Publication Date

2025

Document Type

Thesis

Committee Members

Jeffrey B. Travers, M.D., Ph.D. (Advisor); Yong-jie Xu, M.D., Ph.D. (Committee Member); Ravi P. Sahu, Ph.D. (Committee Member)

Degree Name

Master of Science (MS)

Abstract

Thermal burn injuries (TBI) result in local and systemic effects, particularly when a large body surface area is exposed to TBI. This study investigates the systemic effects of varying degrees of TBI in the murine model, focusing on the role of microvesicle particles (MVP) and Platelet-activating Factor (PAF) in mediating bacterial translocation and systemic inflammation. Utilizing the murine model, we analyzed MVP levels in the skin and blood, bacterial translocation in the gut, and the expression of pro-inflammatory mediators in the major organs at the 2-hour post-burn time point. Our studies revealed that after the two hours’ time point TBI can induce dose-dependent release of MVPs in blood, correlating with higher bacterial translocation and cytokine expression in various organs such as the small intestine, lungs, liver, and kidneys. Additionally, to investigate the roles of PAF and the MVP-generating enzyme acid sphingomyelinase (aSMase) in mediating systemic inflammation, we used mice deficient in PAF receptors (Ptafr−/−) and aSMase (Smpd1−/−). Compared to wild-type mice, Ptafr−/− and Smpd1−/− mice exhibited lesser responses of MVP release, bacterial translocation, and systemic inflammation. To examine the effect of pharmacological interventions, we evaluated the effects of imipramine (a functional inhibitor of aSMase) on MVP release and bacterial translocation at the 2-hour time point and found that imipramine application immediately post-TBI attenuated MVP release and bacterial translocation following varying degrees of TBI. These results show that early pharmacological intervention with aSMase inhibitors could prevent complications such as multiple organ inflammation arising from burn-generated MVP. In conclusion, our studies underscore the roles of MVPs and PAF in the systemic effects of TBI. The successful reduction of MVP release and bacterial translocation with therapeutic agents such as imipramine may serve to limit burn-induced inflammation, sepsis, and multi-organ failure.

Page Count

67

Department or Program

Department of Pharmacology and Toxicology

Year Degree Awarded

2025

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