Neutrophil-derived matrix metalloproteinase-9 is a potent activator of trypsinogen in acinar cells in acute pancreatitis

Journal of Leukocyte Biology

Ingvar Syk¹  Darbaz Awla¹  Aree Abdulla¹  Bengt Jeppsson¹  Sara Regnér¹  Henrik Thorlacius¹ 

[1] Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, Malmö, SwedenDepartment of Clinical Sciences, Malmö, Section for Surgery, Lund University, Malmö, SwedenDepartment of Clinical Sciences, Malmö, Section for Surgery, Lund University, Malmö, Sweden

关键词: amylase;    chemokines;    inflammation;    pancreas;   

DOI  :  10.1189/jlb.0811443

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

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.

【 授权许可】

Unknown