Ethanol use can be an important source of morbidity and mortality worldwide. It is known that half of individuals with significant burn injuries necessitating hospitalization were positive for ethanol (EtOH). Statistically speaking, the majority of these individuals were occasional binge drinkers, not alcoholics. Ethanol use at the time of injury also results in increased morbidity and mortality (> 2-fold) in the burned patients. Validated murine models combining EtOH + thermal burn injury have demonstrated massive acute systemic cytokine release with toxicity of these combined agents involving lung, small intestine and liver, which mimics human pathology. The process by which EtOH augments thermal burn injury-mediated toxicity has been unknown, yet, we have demonstrated a novel mechanism involving the lipid mediator Platelet-activating Factor (1-alkyl-2-acetyl glycerophosphocholine; PAF). This proposal is the renewal of a long-standing grant that has served to characterize PAF effects, focusing on skin pathophysiology. Exerting its effects via a specific G-protein coupled receptor (PAFR) widely expressed, acute PAF exposure results in a systemic pro-inflammatory response that mimics septic shock. Our ongoing and published studies accomplished in the last cycle of this grant have discovered that acute exposure of keratinocytes in vitro or mice in vivo with EtOH followed by thermal burn injury results in a tremendous increase in PAF production, mediated by augmented cytosolic phospholipase A2 (cPLA2) activation. Of importance, PAFR KO mice were completely protected from intoxicated thermal burn injury- induced multi-organ inflammation. Moreover, we discovered that PAF leaves the keratinocyte via subcellular microvesicle particles (MVP) in a process dependent upon PAFR activation and the enzyme acid sphingomyelinase (aSMase). We hypothesize that traveling in MVP protects PAF from degradation from PAF- acetyl hydrolases, and provides the lipid ligand to the PAFR in optimal form. The overall objective of the planned studies in this renewal is to address knowledge gaps in how PAF-filled MVPs are produced and exactly how they generate widespread multi-organ systemic inflammation in response to combining EtOH + thermal burn injury.
Three aims are designed to test the hypothesis that acute EtOH exposure bypasses the tightly regulated PAF synthetic and degradation pathways resulting in exaggerated PAF production in response to thermal burn injury, and that PAFR activation generates PAF-filled MVP via aSMase. The PAF-filled Burn-MVP travel systemically to induce gut bacterial translocation resulting in ?septic shock?.
The first aim will define the mechanisms for EtOH- mediated augmentation of MVP and PAF production.
The second aim will define if MVP serve to protect PAF from degradation and increases PAF's potency by providing the ligand embedded in membrane.
The third aim will define the exact mechanisms by which PAF in Burn-MVP generate systemic toxicity.
This aim will build upon our mechanistic studies to test potential treatment strategies for intoxicated thermal burn injury. These studies will address knowledge gaps and generate new therapeutic approaches for environmental injuries.

Public Health Relevance

Short-term ethanol exposure combined with thermal burn injuries results in an acute systemic multi-organ dysfunction as well as delayed immunosuppression. The experiments described in this proposal are designed to test a novel hypothesis that short-term ethanol exposure results in an augmentation of the production of the bioactive lipid mediator Platelet-activating Factor following environmental skin injuries such as thermal burns or ultraviolet B radiation, which can explain the pathological acute and delayed effects of these combined stressors. The information derived from these studies will result in improved understanding and novel therapeutics for patients suffering environmental skin injuries in the setting of ethanol exposure.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Arthritis, Connective Tissue and Skin Study Section (ACTS)
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Sarkar, Rita
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Wright State University
Schools of Medicine
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Khan, Aiman Q; Travers, Jeffrey B; Kemp, Michael G (2018) Roles of UVA radiation and DNA damage responses in melanoma pathogenesis. Environ Mol Mutagen 59:438-460
Poon, Chien; Sunar, Ulas; Rohrbach, Daniel J et al. (2018) Early assessment of burn severity in human tissue ex vivo with multi-wavelength spatial frequency domain imaging. Toxicol In Vitro 52:251-254
DaSilva-Arnold, Sonia C; Thyagarajan, Anita; Seymour, Leroy J et al. (2018) Phenotyping acute and chronic atopic dermatitis-like lesions in Stat6VT mice identifies a role for IL-33 in disease pathogenesis. Arch Dermatol Res 310:197-207
Ocana, Jesus A; Romer, Eric; Sahu, Ravi et al. (2018) Platelet-Activating Factor-Induced Reduction in Contact Hypersensitivity Responses Is Mediated by Mast Cells via Cyclooxygenase-2-Dependent Mechanisms. J Immunol 200:4004-4011
Fahy, Katherine; Liu, Langni; Rapp, Christine M et al. (2017) UVB-generated Microvesicle Particles: A Novel Pathway by Which a Skin-specific Stimulus Could Exert Systemic Effects. Photochem Photobiol 93:937-942
Wang, Jinju; Zhong, Yun; Ma, Xiaotang et al. (2016) Analyses of Endothelial Cells and Endothelial Progenitor Cells Released Microvesicles by Using Microbead and Q-dot Based Nanoparticle Tracking Analysis. Sci Rep 6:24679
Sahu, Ravi P; Harrison, Kathleen A; Weyerbacher, Jonathan et al. (2016) Radiation therapy generates platelet-activating factor agonists. Oncotarget 7:20788-800
Bihl, Ji C; Rapp, Christine M; Chen, Yanfang et al. (2016) UVB Generates Microvesicle Particle Release in Part Due to Platelet-activating Factor Signaling. Photochem Photobiol 92:503-6
Sahu, Ravi P; Ferracini, Matheus; Travers, Jeffrey B (2015) Systemic chemotherapy is modulated by platelet-activating factor-receptor agonists. Mediators Inflamm 2015:820543
Ferracini, Matheus; Sahu, Ravi P; Harrison, Kathleen A et al. (2015) Topical photodynamic therapy induces systemic immunosuppression via generation of platelet-activating factor receptor ligands. J Invest Dermatol 135:321-323

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