Evidence that keratinocyte microvesicle particles carrying platelet-activating factor mediate the widespread multiorgan damage associated with intoxicated thermal burn injury.

IF 3.6 3区 医学 Q3 CELL BIOLOGY Journal of Leukocyte Biology Pub Date : 2024-10-01 DOI:10.1093/jleuko/qiae078
Rushabh P Lohade, Chad Brewer, Christine M Rapp, Karen M Henkels, Wenfeng Zhang, Anita Thyagarajan, Shikshita Singh, Pranali Manjrekar, Taskin Sabit, Ravi P Sahu, Jeffrey B Travers
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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.

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有证据表明,携带血小板活化因子的角质细胞微囊颗粒介导了与中毒性热烧伤相关的广泛的多器官损伤。
热烧伤可导致严重的发病率和死亡率。乙醇中毒与热烧伤相结合,会导致涉及多个器官的炎症反应加剧,从而增加发病率。最近的研究表明,脂质介质血小板活化因子(PAF)参与了中毒性热烧伤(ITBI)的病理过程。本研究测试了 PAF 和因 ITBI 而产生的亚细胞微囊颗粒(MVP)水平升高在随后的多器官毒性中的作用。首先,用乙醇预孵育 HaCaT 角质细胞的热烧伤导致 MVP 释放增加,抑制 PAF 生成酶细胞膜磷脂酶 A2 和 PAF 受体(PAFR)可阻断 MVP 释放。其次,小鼠的 ITBI 导致促炎细胞因子分泌增加和多个器官的中性粒细胞炎症,而缺乏 PAFR 或 MVP 生成酶酸性鞘磷脂酶(aSMase)的小鼠则不会出现这种情况。此外,之前报道的小鼠 ITBI 中细菌从肠道向肠系膜淋巴结转移的增加也依赖于 PAFR 和 aSMase。经 ITBI 处理的角朊细胞释放的 MVP 含有高水平的 PAFR 激动活性。最后,在 ITBI 后局部使用 aSMase 抑制剂亚胺培南可减轻 ITBI 引起的广泛器官炎症反应,这表明该疗法具有治疗 ITBI 的潜力。这些研究提供的证据表明,皮肤中产生的富含 PAF 的 MVP 随后作用于肠道 PAFR,导致细菌转运,这是导致与 ITBI 相关的多器官功能障碍的机制。由于 aSMase 抑制剂已广泛应用,这些研究可能会为 ITBI 带来有效的治疗方法。
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来源期刊
Journal of Leukocyte Biology
Journal of Leukocyte Biology 医学-免疫学
CiteScore
11.50
自引率
0.00%
发文量
358
审稿时长
2 months
期刊介绍: JLB is a peer-reviewed, academic journal published by the Society for Leukocyte Biology for its members and the community of immunobiologists. The journal publishes papers devoted to the exploration of the cellular and molecular biology of granulocytes, mononuclear phagocytes, lymphocytes, NK cells, and other cells involved in host physiology and defense/resistance against disease. Since all cells in the body can directly or indirectly contribute to the maintenance of the integrity of the organism and restoration of homeostasis through repair, JLB also considers articles involving epithelial, endothelial, fibroblastic, neural, and other somatic cell types participating in host defense. Studies covering pathophysiology, cell development, differentiation and trafficking; fundamental, translational and clinical immunology, inflammation, extracellular mediators and effector molecules; receptors, signal transduction and genes are considered relevant. Research articles and reviews that provide a novel understanding in any of these fields are given priority as well as technical advances related to leukocyte research methods.
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