Increased matrix metalloproteinase expression and activation following experimental acute pancreatitis

Background. The observation that matrix metalloproteinases (MMPs) are centr al to tissue remodeling and may contribute to organ failure prompted us to investigate the role of MMPs in acute pancreatitis. We hypothesize that inc reased expression and activation of MMP-2 and MMP-9 will correlate with org an injury following acute pancreatitis. Methods. Acute pancreatitis was induced in five male rats by retrograde inf usion of 5% sodium taurocholate into the pancreatic duct. Sham laparotomy w as performed on five rats serving as a control. Pancreatitis was confirmed by histology and serum amylase levels. MMP-2 and MMP-9 activity and express ion were assayed by gelatin zymography in the lungs and ascitic fluid of ea ch animal. Lung permeability was assayed by Evans blue dye extravasation. L ung activity of MMP-2 and MMP-9 was confirmed by a specific fluorogenic AMP substrate assay. Results. Lung permeability increased twofold in the animals with severe pan creatitis compared with sham. Analysis of the zymograms from lung homogenat e revealed a threefold increase in active MMP-2 in severe pancreatitis comp ared with sham and no change in MMP-9 activity. Gelatin zymograms of perito neal fluid from severe pancreatitis animals demonstrated increased levels o f active MMP-2 and MMP-9 compared with the sham group. Increases in MMP act ivity were confirmed by MMP activity assay using a fluorogenic substrate. Conclusions. This study demonstrates a correlation between severity of acut e pancreatitis and active MMP-2 and MMP-9 levels in the peritoneal fluid an d MMP-2 activity in lung homogenate. The MMP-mediated degradation of the ba sement membrane offers a potential pharmacologic and therapeutic target for halting the final biologic outcome of severe pancreatitis. (C) 2001 Academ ic Press.