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.