Date of Award

2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Cell Biology, Neurobiology and Anatomy

Abstract

More than half of patients admitted to burn centers for treatment have measurable alcohol levels in their blood. Intoxication that precedes a traumatic burn injury leads to worsened patient outcomes, including higher rates of infection and sepsis. The intestines harbor the largest concentration of bacteria in the human host. Any disruption of the intestinal barrier as a result of intoxication and burn injury could contribute to infection and/or sepsis from gut-derived microbes. Previous work has demonstrated that the intestinal barrier becomes leaky, and that administration of interleukin-22 (IL-22) significantly reduces gut barrier leakiness following alcohol and burn injury. However, the cellular and molecular mechanism by which intestinal barrier leakiness occurs, and how IL-22 mediates intestinal barrier protection remain largely unknown.

The overall objectives of this dissertation are to identify the mechanisms of intestine epithelial barrier disruption, and to elucidate how IL-22 protects the intestine epithelial barrier following alcohol and burn injury. The hypothesis of this project is IL-22 utilizes STAT3 signaling in intestine epithelial cells to promote barrier regeneration and restore the intestinal microbiome following alcohol and burn injury.

Our results demonstrate disruptions to the intestine occur on many levels, including diminished claudin-8 and F-actin tight junction formation between epithelial cells, reduced numbers of proliferating and higher incidence of epithelial cell death, and large overgrowth of bacteria within the lumen of the small intestine. Interleukin-22 is able to restore numbers of proliferating cells to promote intestine barrier regeneration, and significantly elevates antimicrobial peptide (AMP) gene expression while mitigating bacterial overgrowth. Transgenic mice lacking the signal transducer and activator of transcription factor 3 (STAT3) in intestine epithelial cells lose the protective effects of IL-22 administration. Together, our data demonstrate that IL-22 signals through STAT3 to protect the intestine barrier by promoting intestinal epithelial cell proliferation, enhancing AMP gene expression, and preventing bacterial overgrowth following alcohol and burn injury.

Creative Commons License

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

Download

Share

COinS