Protease-antiprotease interactions and the rationale for therapeutic protease inhibitors

A number of pancreatic enzymes have been suggested as the initiating factor for acute pancreatitis. In particular, the relationship between proteases and antiproteases has been examined extensively, based on the suspicion that an imbalance between them is the central factor in the pathogenesis of acute pancreatitis. Animal studies with antiproteolytic agents in models of acute pancreatitis have shown an improvement in outcome. However, more recently, prospective, randomized, multicentre trials treating human acute pancreatitis with antiproteolytic drugs (aprotinin, gabexate mesilate, and even fresh frozen plasma) have failed to show any benefit in the clinical setting. Thus, clinically, it seems likely that antiproteolytic therapy has no effect on the course of severe acute pancreatitis. Today, the mortality in severe acute pancreatitis is determined by septic complications due to infected pancreatic necroses in the late phase 2-3 weeks after the onset of the disease. Death in the early phase of the disease has become increasingly rare where an imbalance between proteases and antiproteases may be involved.