The long-term goal of this research is to test the HYPOTHESIS that the intestine serves as an instigator and a victim of Multisystem Organ Failure (MOF). Two major OBJECTIVES - to further define the role of intestinal stasis in the pathogenesis of MOF, and to determine the mechanisms responsible for the alterations in intestinal motility that lead to intestinal stasis in response to stressors that induce pancreatitis, peritonitis, and endotoxemia will be accomplished by: 1) Correlating changes in intestinal motility in the intact animal with sequelae associated with MOF; 2) Determining if prevention or reversal of intestinal stasis will decrease sequelae; 3) Determining if factors that compromise gut wall barrier functions (epithelial, vascular, and immunologic) enhance sequelae induced by stressors that depress intestinal motility; 4) Identifying the biochemical and molecular changes in gut smooth muscle that may account for changes in contractility; and 5) evaluating the role of selected neurocrines and paracrines in the changes in intestinal motility. Rats and opossums will be instrumented with catheters for measurement of gallbladder emptying and intestinal transit. Enteral contents will be sampled for quantitative bacteriology. Electrodes will be placed into the biliary sphincter (opossum only) and the muscle of the gut at intervals in order to monitor the migrating myoelectric complex. Intestinal transit and myoelectric activity will be correlated with intestinal bacterial overgrowth, bacterial translocation to lymph nodes and distant organ, and liver function during control and after stressors. The role of motility in inducing these sequelae will be tested by reversing the expected depression of motility with prokinetic drugs and by combining stressors that alter motility with stressors that are found in Projects 2, 3, and 4 to alter barrier functions of the gut. The role of extrinsic and intrinsic nerves in intact animals will be investigated pharmacologically using agents that block adrenergic activity and nitric oxide (NO) production. Derangements in muscle will be assessed by evaluating contractility, calcium ATPase, changes in myosin light chain kinase activity, and contractile protein contents, isoforms, and the mRNAs that code for specific isoforms. Paracrine and neurocrine involvement will be assessed by evaluating NO synthase activity and the levels of mRNAs coding for the constitutive and the inducible forms of the enzyme, by determining if antagonists of the enzymes will alter the effects of the stressors, by monitoring changes in the expression of IL-1, IL-6, and TNF and the mRNAs coding for these cytokines, and by determining if antagonists to specific cytokines will alter the effects of the stressors. The data from these experiments may provide a rationale for developing ways to prevent, ameliorate, and/or reverse the lethal outcome of MOF.
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