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

暴露于光气（COCl 2）和磷酰氯（PCl 3）是对公共健康的威胁。COCl 2和PCl 3 接触是工业事故或化学战/恐怖主义行为的结果。接触后，急性 表现为呼吸暂停和肺水肿的肺损伤是主要问题，其导致死亡率， 发病率然而，负责这些肺毒性剂的作用的机制尚未被阐明。 阐明。COCl 2和PCl 3在肺中迅速产生HCl。缩醛磷脂，包括 肺中的血浆乙醇胺（pPE）是酸不稳定的，导致乙醛的产生， 含有多不饱和脂肪酸的溶血磷脂酰乙醇胺（PUFA-LPE）。除了COCl 2和PCl 3 与缩醛磷脂的乙烯基醚键反应，也可以靶向脂质的其它官能团。这些 包括伯胺和共轭二烯，这表明产生了一系列亲脂性化合物 在暴露期间。蛋白质和代谢物的官能团也可以被COCl 2和PCl 3修饰 暴露导致代谢改变。暴露于COCl 2后的广泛发现组学分析 和PCl 3将提供关键的洞察机制负责其毒性。我们假设 COCl 2和PCl 3暴露导致脂质和代谢变化，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鉴定新的代谢性和非代谢性疾病。 COCl 2和PCl 3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 响应于PCl 3暴露于原代人肺微血管内皮细胞（HLMVEC）而升高; 2） PUFA-LPE增强HLMVEC屏障功能障碍; 3）COCl 2暴露于肺脂质导致产生一种 亲脂性醛类和4）PCl 3引起HLMVEC代谢物和代谢产物的深刻变化 暴露后的路径。拟议的研究有两个具体目标。具体目标1将 鉴定COCl 2和PCl 3暴露后新的脂质和代谢产物， 上皮细胞功能障碍具体目标2将确定新的脂质和代谢物质 COCl 2和PCl 3暴露后产生的蛋白质引起内皮和上皮细胞功能障碍。 我们将研究COCl 2和PCl 3暴露于原代人肺微血管内皮细胞， 原代人小气道上皮细胞。这与在LD 50水平下测试这两种不同的毒物一起， 符合本RFA的标准。拟议的研究将检查COCl 2的潜在共同机制， PUFA-LPE介导的PCl 3毒性。此外，还将检查以下独特的脂质和代谢变化 使用非目标分析方法的COCl 2和PCl 3暴露。总的来说，这些研究将提供- 着眼于负责毒性的机制，并将为开发 COCl 2和PCl 3的对策。

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.