Evidence that keratinocyte microvesicle particles carrying platelet-activating factor mediate the widespread multiorgan damage associated with intoxicated thermal burn injury.
J Leukoc Biol
; 116(4): 766-778, 2024 Oct 01.
Article
en En
| MEDLINE
| ID: mdl-38531065
ABSTRACT
Thermal burn injuries can result in significant morbidity and mortality. The combination of ethanol intoxication with thermal burn injury results in increased morbidity through an exaggerated inflammatory response involving many organs. Recent studies have linked involvement of the lipid mediator platelet-activating factor (PAF) in the pathology associated with intoxicated thermal burn injury (ITBI). The present studies tested the roles of PAF and the elevated levels of subcellular microvesicle particles (MVP) generated in response to ITBI in the subsequent multiorgan toxicity. First, thermal burn injury of HaCaT keratinocytes preincubated with ethanol resulted in augmented MVP release, which was blocked by inhibiting the PAF-generating enzyme cytosolic phospholipase A2 and the PAF receptor (PAFR). Second, ITBI of mice resulted in increased proinflammatory cytokine production and neutrophilic inflammation in multiple organs, which were not present in mice deficient in PAFRs or the MVP-generating enzyme acid sphingomyelinase (aSMase). Moreover, the increased bacterial translocation from the gut to mesenteric lymph nodes previously reported in murine ITBI was also dependent on PAFR and aSMase. MVP released from ITBI-treated keratinocytes contained high levels of PAFR agonistic activity. Finally, use of topical aSMase inhibitor imipramine following ITBI attenuated the widespread organ inflammatory response of ITBI, suggesting a potential therapeutic for this condition. These studies provide evidence for PAF-enriched MVP generated in skin, which then act on the gut PAFR, resulting in bacterial translocation as the mechanism for the multiorgan dysfunction associated with ITBI. Inasmuch as aSMase inhibitors are widely available, these studies could result in effective treatments for ITBI.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Esfingomielina Fosfodiesterasa
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Quemaduras
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Factor de Activación Plaquetaria
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Queratinocitos
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Micropartículas Derivadas de Células
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
J Leukoc Biol
Año:
2024
Tipo del documento:
Article
País de afiliación:
Estados Unidos