-017-00715-6 www.nature.com/scientificreports the Role of Heparanase in the pathogenesis of Acute pancreatitis: A potential therapeutic target Iyad Khamaysi 1 , preeti singh 2 , susan Nasser 3 , Hoda Awad 3 , Yehuda Chowers 1 , edmond sabo 4 , edward Hammond 5 , Ian Gralnek 6 , Irena Minkov 4 , Alessandro Noseda 7 , Neta Ilan 2 , Israel Vlodavsky 2 & Zaid Abassi 3,8 Acute pancreatitis (Ap) is one of the most common diseases in gastroenterology. However, neither the etiology nor the pathophysiology of the disease is fully understood and no specifc or efective treatment has been developed. Heparanase is an endoglycosidase that cleaves heparan sulfate (Hs) side chains of Hs sulfate proteoglycans into shorter oligosaccharides, activity that is highly implicated in cellular invasion associated with cancer metastasis and infammation. Given that AP involves a strong infammatory aspect, we examined whether heparanase plays a role in AP. Here, we provide evidence that pancreatic heparanase expression and activity are signifcantly increased following cerulein treatment. Moreover, pancreas edema and infammation, as well as the induction of cytokines and signaling molecules following cerulein treatment were attenuated markedly by heparanase inhibitors, implying that heparanase plays a signifcant role in AP. Notably, all the above features appear even more pronounced in transgenic mice over expressing heparanase, suggesting that these mice can be utilized as a sensitive model system to reveal the molecular mechanism by which heparanase functions in Ap. Heparanase, therefore, emerges as a potential new target in Ap, and heparanase inhibitors, now in phase I/II clinical trials in cancer patients, are hoped to prove benefcial also in AP. Acute pancreatitis (AP) is one of the most common diseases in gastroenterology and about 2% of all hospital- ized patients are diagnosed with the disease 1 . Te incidence of AP per 100,000 population ranges from 10 to 46 cases per year. However, neither the etiology nor the pathophysiology of the disease are fully understood and thus treatment options targeting a specifc underlying cause remain elusive 2, 3 . Tis has prompted considerable interest into studying the initial triggering events of AP in order to develop novel treatments. Much of our current knowledge regarding AP has been gleaned from animal models or isolated cells of the diseased pancreas 2, 4 . Te most common experimental animal model is induction of AP by cholinergic agonists such as carbamylcholine (carbachol), cholecystokinin (CCK) and its analogues, or by scorpion venom 2–4 . Lampel and Kern characterized the clinical and biochemical pattern of acute interstitial pancreatitis in rats afer administration of excessive doses of pancreatic secretagogue and thus established the model of secretagogue-induced pancreatitis 5 . Te most prom- inent characteristic is the development of excessive edema as early as one hour afer the onset of the disease, and induction of tissue infammation 2, 4, 6 . Cerulein is a CCK analogue derived from the Australian tree frog Litoria caerulea and is one of the best characterized AP models in mice 2, 4, 6 . Heparanase is an endoglycosidase that acts both at the cell surface and extracellular matrix (ECM) to cleave heparan sulfate (HS) side chains of HS proteoglycans (HSPGs) into shorter oligosaccharides 7, 8 . Heparanase activity is implicated in the regulation of various physiological and pathological processes 9–12 . Cleavage of HS by heparanase facilitates structural alterations of the ECM and thereby promotes cell invasion associated with infammation, tumor metastasis and angiogenesis 10–14 . Because of its pluripotent pro-infammatory efects 12 , we hypothesized that heparanase may be involved in the pathogenesis of AP. Here, we provide evidence that 1 Department of Gastroenterology, Rambam Health campus, Haifa, israel. 2 cancer and Vascular Biology Research center, the Ruth & Bruce Rappaport faculty of Medicine, technion, Haifa, israel. 3 Department of Physiology, the Ruth & Bruce Rappaport faculty of Medicine, technion, Haifa, israel. 4 Pathology, Rambam Health campus, Haifa, israel. 5 Zucero therapeutics, Brisbane, Queensland, Australia. 6 Haemek Medical center, Afula, israel. 7 Leadiant Biosciences S.A., Mendrisio, Switzerland. 8 Department of Laboratory Medicine, Rambam Health campus, Haifa, israel. iyad Khamaysi and Preeti Singh contributed equally to this work. correspondence and requests for materials should be addressed to i.K. (email: k_iyad@rambam.health.gov.il) Received: 5 September 2016 Accepted: 10 March 2017 Published: xx xx xxxx opeN