title: Human thrombin-derived host defense peptides inhibit neutrophil recruitment and tissue injury in severe acute pancreatitis.
abstract: Severe acute pancreatitis (AP) is characterized by leukocyte infiltration and tissue injury. Herein, we wanted to examine the potential effects of thrombin-derived host defense peptides (TDPs) in severe AP. Pancreatitis was provoked by infusion of taurocholate into the pancreatic duct or by intraperitoneal administration of l-arginine in C57BL/6 mice. Animals were treated with the TDPs GKY20 and GKY25 or a control peptide WFF25 30 min before induction of AP. TDPs reduced blood amylase levels, neutrophil infiltration, hemorrhage, necrosis, and edema formation in the inflamed pancreas. Treatment with TDPs markedly attenuated the taurocholate-induced increase in plasma levels of CXCL2 and interleukin-6. Moreover, administration of TDPs decreased histone 3, histone 4, and myeloperoxidase levels in the pancreas in response to taurocholate challenge. Interestingly, administration of TDPs abolished neutrophil expression of Mac-1 in mice with pancreatitis. In addition, TDPs inhibited CXCL2-induced chemotaxis of isolated neutrophils in vitro. Fluorescent-labeled TDP was found to directly bind to isolated neutrophils. Finally, a beneficial effect of TDPs was confirmed in l-arginine-induced pancreatitis. Our novel results demonstrate that TDPs exert protective effects against pathological inflammation and tissue damage in AP. These findings suggest that TDPs might be useful in the management of patients with severe AP.
authors.affiliation: Department of Clinical Sciences, Section of Surgery, Malmö, Lund University, Sweden;
authors.forename: Mohammed
authors.initials: M
authors.lastname: Merza
authors.affiliation: Department of Clinical Sciences, Section of Surgery, Malmö, Lund University, Sweden;
authors.forename: Milladur
authors.initials: M
authors.lastname: Rahman
authors.affiliation: Department of Clinical Sciences, Section of Surgery, Malmö, Lund University, Sweden;
authors.forename: Songen
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Clinical Sciences, Section of Surgery, Malmö, Lund University, Sweden;
authors.forename: Rundk
authors.initials: R
authors.lastname: Hwaiz
authors.affiliation: Department of Clinical Sciences, Section of Surgery, Malmö, Lund University, Sweden;
authors.forename: Sara
authors.initials: S
authors.lastname: Regner
authors.affiliation: Department of Clinical Sciences, Section of Dermatology and Venereology, Lund, Lund University, Sweden; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
authors.forename: Artur
authors.initials: A
authors.lastname: Schmidtchen
authors.affiliation: Department of Clinical Sciences, Section of Surgery, Malmö, Lund University, Sweden; henrik.thorlacius@med.lu.se.
authors.forename: Henrik
authors.initials: H
authors.lastname: Thorlacius
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D054426:Chemokine CXCL2 / Q000097:blood; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D016177:Macrophage-1 Antigen / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D010179:Pancreas / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019283:Pancreatitis, Acute Necrotizing / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000627:therapeutic use*; D009195:Peroxidase / Q000235:genetics / Q000378:metabolism; D013917:Thrombin / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D006657:Histones; D015850:Interleukin-6; D016177:Macrophage-1 Antigen; D010446:Peptide Fragments; D009195:Peroxidase; D013917:Thrombin
keywords: amylase; chemokines; inflammation; leukocytes; pancreas