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)是对公共健康的威胁。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，这会导致死亡和 发病率。然而，这些肺部毒物的作用机制尚未得到证实。 已澄清。COCl2和PCl3都会在肺部迅速产生HCl。血浆蛋白原磷脂包括 肺中的血浆乙醇胺(PPE)是酸不稳定的，导致脂醛和 含多不饱和脂肪酸的溶血磷脂酰乙醇胺(PUFA-LPE)。除了COCl2和PCl3之外 与血浆原的乙烯基醚键反应，脂类的其他官能团也可能成为靶标。这些 包括伯胺和共轭双烯，这表明产生了一系列亲脂化合物 在曝光过程中。蛋白质和代谢物的官能团也可以被COCl2和PCl3修饰 暴露会导致新陈代谢改变。接触COCl2后的广泛发现组学分析 PCl3将为它们的毒性机制提供关键的见解。我们假设两者都是 接触COCl2和PCl3导致脂质和代谢改变，导致内皮细胞和上皮细胞 功能障碍。将采用有针对性和无针对性的方法来确定新的血脂和代谢 COCl2和PCl3暴露后的变化。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，HLMVEC的表达增加； PUFA-LPE导致HLMVEC屏障功能障碍；3)COCl2暴露在肺脂中导致产生 亲脂醛和PCl3家族引起HLMVEC代谢物和代谢的深刻变化 暴露后的路径。拟议的研究有两个具体目标。具体目标1将 在接触COCl2和PCl3后识别新的脂质和代谢产物，导致内皮和 上皮细胞功能障碍。特定目标2将确定新的脂类和代谢物种 接触COCl2和PCl3后产生的物质会导致内皮和上皮细胞功能障碍。 我们将研究COCl2和PCl3对原代人肺微血管内皮细胞和 原代人小气道上皮细胞。再加上测试这两种不同的毒物的LD50水平， 符合此RFA的标准。拟议的研究将探讨COCl2和COCl2的潜在共同机制。 PUFA-LPE介导的PCl3毒性。此外，还将检查独特的脂类和代谢变化 使用非目标分析方法进行COCl2和PCl3暴露。总的来说，这些研究将提供以下方面的信息： 洞察毒性的机制，并将为开发治疗靶点 应对COCl2和PCl3的对策。