# Platelet Activating Factor and Epidermal Cytoxicity

> **NIH NIH R01** · WRIGHT STATE UNIVERSITY · 2021 · $375,000

## Abstract

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...

## Key facts

- **NIH application ID:** 10078615
- **Project number:** 5R01HL062996-20
- **Recipient organization:** WRIGHT STATE UNIVERSITY
- **Principal Investigator:** Jeffrey B. Travers
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $375,000
- **Award type:** 5
- **Project period:** 1999-07-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10078615

## Citation

> US National Institutes of Health, RePORTER application 10078615, Platelet Activating Factor and Epidermal Cytoxicity (5R01HL062996-20). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10078615. Licensed CC0.

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