Publication Date
2023
Document Type
Thesis
Committee Members
Jeffrey B. Travers, M.D., Ph.D. (Advisor); Michael Kemp, Ph.D. (Committee Member); Ravi P. Sahu, Ph.D. (Committee Member)
Degree Name
Master of Science (MS)
Abstract
Intoxicated thermal burn injury (ITBI) is more severe than thermal burn injury (TBI) alone and causes significant morbidity and mortality. Evidence from mouse models that replicate the human condition of multiple organ dysfunction has been informative. ITBI results in enhanced bacterial translocation from the gut, increased levels of proinflammatory mediators, and immune cell infiltration in various organs, resulting in inflammation in multiple organs with subsequent dysfunction. In addition, ITBI induces delayed systemic immunosuppression. To understand the mechanism(s) underlying ITBI-induced inflammation and damage in multiple organs, we investigate the role of Platelet-activating factor (PAF) and subcellular microvesicle particles (MVPs) in this pathology. ITBI causes an increase in the production of platelet-activating factor (PAF) and the activation of acid-sphingomyelinase (aSMase), which triggers the release of MVPs from keratinocytes. These MVPs are capable of carrying and safeguarding PAF, allowing PAF to bind to various important sites. Our hypothesis is that the PAF carried by these subcellular MVPs can bind to PAF receptors (PAFR) in the gut. This binding can cause dysfunction of the gut barrier, leading to the invasion of bacteria into the lymphatic system, which can result in sepsis and uncontrolled inflammatory responses in multiple organs. To test this hypothesis, we treated wild-type, PAFR knockout, and aSMase (SMPD1) knockout mice with ITBI. One day after the injury, the lungs, small intestine, kidney, liver, and spleen were harvested to measure CXCL1, IL-6, CCL2, IL-18, TNF-⍺, and other inflammation indices. Mesenteric lymph nodes were harvested and assayed for bacteria. The results show that ITBI increased bacterial translocation in the gut and dysregulated inflammatory responses in multiple organs in wild-type mice. However, these responses were significantly reduced in mice deficient of PAFR or aSMase. Moreover, pharmacological inhibition of aSMase by topical application of the inhibitor imipramine also lowered inflammatory responses. These findings thus provide a mechanism and potential therapeutic approaches to prevent patients from the increased inflammatory responses and toxicity associated with ITBI.
Page Count
77
Department or Program
Department of Pharmacology and Toxicology
Year Degree Awarded
2023
Copyright
Copyright 2023, all rights reserved. My ETD will be available under the "Fair Use" terms of copyright law.
ORCID ID
0009-0007-0350-9872
