title: The Role of Heparanase in the Pathogenesis of Acute Pancreatitis: A Potential Therapeutic Target.
abstract: 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 specific or effective 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 inflammation. Given that AP involves a strong inflammatory aspect, we examined whether heparanase plays a role in AP. Here, we provide evidence that pancreatic heparanase expression and activity are significantly increased following cerulein treatment. Moreover, pancreas edema and inflammation, as well as the induction of cytokines and signaling molecules following cerulein treatment were attenuated markedly by heparanase inhibitors, implying that heparanase plays a significant 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 beneficial also in AP.
authors.affiliation: Department of Gastroenterology, Rambam Health Campus, Haifa, Israel. k_iyad@rambam.health.gov.il.
authors.forename: Iyad
authors.initials: I
authors.lastname: Khamaysi
authors.affiliation: Cancer and Vascular Biology Research Center, The Ruth & Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Preeti
authors.initials: P
authors.lastname: Singh
authors.affiliation: Department of Physiology, The Ruth & Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Susan
authors.initials: S
authors.lastname: Nasser
authors.affiliation: Department of Physiology, The Ruth & Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Hoda
authors.initials: H
authors.lastname: Awad
authors.affiliation: Department of Gastroenterology, Rambam Health Campus, Haifa, Israel.
authors.forename: Yehuda
authors.initials: Y
authors.lastname: Chowers
authors.affiliation: Pathology, Rambam Health Campus, Haifa, Israel.
authors.forename: Edmond
authors.initials: E
authors.lastname: Sabo
authors.affiliation: Zucero Therapeutics, Brisbane, Queensland, Australia.
authors.forename: Edward
authors.initials: E
authors.lastname: Hammond
authors.affiliation: HaEmek Medical Center, Afula, Israel.
authors.forename: Ian
authors.initials: I
authors.lastname: Gralnek
authors.affiliation: Pathology, Rambam Health Campus, Haifa, Israel.
authors.forename: Irena
authors.initials: I
authors.lastname: Minkov
authors.affiliation: Leadiant Biosciences S.A., Mendrisio, Switzerland.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Noseda
authors.affiliation: Cancer and Vascular Biology Research Center, The Ruth & Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Neta
authors.initials: N
authors.lastname: Ilan
authors.affiliation: Cancer and Vascular Biology Research Center, The Ruth & Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
authors.affiliation: Department of Physiology, The Ruth & Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.|Department of Laboratory Medicine, Rambam Health Campus, Haifa, Israel.
authors.forename: Zaid
authors.initials: Z
authors.lastname: Abassi
mesh_terms: D000208:Acute Disease; D000818:Animals; D056668:Cathepsin L / Q000235:genetics / Q000378:metabolism; D002108:Ceruletide / Q000009:adverse effects; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004789:Enzyme Activation; D015870:Gene Expression; D005966:Glucuronidase / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010179:Pancreas / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D010195:Pancreatitis / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000099175:Heparanase
chemical_list: D056668:Cathepsin L; D002108:Ceruletide; D005966:Glucuronidase; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D000099175:Heparanase