Cigarette Smoke-derived Electrophilic Aldehydes and Airway Inflammation

香烟烟雾衍生的亲电醛与气道炎症

基本信息

批准号：
8484841
负责人：
ALBERT VAN DER VLIET
金额：
$ 38.13万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-07 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8484841
关键词：
Acrolein Acute Acute Lung Injury Address Adjuvant Adverse effects Affect Aldehydes Alkylation Allergic Allergic inflammation Alveolar Macrophages Anti-Inflammatory Agents Anti-inflammatory Antigen-Presenting Cells Antigens Antioxidants Asthma Attenuated Bacterial Infections Belief Breathing Cell Maturation Cells Childhood Chronic Chronic Obstructive Airway Disease Chronic lung disease Cystathionine Cysteine Metabolism Pathway Dendritic Cells Development Disease Drug Metabolic Detoxication Environmental Exposure Environmental Pollutants Enzymes Eosinophilia Epithelial Epithelial Cells Exposure to Extrinsic asthma Genetic Polymorphism Glutathione S-Transferase Goals Health Homo Host Defense Hydrogen Sulfide Immune response Immune system Immunosuppression Immunosuppressive Agents In Vitro Infection Inflammation Inflammatory Injury Knockout Mice Lipopolysaccharides Lung Lung diseases MAPK9 gene Macrophage Activation Malignant neoplasm of lung Mediating Mediator of activation protein Metabolic Metabolism Metaplasia Modeling Modification Mucous body substance Mus Ovalbumin Oxidation-Reduction Oxidative Stress Pathway interactions Post-Translational Protein Processing Predisposition Production Property Proteins Proteomics Reactive Oxygen Species Regulation Respiratory Tract Infections Severities Signal Transduction Small Interfering RNA Smoking Sulfhydryl Compounds System Transcription Factor AP-1 Transgenic Organisms United States National Institutes of Health Virus Diseases airway inflammation allergic airway disease allergic airway inflammation base cigarette smoke-induced cigarette smoking cigarette smoking cytokine design eosinophil global health in vivo insight interest macrophage mouse model neutrophil prevent protective effect respiratory response thioredoxin reductase tumor

项目摘要

DESCRIPTION (provided by applicant): Cigarette smoking remains a major global health burden and is strongly associated with increased childhood respiratory infections and development of chronic lung diseases such as COPD, asthma and lung cancer. The adverse health effects of cigarette smoke (CS) are largely related to its immuno-suppressive properties leading to impaired innate immune responses, host defense, and tumor surveillance. Although it is commonly thought that these effects are due to CS-derived reactive oxygen species (ROS), largely based on observations of protective effects of thiol-based antioxidants, the main thiol-reactive agents within CS are acrolein (2,3- propenal) and other related unsaturated aldehydes. Our recent studies in mice have demonstrated immunosuppressive effects of acrolein on alveolar macrophages that mimic those of CS. Acute mechanisms associated with direct and transient alkylation of redox-sensitive protein targets appear to be critical in this respect, diretly affecting activation of NF-?B or AP-1 and altering cellular redox regulation. However, the specific functional consequences of these protein alkylations are not known. Acrolein exposure also mimics some of the variable effects of cigarette smoking on asthma development and severity, by promoting allergic sensitization but also by suppressing allergic inflammation. These effects of acrolein were associated with increased epithelial injury and are likely mediated by altered epithelial barrier integrity and interaction with dendritic cells, the main antigen-presentng cell in the lung, although the mechanisms by which acrolein impacts on epithelial integrity and production of mediators that regulate dendritic cell maturation are not known. The main goal of the present proposal is to elucidate the mechanisms by which acrolein alters innate macrophage and epithelial immune responses as well as allergic inflammation, and to identify the importance of direct alkylation of critical enzyme systems. We plan to determine the importance of direct protein modifications in acrolein-induced suppression of innate immune responses (Aim 1), using newly developed proteomic approaches and analysis of the functional importance of these modifications in target proteins, and explore the consequences of acrolein exposure on allergic inflammation and sensitization (Aim 2), focusing on alterations in epithelial barrier function and mediator production in association with direct alkylation or relevant target proteins. Also, based on recent studies indicating that acrolein is detoxified by glutathione S-transferase P1 (GSTP1) and by hydrogen sulfide (H2S), a newly recognized endogenous mediator produced by (homo)cysteine metabolism by cystathionine ¿-synthase (CBS), we will explore the importance of GSTP1 and CBS/H2S in modulating acrolein-induced alterations in immune responses (Aim 3). Collectively, these studies will not only offer important insights into the potential contribution of acrolein to CS-related disease, but may also be relevant to understanding the actions of other relevant endogenous or environmental electrophiles.

描述（由申请人提供）：吸烟仍然是全球主要的健康负担，并且与儿童呼吸道感染的增加和慢性肺病（如慢性阻塞性肺病、哮喘和肺癌）的发展密切相关。吸烟（CS）对健康的不利影响是。很大程度上与它的免疫抑制特性有关，导致先天免疫反应、宿主防御和肿瘤监测受损，尽管人们通常认为这些影响是由 CS 衍生的活性氧 (ROS) 引起的，这主要是基于对保护作用的观察。的基于硫醇的抗氧化剂，CS 中的主要硫醇反应剂是丙烯醛（2,3-丙烯醛）和其他相关的不饱和醛。我们最近对小鼠的研究表明，丙烯醛对肺泡巨噬细胞具有模拟 CS 的免疫抑制作用。与氧化还原敏感蛋白靶标的直接和瞬时烷基化相关的在这方面似乎至关重要，直接影响 NF-κB 或 AP-1 的激活和然而，这些蛋白质烷基化的具体功能后果尚不清楚，它也通过促进过敏性致敏和抑制过敏性炎症来模拟吸烟对哮喘发展和严重程度的一些不同影响。丙烯醛的增加与上皮损伤增加有关，并且可能是通过改变上皮屏障完整性以及与树突状细胞（肺中主要抗原呈递细胞）的相互作用介导的，尽管其机制丙烯醛对上皮完整性和调节树突状细胞成熟的介质产生的影响尚不清楚。本提案的主要目标是阐明丙烯醛改变先天巨噬细胞和上皮免疫反应以及过敏性炎症的机制。我们计划利用新开发的技术确定直接蛋白质修饰在丙烯醛诱导的先天免疫反应抑制中的重要性（目标 1）。蛋白质组学方法和分析靶蛋白中这些修饰的功能重要性，并探索丙烯醛暴露对过敏性炎症和致敏的影响（目标 2），重点关注与直接烷基化或相关靶点相关的上皮屏障功能和介质产生的变化此外，最近的研究表明，丙烯醛可通过谷胱甘肽 S-转移酶 P1 (GSTP1) 和硫化氢 (H2S) 解毒。新认识的由胱硫醚代谢（同）半胱氨酸产生的内源性介质 ¿ -合成酶（CBS），我们将探讨 GSTP1 和 CBS/H2S 在调节丙烯醛诱导的免疫反应改变中的重要性（目标 3），这些研究不仅将为丙烯醛对 CS- 的潜在贡献提供重要见解。相关疾病，但也可能与了解其他相关内源性或环境亲电体的作用有关。