title: Neutrophil-derived matrix metalloproteinase-9 is a potent activator of trypsinogen in acinar cells in acute pancreatitis.
abstract: MMPs are generally considered to regulate degradation and remodeling of the ECM. Convincing data also implicate a role for MMPs in inflammatory conditions, such as AP, although the mechanisms are not known. The aim of this study was to define the role of MMPs in regulating activation of trypsinogen and tissue damage in AP, which was induced by infusion of taurocholate into the pancreatic duct in mice. A broad-spectrum MMP inhibitor (BB-94) and MMP-9 gene-deficient mice were used. Neutrophil secretions and rMMP-9 were used to stimulate trypsinogen activation in isolated acinar cells. Taurocholate challenge increased serum amylase, neutrophil infiltration, MIP-2 (CXCL2) formation, trypsinogen activation, and tissue damage in the pancreas. Treatment with the broad-spectrum inhibitor of MMPs, BB-94, markedly reduced activation of trypsinogen, levels of CXCL2, infiltration of neutrophils, and tissue damage in AP. Taurocholate challenge increased serum levels of MMP-9 but not MMP-2. Taurocholate-induced amylase levels, neutrophil accumulation, production of CXCL2, trypsinogen activation, and tissue damage in the pancreas were abolished in MMP-9-deficient mice. Moreover, secretions from activated neutrophils isolated from WT but not from MMP-9-deficient animals stimulated trypsinogen activation in acinar cells. Notably, rMMP-9 greatly enhanced activation of trypsinogen in acinar cells. These findings demonstrate that neutrophil-derived MMP-9 is a potent activator of trypsinogen in acinar cells and regulates pathological inflammation and tissue damage in AP.
authors.affiliation: Department of Clinical Sciences, Section for Surgery, Lund University, S-205 02 Malmö, Sweden.
authors.forename: Darbaz
authors.initials: D
authors.lastname: Awla
authors.forename: Aree
authors.initials: A
authors.lastname: Abdulla
authors.forename: Ingvar
authors.initials: I
authors.lastname: Syk
authors.forename: Bengt
authors.initials: B
authors.lastname: Jeppsson
authors.forename: Sara
authors.initials: S
authors.lastname: Regnér
authors.forename: Henrik
authors.initials: H
authors.lastname: Thorlacius
mesh_terms: D061354:Acinar Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D000208:Acute Disease; D000818:Animals; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D020780:Matrix Metalloproteinase 9 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000201:enzymology*; D010195:Pancreatitis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D009195:Peroxidase / Q000378:metabolism; D013656:Taurocholic Acid / Q000494:pharmacology; D014362:Trypsinogen / Q000378:metabolism*
chemical_list: D013656:Taurocholic Acid; D014362:Trypsinogen; D009195:Peroxidase; D020780:Matrix Metalloproteinase 9