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.

接触氯（Cl2）和溴气体（Br2）是公共健康威胁。Cl2和Br2暴露作为一种