Date of Award

2013

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Cell Biology, Neurobiology and Anatomy

Abstract

More than one million burn injuries are reported yearly within the United States. These injuries result in approximately 500,000 emergency room visits and 40,000 hospitalizations annually. Greater than 50% of these injuries occur under the influence of alcohol/ethanol (EtOH) intoxication. Burn victims who sustain injury under the influence of EtOH exhibit significantly higher rates of morbidity and mortality than patients without EtOH exposure at the time of injury. Several lines of evidence suggest that gut pathogens and/or their products may play a role in the development of sepsis and multiple organ failure reported in burn and trauma patients. In line with this hypothesis, our laboratory has demonstrated increased intestinal tissue damage, leakiness and bacterial translocation as well as intestinal T lymphocyte suppression following EtOH intoxication and burn injury.

Th17 cells are implicated in gut homeostasis and in the containment of gut pathogens. We investigated the effects of EtOH exposure and burn injury on intestine associated lymphoid Peyer's patch (PP) Th17 effector functions. We further examined whether in vivo modulation of IL-22 influences gut barrier function and bacterial load following EtOH and burn injury.

Our murine model of EtOH intoxication and burn injury demonstrates decreased CD3/CD28 dependent expression of Th17 effector cytokines IL-17 and IL-22 in PP cells one day post injury. We further demonstrate restoration of IL-22 following restitution of IL-23, as well as restoration of IL-17 in response to PMA and ionomycin. Mechanistically, we found that IL-23 dependent induction of IL-22 is regulated, at least in part, by the aryl hydrocarbon receptor. In vivo, we found decreased levels of antimicrobial peptides Reg3β and Reg3γ, as well as increased gut permeability and bacterial growth, one day post EtOH exposure and burn injury. Treating animals with IL-22 resulted in increased expression of Reg3β and Reg3γ, decreased gut permeability and decreased gut bacterial growth following EtOH and burn injury.

Together, our data demonstrating suppressed IL-17 and IL-22 following EtOH and burn injury and recusing of gut immune and barrier function with IL-22 treatment implicate IL-22 as a possible therapeutic target following EtOH and burn injury.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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