This proposal will test the hypothesis that biliary and gut stasis contribute to the overwhelming enteral sepsis associated with multiple organ failure.
The Specific Aims are the following: (1) To ascertain the effect of hemorrhagic shock on gallbladder emptying and contractility and its absorptive function; (2) To determine the effect of shock on the myoelectric and propulsive activity of the biliary sphincter and small bowel; (3) To characterize the location and rate of flow of bile acids through the enterohepatic circulation before and following shock; (4) To assess the role of gut motility and bile acid delivery to the ileum on bacterial colonization of the gut and the permeation of its epithelium by enteric organisms and endoxin. Permeation of enteric organisms and endotoxin through its epithelium will also be assessed. Opossums will be instrumented with appropriate catheters for measurement of gallbladder emptying, transpapillary fluid flow, and the rate of movement of enteral fluids, bile and bile acids down the intestine tract. Enteral contents will be sampled for quantitative bacteriology. Electrodes will be placed into the biliary sphincter and the smooth muscle of the gut at intervals in order to measure the effects of morphine, hemorrhagic shock, and enteral deprivation of nutrients on the migrating myoelectric complex of the gastrointestinal tract. Gallbladders will be harvested at intervals after shock for the determination of gallbladder wall contractility in response to acetycholine and cholecystokinin in an in vitro bath. Phosphorylation of myosin light chain 20 will be estimated as well as the absorption of sodium by the gallbladder wall placed in Ussing chambers. The effects of enteral bile acid deprivation and reconstitution on gut bacterial colonization and translocation will be studied by diverting bile from the gut through a jejunal conduit from the gallbladder to urinary bladder. Native bile and bile acids in varying composition and rates will be returned to the gut lumen at intervals following hemorrhagic shock. These studies should establish the relationship between luminal bile acids and gallbladder, biliary sphincter, and gut motility on bacterial colonization of the gut following hemorrhagic shock. The establishment of the primacy of a disturbance of biliary and gut motility in the pathogenesis of post-traumatic sepsis might offer a conceptual approach to the prevention of multiple organ failure.
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