{"doi":"10.1111/srt.13743","title":"Intoxicated thermal burn injury‐mediated systemic immunosuppression involves platelet‐activating factor and microvesicle particles","abstract":"To the Editor: Dear Editor, Thermal burn injury is a significant medical problem with more than 100, 000 hospitalizations and 3500 deaths in the United States annually.1 It has been estimated that half of all serious thermal burn injuries involve ethanol intoxication, which results in an increased morbidity and mortality via an exaggerated inflammatory response involving many systemic organs.2-4 Intoxicated thermal burn injury (ITBI) has been modeled in mice, revealing similar pathologies to those ascribed in published reports involving human patients.5-10 In addition to acute multi-organ dysfunction (MOD) occurring within 24 h, a delayed effect of thermal burn injury, which is enhanced in ITBI, is a systemic immunosuppressive response.11-13 The consequences of systemic immunosuppression include increased susceptibility to infection.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). Microvesicle particles are then released in response to the actions of aSMase on the plasma membrane, which contain high levels of PAF. The resultant PAF-laden MVP travel systemically. 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. To that end, our first studies employed a validated model of murine ITBI previously used by our10, 11 and other investigators.5, 7, 8 These studies were approved by our institution's animal review panel. Briefly, female aged 6−8-week-old mice (all on C57BL/6 background) were anesthetized with ketamine/xylazine (100 and 10 mg/kg, respectively) and fur removed from dorsal back skin. Mice were given 2.4 g/kg of ethanol in distilled water or water alone and 30 min later underwent an 8 s exposure to a stainless-steel metal block heated to 90°C to provide an approximately 12.5% body surface area burn. Five days post-thermal burn injury, mice were sensitized to 50 µL of dinitrofluorobenzene (DNFB) on dorsal back skin at least 2 cm away from the burn site. Nine days later, mice were anesthetized, and ear thickness measured using Mitutoyo calipers. Twenty microliter of DNFB was applied to one ear and 20 µL 4:1 acetone:olive oil vehicle was applied to the other ear. Twenty-four hours later, the mice were anesthetized, and ear thickness reassessed. The differences in ear thickness serve as an indicator of inflammation in these contact hypersensitivity (CHS) tests. In some experiments, 250 ng of the PAF agonist carbamoyl-PAF (CPAF) was injected i.p. or 200 µg histamine was subcutaneously injected, both as positive controls for inhibition of CHS reactions to DNFB. The role of aSMase on the immunomodulatory effects of ITBI were assessed using two strategies. First, a global aSMase KO mouse (Smpd1-/-) was used as per our previous reports using ultraviolet B radiation (UVB) or topical photodynamic therapy (PDT).16, 17 As shown in Figure 1, ITBI resulted in decreased levels of elicitation reactions to DNFB in wild-type C57BL6, which had no effect in aSMase-deficient mice. Treatment of aSMase KO mice w","journal":"Skin Research and Technology","year":2024,"id":468303,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9667,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":657230,"name":"Christine M. Rapp","orcid":"0000-0001-7114-7796","position":1,"is_corresponding":false},{"id":498578,"name":"Karen M. Henkels","orcid":null,"position":2,"is_corresponding":false},{"id":381163,"name":"Jeffrey B. Travers","orcid":"0000-0001-7232-1039","position":3,"is_corresponding":false},{"id":955806,"name":"Rushabh P. Lohade","orcid":"0009-0007-0350-9872","position":0,"is_corresponding":true}],"reference_count":18,"raw_metadata":null,"created_at":"2026-07-19T02:05:19.071498Z","pmid":"38881182","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}