Cigarette Smoke-derived Electrophilic Aldehydes and Airway Inflammation

香烟烟雾衍生的亲电醛与气道炎症

• 批准号: 8628126
• 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
• 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/8628126
• 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

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以及慢性肺病（如慢性阻塞性肺病、哮喘和肺癌）的发展密切相关。香烟烟雾（CS）对健康的不利影响很大程度上与其免疫抑制特性有关，导致先天免疫反应、宿主防御和肿瘤监测受损。尽管人们普遍认为这些作用是由 CS 衍生的活性氧 (ROS) 引起的，但主要基于对硫醇基抗氧化剂的保护作用的观察，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类似于 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急性机制似乎在这方面至关重要，直接影响 NF-κB 或 AP-1 的激活并改变细胞氧化还原调节。然而，这些蛋白质烷基化的具体功能后果尚不清楚。丙烯醛暴露还模仿了吸烟对哮喘发展和严重程度的一些可变影响，通过促进过敏性敏化和抑制过敏性炎症。丙烯醛的这些作用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，尽管丙烯醛影响上皮完整性和调节树突状细胞成熟的介质产生的机制尚不清楚。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，并确定关键酶系统直接烷基化的重要性。我们计划使用新开发的蛋白质组学方法和分析目标蛋白中这些修饰的功能重要性，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），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的上皮屏障功能和介质产生的改变。 相关靶蛋白。此外，最近的研究表明丙烯醛可以通过谷胱甘肽 S-转移酶 P1 (GSTP1) 和硫化氢 (H2S) 解毒，硫化氢 (H2S) 是一种新认识的内源性介体，由胱硫醚 ¿-合酶 (CBS) 的（同）半胱氨酸代谢产生，我们将探讨 GSTP1 和 CBS/H2S 在调节中的重要性。 丙烯醛诱导的免疫反应改变（目标 3）。总的来说，这些研究不仅将为丙烯醛对 CS 相关疾病的潜在贡献提供重要见解，而且还可能有助于了解其他相关内源性或环境亲电子试剂的作用。