Platelet-activating factor and epidermal cytotoxicity - thermal burn injuries requiring hospitalization occur in an estimated 100,000 victims in the US each year resulting in over 3500 deaths

The National Institute of Arthritis and Musculoskeletal and Skin Diseases awarded Wright State University $429,136 on August 1, 2026, under the Arthritis, Musculoskeletal and Skin Diseases Research program (CFDA 93.846). The award funds a revised renewal of ongoing research investigating platelet-activating factor (PAF) and its role in thermal burn injury pathophysiology. The research addresses a critical gap in understanding how large body surface area burns trigger systemic inflammatory response and immunosuppression, with the goal of identifying therapeutic interventions. The investigative team will examine how burn injury triggers PAF synthesis in keratinocytes, leading to formation of microvesicle particles that perpetuate both acute multiple organ dysfunction and delayed immunosuppression characteristic of thermal burn injury. Performance occurs in Dayton, Ohio, with work running through May 31, 2031.

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.