ACUTE PANCREATITIS--ROLES OF CYTOKINES AND ANTIOXIDANTS

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The overall objective of these studies is to apply molecular, cellular, and transgenic approaches to elucidate the roles of inflammation and oxidative stress in acute pancreatitis In the mouse. These studies will also provide important information regarding mechanisms by which the pancreas can be protected during acute pancreatitis. The mechanisms of induction of acute pancreatitis aryl methods to prevent and treat this disorder are poorly understood. Thus, this devastating illness remains a significant clinical problem, and treatment is largely supportive. Inflammatory cytokines have been implicated in acute pancreatitis, but the regulation of cytokine gene expression has not been examined and direct evidence for their roles has not been obtained. Other recent studies indicate that free radicals may play a key role In acute pancreatitis. Oxidative stress activates the expression of several protective genes, but the regulation of these antioxidant genes has not been examined during acute pancreatitis. Furthermore, the potential protective roles of intracellular antioxidants in acute pancreatitis have not been thoroughly examined. The specific aims of this proposal are, therefore, to: 1) Examine the regulation and potential roles of cytokines in caerulein- or choline-deficient ethionine-supplemented diet-Induced pancreatitis in the mouse; and 2) examine the roles of oxidative stress in these models of acute pancreatitis. Aim 1 will be approached by determining the temporal and spatial patterns of pancreatic expression of the tumor necrosis factor-alpha, Interleukin-1 (alpha and beta) and interleukin-6 genes using Northern blotting, in situ hybridization and immunohistochemistry. The effects of recombinant cytokines on gene expression and cellular functions in isolated pancreatic acini will be examined and transgenic mice that constitutively express cytokines or cytokine antagonists in the pancreas will be created to serve as models for delineating the functional roles of inflammation in acute pancreatitis. Aim 2 will be approached by determining the temporal and spatial patterns of expression, during acute pancreatitis, of the antioxidant genes encoding metallothionein, heme oxygenase and Mn-superoxide dismutase. In addition, effects of exogenous antioxidants and oxidative stress-Inducing chemicals on the activation of gene expression and the induction of acute pancreatitis will be examined in vivo in the pancreas, and in vitro in cultured pancreatic acini. Finally, the functional role of the intracellular antioxidant metallothionein In acute pancreatitis will be examined using genetic mouse models that have targeted deletions of the metallothionein genes, that over-express metallothionein in many tissues including the pancreas, or that over-express metallothionein specifically in pancreatic acinar cells.