Oxidative stress in acute pancreatitis

The present work critically reviews the evidence for an involvement of free radicals in the pathophysiology of acute pancreatitis and the potential of treatment with antioxidants and scavenger substances. Data originating fro m clinical trials, experimental pancreatitis studies and in vitro investiga tions are included. Enhanced free radical activities and increased concentr ations of lipid peroxides in plasma and tissue have been found in both pati ents and experimental animals with acute pancreatitis. The individual contr ibution of possible sources of free radicals (e.g., invading inflammatory c ells, xanthine oxidase, cytochromes P450, nitric oxide synthase) is not yet clear, however. Since prophylactic administration of antioxidants diminish ed, in particular, pancreatic edema formation, free radicals seem to play a n important role in the genesis of edema in acute pancreatitis. An involvem ent of free radicals in the pathogenesis of pancreatic necrosis could not y et be proven. Thus, no antioxidant treatment has proven useful for therapy of fulminant pancreatitis in animals to date, However, in severe acute panc reatitis characterized by death occurring after 12-18 hours, the seleno-org anic compound Ebselen, which has a glutathione peroxidase-like activity, an d the membrane permeable ascorbic acid derivative CV-3611 have been demonst rated to be effective. To date, controlled clinical studies have failed to demonstrate the therapeutic efficacy of antioxidant selenium or glutathione precursor supplementation. Therefore, further controlled clinical trials a re needed to determine whether supplements of antioxidants can alter the cl inical course of acute pancreatitis. Since the nitric oxide radical may eve n protect the pancreas, a purely negative discussion of the role of free ra dicals on the pancreas is not justified. The actual role of free radicals i n acute pancreatitis, i.e. serving the body's defense against infection, be ing an epiphenomenon of the inflammatory process without pathophysiological relevance, or having true pathogenic significance, is not yet clear. Lipid peroxidation may perhaps not be the cause but rather the sequel of pancrea tic inflammation and may likely reflect the severity of the systemic inflam matory response rather than that of pancreatic parenchyma damage. In vitro, exposure of isolated pancreatic acinar cells to oxidative stress caused ra pid cell damage and death. Such knowledge from cellular studies might help to plan therapeutical trials to evaluate potentially effective therapies in the experimental animal, as well as in patients suffering from pancreatiti s. Thus, to further clarify the role of oxidative stress in acute pancreati tis, an integrated approach is needed, including investigations at various biological levels, from isolated cells or even organelles to laboratory ani mals and, finally, clinical studies in man.