Alcohol is a contributing factor in post burn morbidity and mortality. Our laboratory has previously demonstrated that acute alcohol intoxication suppresses intestinal immune function and enhances bacterial translocation, yet the mechanism responsible for these observations remains unknown. Current evidence suggest that T helper (Th) 17 lymphocytes play a critical role in maintaining normal barrier function and minimizing invasion of bacteria across the intestinal epithelium. Additionally, interleukin IL-23, a cytokine released predominantly by dendritic cells, is crucial in Th17 differentiation and antimicrobial expression. Preliminary studies from our laboratory demonstrated decreased levels of Th17 effector cytokine IL-17 as well as decreased levels of the p40 subunit of IL-23 in Peyer's patches following alcohol intoxication and burn injury. Peyer's patches are small immune cell-containing lymphoid organs along the small intestine that are critical to bacterial containment. Based on these observations, we hypothesize that alcohol intoxication prior to burn injury disrupts IL-23 production from dendritic cells within Peyer'spatches, which in turn impairs Th17 effector functions and antimicrobial expression within the intestine.
Three specific aims have been developed to examine this hypothesis.
Aim 1 will establish the effects of acute alcohol exposure on post burn IL-23 release within the intestine and correlate these findings with altered secretion of Th17 cytokines IL-17 and IL-22 and antimicrobial expression.
Aim 2 will determine if administration of recombinant IL- 23, improves intestinal Th17 effector functions and antimicrobial peptide expression following alcohol intoxication and burn injury.
Aim 3 will focus on the role of STAT3 and ROR-3t activation in IL-23 mediated regulation of Th17 responses following alcohol intoxication and burn injury. Studies will be carried out using a mouse model of acute alcohol exposure and thermal injury. Overall, this proposal will yield novel data that may aid in the development of targeted therapeutic interventions for patients who sustain burn injury after exposure to alcohol.
Each year over 100,000 hospitalizations and 5,000 deaths within the United States are associated with burn injury, nearly half of these burn injuries are sustained under the influence of acute alcohol intoxication. These patients go on to demonstrate increased rates of infection, morbidity and mortality when compared to that of patients who were not under the influence of alcohol at the time of injury. The proposed studies will potentially provide a mechanism by which alcohol complicates burn injury and reveal valuable therapeutic targets to improve the care of patients who sustain injury following exposure to alcohol.
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