The consumption of alcohol is a risk factor in patients with burn injury. Recent findings suggest that patients with bum injury and alcohol exposure exhibit higher rates of infection and are more likely to die than patients with similar extent of bum injury without alcohol. The definitive cause of increased infection in bum patients with alcohol exposure is not known. One possibility is that these patients succumb to opportunistic pathogens originating from their own gastrointestinal tract due to a suppression of intestinal immune defense. Therefore, we hypothesize that alcohol exposure prior to thermal injury exacerbates suppression of the intestinal immune defense, which results in increased gut bacterial translocation to extra-intestinal sites leading to sepsis and multi-organ failure. Since T cells play a critical role in maintaining immunity against gut bacteria, our studies are designed to investigate the mechanisms of how alcohol attenuates intestinal T cell function in burn-injured rats. We will test this hypothesis in a rat model of acute alcohol consumption and thermal injury using T cells from intestinal lymphoid organs including Peyer's patches, intra epithelial cells, lamina propria and mesenteric lymph nodes. In the first aim, we will investigate if the increased bacterial translocation following acute alcohol exposure prior to thermal injury is accompanied by a suppression of intestinal T cell functions. T cell functions will be assessed by measuring the T cell proliferation, IL-2, IL-4 and IFN-Y production. Since a number of immunomodulatory mediators including PGE2 and corticosterone are shown to be released excessively in injury conditions such as alcohol and burn, in the second aim, we will investigate if alterations in T cell functions, and enhanced bacterial translocation following acute alcohol exposure prior to thermal injury are due to increased production of PGE2, corticosterone, or both. We have previously demonstrated that sepsis suppresses T cell functions through the down-regulation of intracellular signaling molecules. Additionally, we found that the suppression of T cell function during sepsis is due to increased production Of PGE2. Therefore, in the third aim, we will determine if inappropriate activation of intracellular signaling molecules are responsible for PGE2- and /or glucocorticoid-related alterations in intestinal T cell functions after acute alcohol exposure prior to thermal injury. These studies will provide information critical to the role of T cell in alcohol-related intestinal immune dysfunction and thereby in increased gut bacterial translocation in burn injury. Moreover, identification of the mechanism underlying the intestinal T cell suppression could lead to therapeutic interventions for the treatment of bum patients with alcohol exposure.
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