Lipid and metabolic mechanisms responsible for phosgene and phosphorus trichloride exposure toxicity

导致光气和三氯化磷暴露毒性的脂质和代谢机制

• 批准号: 10708475
• 负责人: James L Edwards
• 金额: $ 30.3万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708475
• 关键词: Accidents; Acids; Acute Lung Injury; Aldehydes; Amines; Apnea; Chemical Warfare; Chemical Warfare Agents; Chemical Weapons; Chemicals; Chlorides; Data; Development; Dose; Endothelial Cells; Endothelium; Epithelial Cells; Epithelium; Esterification; Exposure to; Family; Flame Retardants; Functional disorder; Future; Goals; Herbicides; Human; Industrial Accidents; Industrialization; Industry; Inhalation Exposure; Lethal Dose 50; Lipids; Lung; Lysophospholipids; Masks; Mediating; Mediator; Metabolic; Metabolic Pathway; Molecular; Morbidity - disease rate; Mus; Mustard Agent; Oils; Pathway interactions; Permeability; Pesticides; Phosgene; Phospholipids; Phosphorus; Plasma; Plasmalogens; Plasticizers; Polyunsaturated Fatty Acids; Polyurethanes; Production; Proteins; Public Health; Pulmonary Edema; Pulmonary Surfactants; Rattus; Reaction; Regimen; Research; Role; Schedule; Shipping; Terrorism; Testing; Therapeutic; Time; Toxic effect; Water; airway epithelium; chemical countermeasure; diene; ethanolamine plasmalogens; fatty aldehyde; functional group; insight; lipidomics; lipophilicity; lung microvascular endothelial cells; metabolomics; mortality; novel; plasmenylethanolamine; programs; response; small molecule libraries; symposium; targeted treatment; therapeutic target; toxicant; vinyl ether

Exposures to phosgene (COCl2) and phosphorous trichloride (PCl3) are public health threats. COCl2 and PCl3 exposures are the result of industrial accidents or chemical warfare/terrorism acts. Following exposures, acute lung injury presenting as apnea and pulmonary edema are major concerns, which contribute to mortality and morbidity. However, mechanisms responsible for the action of these pulmonary toxic agents have not been elucidated. Both COCl2 and PCl3 rapidly produce HCl in the lung. Plasmalogen phospholipids including plasmenylethanolamine (pPE) in the lung are acid-labile leading to the production of lipidic aldehydes and lysophosphatidylethanolamine containing polyunsaturated fatty acids (PUFA-LPE). In addition to COCl2 and PCl3 reacting with the vinyl ether bond of plasmalogens, other functional groups of lipids may also be targeted. These include primary amines and conjugated dienes suggesting that an array of lipophilic compounds is produced during exposures. Functional groups of proteins and metabolites may also be modified by COCl2 and PCl3 exposures leading to metabolic alterations. Extensive discovery omics analyses following exposures to COCl2 and PCl3 will provide critical insights into mechanisms responsible for their toxicity. We hypothesize that both COCl2 and PCl3 exposures result in lipid and metabolic changes leading to endothelial and epithelial cell dysfunction. Both targeted and untargeted approaches will be performed to identify novel lipidic and metabolic changes following COCl2 and PCl3 exposures. In support of this hypothesis, pilot data show: 1) PUFA-LPE levels are elevated in response to PCl3 exposure to primary human lung microvascular endothelial cells (HLMVEC); 2) PUFA-LPE elicits HLMVEC barrier dysfunction; 3) COCl2 exposure to lung lipids results in the production of a family of lipophilic aldehydes and 4) PCl3 elicits profound changes in HLMVEC metabolites and metabolic pathways following exposure. There are two specific aims for the proposed studies. Specific Aim 1 will identify novel lipid and metabolic products following COCl2 and PCl3 exposures resulting in endothelial and epithelial cell dysfunction. Specific Aim 2 will identify mechanisms by which novel lipid and metabolic species produced following COCl2 and PCl3 exposures elicit endothelial and epithelial cell dysfunction. We will investigate COCl2 and PCl3 exposures to both primary human lung microvascular endothelial cells and primary human small airway epithelial cells. This, together with testing these two distinct toxicants at LD50 levels, meet criteria for this RFA. The proposed studies will examine a potential common mechanism for COCl2 and PCl3 toxicity mediated by PUFA-LPE. Additionally, unique lipid and metabolic changes will be examined following COCl2 and PCl3 exposures using untargeted analytical approaches. Collectively, these studies will provide in- sights into the mechanisms responsible for toxicity and will provide therapeutic targets for the development of countermeasures to COCl2 and PCl3.

接触光气 (COCl2) 和三氯化磷 (PCl3) 会威胁公共健康。 COCl2 和 PCl3 暴露是工业事故或化学战/恐怖主义行为的结果。暴露后，急性 表现为呼吸暂停和肺水肿的肺损伤是主要问题，这会导致死亡率和 发病率。然而，这些肺毒剂的作用机制尚未明确。 阐明了。 COCl2 和 PCl3 都在肺中迅速产生 HCl。缩醛磷脂包括 肺中的质纤乙醇胺 (pPE) 对酸不稳定，导致产生脂质醛和 含有多不饱和脂肪酸（PUFA-LPE）的溶血磷脂酰乙醇胺。除COCl2和PCl3外 与缩醛磷脂的乙烯基醚键反应，脂质的其他官能团也可能成为目标。这些 包括伯胺和共轭二烯，表明产生了一系列亲脂性化合物 曝光期间。蛋白质和代谢物的官能团也可能被 COCl2 和 PCl3 修饰 暴露导致代谢改变。接触 COCl2 后进行广泛的发现组学分析 和 PCl3 将提供对其毒性机制的重要见解。我们假设两者 COCl2 和 PCl3 暴露会导致脂质和代谢变化，从而导致内皮和上皮细胞 功能障碍。将采用靶向和非靶向方法来识别新的脂质和代谢 COCl2 和 PCl3 暴露后发生变化。为了支持这一假设，试点数据显示：1) PUFA-LPE 水平 PCl3 暴露于原代人肺微血管内皮细胞 (HLMVEC) 后，其浓度升高； 2） PUFA-LPE 引起 HLMVEC 屏障功能障碍； 3) COCl2 暴露于肺脂质会导致产生 亲脂性醛家族和 4) PCl3 引起 HLMVEC 代谢物和代谢的深刻变化 暴露后的途径。拟议的研究有两个具体目标。具体目标 1 将 识别 COCl2 和 PCl3 暴露后的新型脂质和代谢产物，导致内皮细胞和 上皮细胞功能障碍。具体目标 2 将确定新型脂质和代谢物种的机制 COCl2 和 PCl3 暴露后产生的 COCl2 和 PCl3 会引起内皮和上皮细胞功能障碍。 我们将研究原代人肺微血管内皮细胞和 PCl3 暴露于 COCl2 和 PCl3 的情况。 原代人小气道上皮细胞。再加上测试这两种不同毒物的 LD50 水平， 符合此 RFA 的标准。拟议的研究将探讨 COCl2 和 PUFA-LPE 介导的 PCl3 毒性。此外，将在以下检查独特的脂质和代谢变化 使用非目标分析方法测定 COCl2 和 PCl3 暴露。总的来说，这些研究将提供—— 着眼于毒性机制，并将为开发提供治疗靶点 针对 COCl2 和 PCl3 的对策。