NIH grant: Platelet-activating Factor and Epidermal Cytotoxicity (9R01AR087686-23A1)

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NIH grant 9R01AR087686-23A1: Platelet-activating Factor and Epidermal Cytotoxicity
Institute: {'code': 'AR', 'abbreviation': 'NIAMS', 'name': 'National Institute of Arthritis and Musculoskeletal and Skin Diseases', 'admin_org_id': '12500006', 'admin_funding_url': ''}. PI: Jeffrey B. Travers. Award: $429136.
Start: 2026-08-01T00:00:00.
Thermal burn injuries requiring hospitalization occur in an estimated 100,000 victims in the US each year
resulting in over 3500 deaths. The clinical pathology of large body surface area (BSA) burns is well known and
has been modeled in mice. An acute response results in a widespread systemic inflammatory response involving
neutrophils resulting in multiple organ dysfunction (MOD). Later deficits in both innate and adaptive immunity
are noted which result in an increased susceptibility to infection. Though the pathology is known, the exact
mechanism(s) by which a skin injury can generate such profound systemic effects has been an important
knowledge gap resulting in suboptimal care. We have discovered a novel pathologic process involving the potent
family of lipid mediators known as Platelet-activating Factor (1-alkyl-2-acetyl glycerophosphocholine; PAF) that
not only provides an explanation for burn pathologies, but importantly offers a potentially life-saving intervention.
This proposal is the revised 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.
However, PAF is quickly metabolized by specialized acetylhydrolase enzymes. Our ongoing and published
studies accomplished in the last cycle of this long-running grant have provided strong premise for a new
paradigm involving PAF that can explain both the acute MOD and the delayed immunosuppression associated
with thermal burn injury (TBI). In this model, burn injury triggers PAF synthesis which then via the keratinocyte
PAFR induces translocation of acid sphingomyelinase (aSMase) to the plasma membrane forming microvesicle
particles (MVP). The shed BURN-MVP contain PAF which allows this potent yet metabolically labile lipid to
travel systemically. The PAF-laden MVP activate intestinal PAFR causing bacterial translocation resulting in
MOD and interact with the mast cell PAFR inducing immunosuppression. In this revision we supply direct
evidence that “adding back” BURN-MVP from a keratinocyte cell line to mice replicates burn-induced bacterial
translocation. Add-back studies from the original application are now removed as they will be completed in time.
Three aims are designed to test the hypothesis that MVP bypass 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 causing systemic immunosuppression/MOD. Aim 1 will
use murine models to further characterize this model and assess ability of aSMase inhibitors (FIASM) to block
TBI-induced acute MOD/delayed immunosuppression. Aim 2 consists of both prospective and interventional
human studies designed to validate the murine models & testing FIASM. Based upon our exciting initial findings
that BURN-MVP reproduces the systemic pathology, Aim 3 will define contents of burn-derived MVP.
These studies will address knowledge gaps and generate new therapeutic approaches for severe burn injuries.

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