Increased Matrix Metalloproteinase Expression and Activation following Experimental Acute Pancreatitis

Abstract

Background. The observation that matrix metalloproteinases (MMPs) are central to tissue remodeling and may contribute to organ failure prompted us to investigate the role of MMPs in acute pancreatitis. We hypothesize that increased expression and activation of MMP-2 and MMP-9 will correlate with organ injury following acute pancreatitis.Methods. Acute pancreatitis was induced in five male rats by retrograde infusion of 5% sodium taurocholate into the pancreatic duct. Sham laparotomy was performed on five rats serving as a control. Pancreatitis was confirmed by histology and serum amylase levels. MMP-2 and MMP-9 activity and expression were assayed by gelatin zymography in the lungs and ascitic fluid of each animal. Lung permeability was assayed by Evans blue dye extravasation. Lung activity of MMP-2 and MMP-9 was confirmed by a specific fluorogenic MMP substrate assay.Results. Lung permeability increased twofold in the animals with severe pancreatitis compared with sham. Analysis of the zymograms from lung homogenate revealed a threefold increase in active MMP-2 in severe pancreatitis compared with sham and no change in MMP-9 activity. Gelatin zymograms of peritoneal fluid from severe pancreatitis animals demonstrated increased levels of active MMP-2 and MMP-9 compared with the sham group. Increases in MMP activity were confirmed by MMP activity assay using a fluorogenic substrate.Conclusions. This study demonstrates a correlation between severity of acute pancreatitis and active MMP-2 and MMP-9 levels in the peritoneal fluid and MMP-2 activity in lung homogenate. The MMP-mediated degradation of the basement membrane offers a potential pharmacologic and therapeutic target for halting the final biologic outcome of severe pancreatitis.