Despite the extensive use of animal models to study the physiological and pathological effects of alcohol, insufficient and uncontrolled voluntary alcohol consumption appears to be a major obstacle for reproducing the whole spectrum of alcohol induced organ damage associated with human alcoholic disease. At present, there is no relatively inexpensive animal model for chronic ethanol intoxication which produces liver injury beyond fat accumulation. Furthermore, there is no established animal model for production of pancreas pathology in response to chronic ethanol intake. The achievement of such a model is the long-range goal of this research. We have obtained preliminary results indicating that continuous chronic intragastric administration of ethanol produces severe liver and pancreas pathology in the rat. Chronic double lumen gastrostomy and central venous cannulas have been employed to permit independent administration of ethanol and nutritionally defined diet, as well as daily blood ethanol determinations. Using this method, continuously high blood alcohol levels were achieved during a period of 4-12 weeks. Despite the use of a low fat diet, liver histophatology showed severe, progressive fat accumulation, focal mononuclear cellular infiltration, cell necrosis, and signs of scarring. These changes were accompanied by marked and progressive elevation of plasma transaminase levels. In addition, the plasma response of pancreatic trypsinogen to hormonal stimulation was significantly higher in ethanol treated rats. This finding appeared to be consistent with an observed increase and dispersion of zymogen granules in pancreatic ascinar cells. We have also demonstrated a novel finding: that there is a cyclical pattern to blood ethanol levels during constant infusion of ethanol. We propose to confirm and extend our preliminary results in a series of experiments to answer the following questions: 1) Can significant and progressive liver injury be consistently achieved with this model? 2) Can pancreatic changes consistent with pathogenesis of pancreatitis be achieved? and 3) What factors influences the cyclic pattern of blood ethanol levels?
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