Platelet‐activating factor and microvesicle particles as potential mediators for the toxicity associated with intoxicated thermal burn injury

Abstract

Thermal burn injuries (TBIs) in patients who are alcohol-intoxicated result in greater morbidity and mortality. The systemic toxicity found in human patients, which includes both immediate systemic cytokine generation with multiple organ failure and a delayed systemic immunosuppression, has previously been replicated in mouse models combining ethanol and localized TBI. Though considerable insights have been provided with these models, the exact mechanisms for these pathologic effects are unclear. In this review, we highlight the roles of the lipid mediator platelet-activating factor (PAF) and subcellular microvesicle particle (MVP) release in response to intoxicated thermal burn injury (ITBI) as effectors in the pathology. Particularly, MVP is released from keratinocytes in response to PAF receptor (PAFR) activation due to excess PAF produced by ITBI. These subcellular particles carry and thus protect the metabolically labile PAF which enable binding of this potent lipid mediator to several key sites. We hypothesize that PAF carried by MVP can bind to PAFR within the gut, activating myosin light chain kinase (MLCK). The subsequent gut barrier dysfunction in response to MLCK activation then allows bacteria to invade the lymphatic system and, eventually, the bloodstream, resulting in sepsis and resultant dysregulated inflammation in multiple organs. PAF in MVP also activate the skin mast cell PAFR resulting in migration of this key effector cell to the lymph nodes to induce immunosuppression. This review thus provides a mechanism and potential therapeutic approaches for the increased toxicity and immunosuppressive outcomes of TBI in the presence of acute ethanol exposure.

Intoxicated thermal burn injury‐mediated systemic immunosuppression involves platelet‐activating factor and microvesicle particles

“…9,13 Recent studies by our group have used keratinocyte and murine models of ITBI to demonstrate the role of the lipid mediator Platelet-activating Factor (PAF) and subcellular microvesicle particles (MVP). 10,14 These studies have supported a model (reviewed in Rohan et al 15 ) whereby thermal burn injury and ethanol synergistically activate cytosolic phospholipase A2 (cPLA2) resulting in high levels of PAF biosynthesis. 11 PAF acting on the keratinocyte PAF receptor (PAFR) then triggers the activation of and the translocation to the plasma membrane the enzyme acid sphingomyelinase (aSMase).…”

“… 10 , 14 These studies have supported a model (reviewed in Rohan et al. 15 ) whereby thermal burn injury and ethanol synergistically activate cytosolic phospholipase A2 (cPLA2) resulting in high levels of PAF biosynthesis. 11 PAF acting on the keratinocyte PAF receptor (PAFR) then triggers the activation of and the translocation to the plasma membrane the enzyme acid sphingomyelinase (aSMase).…”

“…In the context of MOD, the PAF-laden MVP travel to the small intestine and act upon the gut epithelial PAFR, which activates myosin-light chain kinase (MLCK) resulting in increased intestinal permeability and release of gut bacteria into the circulation. 15 Regarding the delayed immunosuppression, our previous studies have demonstrated the dependence of ITBI-induced decrease in delayed-type hypersensitivity reactions on PAFR expression. 11 The goal of the present short report was to assess the role of aSMase in ITBI-induced systemic immunosuppression.…”

“…In the context of MOD, the PAF‐laden MVP travel to the small intestine and act upon the gut epithelial PAFR, which activates myosin‐light chain kinase (MLCK) resulting in increased intestinal permeability and release of gut bacteria into the circulation. 15 …”