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: 10507044
• 负责人: DAVID A. FORD
• 金额: $ 46.29万
• 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/10507044
• 关键词: Accidents; Acids; Acute; Acute Lung Injury; Aldehydes; Animals; Blood Circulation; Blood Coagulation Disorders; Blood Vessels; Bromine; C57BL/6 Mouse; Cardiopulmonary; Caring; Cells; Chemical Warfare; Chemical Warfare Agents; Chemicals; Chemistry; Chlorine; Data; Development; Disinfection; Dose; Exposure to; Failure; Female; Functional disorder; Future; Gases; Goals; Halogens; Human; Incubated; Industrial Accidents; Industrialization; Injury; Lead; Lethal Dose 50; Lipids; Lung; Maintenance; Measures; Mediating; Mediator of activation protein; 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; Time; Toxic effect; Training; Water; Weight; chemical countermeasure; common treatment; cytokine; experimental study; extracellular; hypobromous acid; in vivo; indexing; lung injury; male; 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.

接触氯(Cl2)和溴气体(Br2)是公共健康威胁。Cl2和BR2暴露发生在 工业事故和化学战的结果。心肺衰竭是一个主要的问题。 暴露后，这会导致死亡和发病率；但末端器官的潜在机制 接触Cl2或Br2后的损伤仍有待确定。我们发现Cl2和Br2气体暴露的目标 宿主血浆蛋白原脂质，导致肺和肺中2-卤代脂肪醛和2-卤代脂肪酸的高水平 发行量。最近，我们发现了2-氯脂肪酸，在小鼠和大鼠的血浆中发现的水平。 暴露在Cl2中，可引起中性粒细胞胞外陷阱(Net)的形成。由于网络是关键的和早期的发起人 导致终末器官损伤的凝血疾病，拟议的研究将检验Cl2和BR2 衍生的2-卤代脂肪酸诱导净形成以诱导肺损伤。此外，我们的初步数据显示，2- 溴脂肪酸也会导致网形成，强调了网形成作为一种统一剂的潜力 介导Cl2和Br2气体毒性的机制，将确定共同的治疗靶点和 对策发展机遇。此外，虽然Cl2和Br2相似，但它们的独特之处在于 理化性质决定了它们造成伤害的机制不同。突出这一点 我们已经证明了2-溴脂肪醛与亲核试剂的反应活性是亲核剂的25倍。 2-氯代脂肪醛。除了测试网络形成的作用外，拟议的研究还将确定 2-溴代脂肪和2-氯代醛及其各自的2-卤代脂肪酸的蛋白质靶标 NET的形成，我们预计这些研究的结果将显示重叠和独特的目标 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目标。 具体目标1将确定氯磷脂和溴磷脂是网络形成和随后 接触Cl2和Br2后的肺损伤。 特定目标2将确定氯磷脂和溴磷脂在人体内诱导网络形成的机制 中性粒细胞。 我们将使用小鼠和大鼠的Cl2和Br2气体暴露模型。这一点，加上测试两个截然不同的 LD50级别的毒物，符合本RFA的标准。总的来说，拟议的研究将勾勒出一个共同的 卤脂刺激的网络形成和器官衰竭介导Cl2和Br2毒性的机制。这 机理可能导致这两种化学对策的共同治疗研究 计划在未来关注的问题。