Halolipid-Neutrophil Extracellular Trap Axis in Halogen Lung Injury

卤素肺损伤中的氟脂-中性粒细胞胞外俘获轴

• 批准号: 10685387
• 负责人: DAVID A. FORD
• 金额: $ 45万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-18 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10685387
• 关键词: Accidents; Acids; Acute; Acute Lung Injury; Aldehydes; Animals; Blood Coagulation Disorders; Blood Vessels; Bromine; C57BL/6 Mouse; Cardiopulmonary; Caring; Cells; Chemical Warfare; Chemical Warfare Agents; Chemicals; Chemistry; Chlorine; Circulation; Data; Development; Disinfection; Dose; Dryness; Endowment; Exposure to; Failure; Female; Functional disorder; Future; Gases; Goals; Halogens; Human; Incubated; Industrial Accidents; Industrialization; Injury; Lethal Dose 50; Lipids; Lung; Maintenance; Measures; Mediating; Mediator; Modeling; Morbidity - disease rate; Mus; Organ; Organ failure; Pathway interactions; Pharmacologic Substance; Phospholipids; Plasma; Plasmalogens; Production; Property; Proteins; Proteome; Public Health; Rattus; Regimen; Research; Role; Sprague-Dawley Rats; Swimming Pools; Testing; Therapeutic; Toxic effect; Training; Water; Weight; chemical countermeasure; chlorine gas; common treatment; cytokine; experimental study; extracellular; hypobromous acid; in vivo; indexing; lung injury; male; manufacture; manufacturing process; mortality; neutrophil; organ injury; programs; therapeutic target; toxicant; water treatment

Exposures to chlorine (Cl2) and bromine gases (Br2) are public health threats. Cl2 and Br2 exposures occur as a result of industrial accidents as well as in chemical warfare. Cardiopulmonary failure is a major concern following exposures, which contributes to mortality and morbidity; but the mechanisms underlying end organ injury after exposure to Cl2 or Br2 remain to be determined. We discovered that Cl2 and Br2 gas exposure target host plasmalogen lipids, resulting in high levels of 2-halofatty aldehyde and 2-halofatty acids in the lung and circulation. Recently, we have shown 2-chlorofatty acids, at levels found in the plasma of mice and rats exposed to Cl2, elicit neutrophil extracellular trap (NET) formation. Since NETs are critical and early initiators of coagulopathies that cause end organ injury, the proposed studies will test the hypothesis that Cl2 and Br2 derived 2-halofatty acids elicit NET formation to induce lung injury. Furthermore, our preliminary data show 2- bromofatty acid also causes NET formation, underscoring the potential for NET formation as a unifying mechanism mediating both Cl2 and Br2 gas toxicity that will identify common therapeutic targets and countermeasure development opportunities. Moreover, while Cl2 and Br2 are similar, their unique physicochemical properties endow differences in mechanisms by which each cause injury. Salient to this proposal, we have shown that 2-bromofatty aldehyde reactivity with nucleophiles is 25-fold greater than that of 2-chlorofatty aldehyde. In addition to testing the role of NET formation, proposed studies will also identify protein targets of 2-bromofatty and 2-chlorofatty aldehydes and their respective 2-halofatty acids in mediating NET formation, and we anticipate results from these studies will demonstrate overlapping and unique targets in the pathways by which Cl2 and Br2 mediate circulatory and pulmonary dysfunction. There are two specific aims for the proposed studies. Specific Aim 1 will identify chlorolipids and bromolipids as critical mediators of NET formation and subsequent lung injury following Cl2 and Br2 exposure. Specific Aim 2 will identify mechanisms by which chlorolipids and bromolipids elicit NET formation in human neutrophils. We will employ both mouse and rat models of Cl2 and Br2 gas exposure. This, together with testing two distinct toxicants at LD50 levels, meet criteria for this RFA. Collectively, the proposed studies will delineate a common mechanism for Cl2 and Br2 toxicity mediated by halolipid-stimulated NET formation and organ failure. This mechanism could lead to a common treatment for both of these Chemical Countermeasures Research Program concerns in the future.

对氯（CL2）和溴气体（BR2）的暴露是公共卫生威胁。 CL2和BR2暴露作为一个 工业事故以及化学战的结果。心肺失败是一个主要问题 曝光后，导致死亡率和发病率；但是末端器官的基础机制 暴露于CL2或BR2后的伤害仍有待确定。我们发现CL2和BR2气体暴露目标 宿主血浆脂质，导致肺中高水平的2-半醛醛和2-卤代酸的酸， 循环。最近，我们在小鼠和大鼠的血浆中发现了2-氯富酸酸 暴露于CL2时，会引起中性粒细胞外陷阱（净）形成。由于网是至关重要的，并且是早期的发起者 造成最终器官损伤的凝血病，拟议的研究将检验CL2和BR2的假设 衍生的2个半脂肪酸会引起净形成以诱导肺损伤。此外，我们的初步数据显示2- 溴化酸还会引起净形成，突显了净形成的潜力 介导CL2和BR2气体毒性的机制，将确定常见的治疗靶标和 对策开发机会。而且，虽然CL2和BR2相似，但它们的独特 物理化学特性赋予每种造成损伤的机制的差异。对此很重要 提案，我们已经表明，与亲核试剂的2-溴化醛反应性大于25倍 2-氯氟醛。除了测试净形成的作用外，拟议的研究还将确定 介导的2-溴法和2-氯富醛醛的蛋白质靶标 净形成，我们预计这些研究的结果将证明重叠和独特的目标 CL2和BR2介导循环和肺功能障碍的途径。 拟议的研究有两个具体的目标。 特定目标1将识别叶绿素和溴脂质作为净形成的关键介体，随后 CL2和BR2暴露后的肺损伤。 特定的目标2将确定叶绿素和溴脂引起人类净形成的机制 中性粒细胞。 我们将使用CL2和BR2气体暴露的小鼠和大鼠模型。这与测试两个不同的 LD50水平的有毒物质符合此RFA的标准。总的来说，拟议的研究将描述一个常见 CL2和BR2毒性的机制是由卤素刺激的净形成和器官衰竭介导的。这 机制可能会导致这两种化学对策研究的共同治疗 计划将来关注。