ROLE OF MACROPHAGE OVERACTIVATION IN THE DEVELOPMENT OF ACUTE PANCREATIC INJURY IN RATS

Background An increase in systemic inflammatory mediators from stimula ted leucocytes and macrophages has been noted during acute pancreatiti s. The role of cytolytic inflammatory macrophages and potential mechan isms in the development of acute pancreatic injury and endothelial bar rier dysfunction are less well defined. Methods Rats were challenged b y an intraperitoneal injection of cytolytic or non-cytolytic inflammat ory macrophage stimulators at various concentrations. The effects of o xygen free radicals, prostaglandin and extracellular calcium influx on macrophage-associated pancreatic endothelial compromise, measured by pancreatic intravascular plasma volume, pancreatic interstitial fluid volume, and the pancreatic extravascular human serum albumin distribut ion volume, were explored. Results Zymosan-induced overactivation of c ytolytic inflammatory macrophages resulted in the development of acute pancreatic endothelial dysfunction in a dose- and time-dependent patt ern. An increase in pancreatic water content and interstitial fluid vo lume was observed following a higher dose (0.5 mg/g) of concanavalin A without alteration in plasma lipase level, while thioglycollate mediu m did not compromise pancreatic endothelial barrier function. Oxygen f ree radicals, but also prostaglandins and extracellular calcium influx , seemed to be involved in macrophage overactivation-induced pancreati c injury. Conclusion Overactivation of cytolytic macrophages plays a r ole in the pathogenesis of pancreatic injury by initiating the develop ment of endothelial barrier dysfunction. Multiple inflammatory mediato rs from overactivated macrophages act as intercellular signals between macrophages and the endothelium during acute pancreatic injury.