Date of Award

2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Cell Biology, Neurobiology and Anatomy

Abstract

The increasing prevalence of binge drinking and its high association with traumatic injury warrant further investigation into the mechanisms underlying the worsened clinical outcomes associated with this combined injury. Existing literature suggests the liver is at the center of the postburn systemic response with crosstalk between the intestinal microbiome and the liver playing an important role after injury. There is a paucity in the literature, however, regarding the role of the gut-liver axis in the common clinical scenario of burns preceded by alcohol intoxication. Previous studies in our laboratory demonstrated intoxication potentiates postburn hepatic damage and IL-6 production in a dose-dependent manner. We now demonstrate through two separate approaches that interruption of gut-liver crosstalk, through restoration of intestinal barrier function or prophylactic sterilization of the gut, attenuates hepatic damage and IL-6 production after the combined injury, highlighting the role of intestinal damage and subsequent bacterial translocation. We show through antecedent Kupffer cell depletion, that Kupffer cells play a critical role in mediating the injurious hepatic response to intoxication and burn. Furthermore our results indicate alcohol increases postburn Kupffer cell sensitivity to LPS through increased p38 MAPK signaling, providing a potential mechanism for the increased hepatic and systemic levels of IL-6 found in the combined injury. Accordingly, global p38 inhibition also attenuated hepatic damage and IL-6 production in alcohol-exposed and burn injured mice. Taken together, these studies suggest that specifically targeting Kupffer cell p38 in the setting of intoxication and burn may have therapeutic benefit. This was supported by the decreased pulmonary inflammation associated with lowered IL-6 levels in all experimental interventions used. Finally we found alcohol increased intestinal damage through potentiating bradykinin signaling, leading to greater fluid extravasation from the vascular compartment. The subsequent intestinal barrier breakdown may be the inciting event that alters the gut-liver axis. In summation, the studies contained herein reveal that the gut-liver axis drives pulmonary inflammation after intoxication and burn injury. We demonstrate multiple mechanisms by which alcohol modulates the post burn hepatic response and provide preliminary evidence for potential therapeutic targets for this common clinical scenario.

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.

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