Mast Cell Activation as a Common Mechanism of Pulmonary Toxicity by Chemical Threat Agents

肥大细胞激活是化学威胁剂肺部毒性的常见机制

• 批准号: 10887265
• 负责人: ALISON K BAUER
• 金额: $ 46.25万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-20 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10887265
• 关键词: Acute; Acute Lung Injury; Alkylating Agents; Biological Markers; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Cell Degranulation; Cell Line; Cell model; Cells; Chemical Exposure; Chemical Warfare Agents; Chemicals; Data; Diesel Exhaust; Eicosanoids; Environment; Exposure to; Fatty Acids; Formaldehyde; Future; G-Protein-Coupled Receptors; Goals; Health; Heavy Metals; Herbicides; Histamine Release; Human; Immune; Immune response; Immune system; Immunologic Surveillance; In Vitro; Individual; Industrialization; Inflammation; Inflammatory; Injury; Innate Immune Response; Insecticides; Intervention; Lead; Link; Lipids; Location; Lung; Mechlorethamine; Mediating; Mediator; Methods; Mucous Membrane; Mus; Mustard Gas; Ozone; Pathway interactions; Pesticides; Pharmacologic Substance; Plasma; Play; Prevention; Production; Prophylactic treatment; Publishing; Pulmonary Inflammation; Pulmonary Pathology; Riots; Risk; Role; Safety; Sampling; Security; Signal Transduction; Surface; Terrorism; Testing; Therapeutic; Tissues; Toxic effect; Wild Type Mouse; Xenobiotics; adaptive immune response; cell type; chemical threat; chemokine; cigarette smoke; cytokine; in vivo; lipid mediator; liquid chromatography mass spectrometry; lung injury; mast cell; mouse model; nanoparticle; new therapeutic target; novel; receptor; recruit; response; sensor; targeted agent; targeted treatment; therapeutic biomarker; therapeutic target; toxicant; transcriptome sequencing; treatment effect

Project Abstract The Department of Homeland Security considers numerous chemical threat agents a concern for human health, specifically those that are acute pulmonary toxicants. In acute lung injury, inflammation is critical thus we propose that inflammation is a common mechanism of lung injury caused by chemical threat agents due to mast cell activation through non-IgE mechanisms. We and others have shown mast cell activation to be critical in response to a wide range of xenobiotics including nitrogen mustard, ozone, diesel exhaust, insecticides/herbicides, cigarette smoke, heavy metals and nanoparticles as examples. Mast cells are a logical cell type to study in pulmonary injury from chemical threat agents due to 1) their location at interfaces with the external environment (e.g., lung); 2) their roles as sensors for initiating both innate and adaptive immune responses; and 3) their immediate response to danger signals through degranulation and release of preformed mediators. We have demonstrated that mast cell activation is a major contributor to the pulmonary toxicity and inflammation observed following nitrogen mustard (NM) exposure, a surrogate of sulfur mustard. Currently there are few shared mechanisms which have been identified between these chemical threat agents, thus identification of common pathways would be beneficial for future therapeutic targets and biomarkers of exposure. We propose to examine common mechanisms using three specific classes of chemicals (alkylating agents (NM), pesticides (chloropicrin), and industrial chemicals (formaldehyde)). Our overall hypothesis is that activation of mast cells by nitrogen mustard, formaldehyde, and chloropicrin is a common initiating step in recruitment and propagation of immune responses in the lung. In aims 1 and 2 we will use mast cell deficient mice to investigate pulmonary inflammation and injury and in aim 3 a human mast cell line to further examine mechanisms by which these agents lead to mast cell activation. In aim 1, we will determine the in vivo contribution of mast cells in pulmonary injury, toxicity, and altered function resulting from chemical threat exposures using WT and mast cell deficient mice. In aim 2 we will examine bioactive lipid profiles and their contribution to pulmonary injury and toxicity from chemical threat exposures from aim 1 plasma and bronchoalveolar lavage samples based on published data with NM that shows increased pro-inflammatory bioactive lipid release upon exposure. Lastly, in aim 3 we will elucidate the role non-IgE mast cell activation through the Mas-Related G-Protein Coupled Receptor (MRGPRX2), in mast cells exposed chemical threat exposures using ROSA cells deficient in MRPGRX2 to identify a novel target. Collectively, our goal is to establish activation of mast cells via MRPGRX2 as a common mechanism across several chemical classes which are linked with pulmonary toxicity. Secondly, we will identify novel therapeutic targets for prevention and/or treatment of the effects of these potential chemical warfare agents through targeting of mast cells and/or the MRGPRX2 receptor.

项目摘要 国土安全部认为许多化学威胁剂对人类健康构成威胁， 特别是那些急性肺部毒物。在急性肺损伤中，炎症是至关重要的，因此我们建议 炎症是由肥大细胞引起化学威胁剂引起的肺损伤的常见机制， 通过非IgE机制激活。我们和其他人已经证明肥大细胞的激活在反应中是至关重要的 包括氮芥、臭氧、柴油机废气、杀虫剂/除草剂， 香烟烟雾、重金属和纳米颗粒作为例子。肥大细胞是一个合乎逻辑的细胞类型的研究 由于1）化学威胁剂位于与外部环境的界面处， (e.g.,肺）; 2）它们作为启动先天性和适应性免疫应答的传感器的作用;以及3）它们的 通过脱颗粒和释放预先形成的介质对危险信号立即作出反应。我们有 表明肥大细胞活化是观察到的肺毒性和炎症的主要原因 氮芥（NM）暴露后，硫芥的替代品。目前，很少有共享 这些化学威胁剂之间已经确定的机制，从而确定共同的 这些途径将有利于未来的治疗靶点和暴露的生物标志物。我们建议研究 使用三种特定类别的化学品（烷化剂（NM），农药（氯化苦）， 和工业化学品（甲醛））。我们的总体假设是氮激活肥大细胞 芥子气，甲醛和氯化苦是一个共同的启动步骤，在招聘和繁殖 肺部的免疫反应。在目标1和2中，我们将使用肥大细胞缺陷小鼠研究肺 目的3是人肥大细胞系，以进一步研究这些细胞在炎症和损伤中的作用机制。 试剂导致肥大细胞活化。在目的1中，我们将确定肥大细胞在肺组织中的体内作用， 使用WT和肥大细胞缺陷型的化学威胁暴露导致的损伤、毒性和功能改变 小鼠在目标2中，我们将研究生物活性脂质的分布及其对肺损伤和毒性的作用， 基于已发表数据的aim 1血浆和支气管肺泡灌洗样本的化学威胁暴露 其中NM在暴露时显示增加的促炎生物活性脂质释放。最后，在目标3中， 阐明非IgE肥大细胞活化通过Mas相关G蛋白偶联受体的作用 （MRGPRX 2），在暴露于化学威胁暴露的肥大细胞中，使用MRPGRX 2缺陷的ROSA细胞， 确定新目标总的来说，我们的目标是通过MRPGRX 2激活肥大细胞， 与肺毒性有关的几种化学类别的机制。第二，我们将确定 用于预防和/或治疗这些潜在的化学战剂的作用的新的治疗靶点 通过靶向肥大细胞和/或MRGPRX 2受体。