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

基本信息

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
项目类别：
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

项目摘要

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.

接触氯气 (Cl2) 和溴气 (Br2) 会威胁公共健康。 Cl2 和 Br2 暴露作为工业事故和化学战的结果。心肺衰竭是一个主要问题接触后会导致死亡率和发病率；但终末器官的机制接触 Cl2 或 Br2 后的伤害仍有待确定。我们发现Cl2和Br2气体暴露目标宿主缩醛磷脂脂质，导致肺部产生高水平的 2-卤代脂肪醛和 2-卤代脂肪酸循环。最近，我们发现小鼠和大鼠血浆中的 2-氯脂肪酸水平暴露于 Cl2 会引发中性粒细胞胞外陷阱 (NET) 的形成。由于 NET 是关键且早期的发起者导致终末器官损伤的凝血病，拟议的研究将检验 Cl2 和 Br2 的假设衍生的 2-卤代脂肪酸引发 NET 形成，从而诱发肺损伤。此外，我们的初步数据显示 2- 溴脂肪酸也会导致 NET 形成，这强调了 NET 形成作为统一药物的潜力。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，但它们独特的物理化学特性赋予每种造成伤害的机制不同。突出这一点提案中，我们已经证明 2-溴脂肪醛与亲核试剂的反应活性比 2-溴脂肪醛高 25 倍 2-氯脂肪醛。除了测试 NET 形成的作用外，拟议的研究还将确定 2-溴脂肪醛和2-氯脂肪醛及其各自的2-卤脂肪酸在介导中的蛋白质靶标 NET 的形成，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目标。具体目标 1 将确定氯脂和溴脂作为 NET 形成及其后续过程的关键介质 Cl2 和 Br2 暴露后的肺损伤。具体目标 2 将确定氯脂和溴脂在人体中引发 NET 形成的机制中性粒细胞。我们将采用 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，符合本 RFA 的标准。总的来说，拟议的研究将描绘出一个共同的由氟脂刺激 NET 形成和器官衰竭介导的 Cl2 和 Br2 毒性机制。这机制可能会导致这两种化学对策研究的共同处理计划关注未来。