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

基本信息

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
项目类别：
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

项目摘要

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，炎症至关重要，因此我们建议炎症是肥大细胞化学威胁剂引起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激活对于反应至关重要多种异生物质，包括氮芥、臭氧、柴油机尾气、杀虫剂/除草剂、以香烟烟雾、重金属和纳米颗粒为例。肥大细胞是一种合乎逻辑的研究细胞类型化学威胁剂造成的肺部损伤是由于 1) 它们位于与外部环境的界面处（例如肺）； 2）它们作为启动先天性和适应性免疫反应的传感器的作用； 3）他们的通过脱粒和释放预制介质对危险信号立即做出反应。我们有证明肥大细胞激活是观察到的肺毒性和炎症的主要原因暴露于氮芥 (NM) 后，硫芥的替代品。目前分享的还很少这些化学威胁剂之间已确定的机制，从而确定了共同点途径将有利于未来的治疗靶点和暴露的生物标志物。我们建议审查使用三类特定化学品（烷化剂（NM）、杀虫剂（氯化苦）的常见机制，和工业化学品（甲醛））。我们的总体假设是氮激活肥大细胞芥末、甲醛和氯化苦是招募和繁殖的常见起始步骤肺部的免疫反应。在目标 1 和 2 中，我们将使用肥大细胞缺陷小鼠来研究肺炎症和损伤，目标 3 是人类肥大细胞系，以进一步检查这些细胞的机制剂导致肥大细胞激活。在目标 1 中，我们将确定肥大细胞在肺组织中的体内贡献使用 WT 和肥大细胞缺陷的化学威胁暴露导致的损伤、毒性和功能改变老鼠。在目标 2 中，我们将检查生物活性脂质谱及其对肺损伤和毒性的贡献基于已发表数据的目标 1 血浆和支气管肺泡灌洗样本的化学威胁暴露 NM 显示暴露后促炎生物活性脂质释放增加。最后，在目标 3 中，我们将阐明 Mas 相关 G 蛋白偶联受体对非 IgE 肥大细胞激活的作用 (MRGPRX2)，在肥大细胞中使用缺乏 MRPGRX2 的 ROSA 细胞暴露化学威胁确定一个新目标。总的来说，我们的目标是通过 MRPGRX2 建立肥大细胞的激活作为一种常见的方法。与肺毒性相关的几种化学类别的机制。其次，我们要确定预防和/或治疗这些潜在化学战剂影响的新治疗靶点通过靶向肥大细胞和/或 MRGPRX2 受体。