The Mechanism of Tobacco-Induced Decrements in Mucociliary Clearance

烟草引起的粘液纤毛清除能力下降的机制

• 批准号: 9355468
• 负责人: Vivian Y Lin
• 金额: $ 3.46万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2019-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9355468
• 关键词: Acrolein; Acute; Address; Affect; Aldehydes; Blood; Breathing; Bronchi; Cause of Death; Cells; Chemicals; Chloride Channels; Chronic; Chronic Bronchitis; Chronic Obstructive Airway Disease; Cigarette; Cilia; Clinical; Clinical Research; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; DNA Sequence Alteration; Data; Defect; Defense Mechanisms; Development; Disease; Disease Progression; Drug Targeting; Electronic cigarette; Epithelial; Etiology; Exhibits; Functional disorder; Goals; Health Care Costs; Host Defense; Human; Hydration status; Imaging technology; Impairment; In Vitro; Inhalant dose form; Interruption; Ion Channel; Ion Transport; Lung diseases; Mainstreaming; Membrane Proteins; Methods; Morbidity - disease rate; Mucociliary Clearance; Mucous body substance; Mus; Mutation; Obstruction; Obstructive Lung Diseases; Optical Coherence Tomography; Pathogenesis; Pathology; Patients; Pb clearance; Pharmacology; Phenotype; Play; Proteins; Pulmonary Cystic Fibrosis; Pulmonary Emphysema; Quality of life; Respiratory physiology; Risk Factors; Severities; Smoke; Smoker; Smoking; Stroke; Surface; System; Testing; Therapeutic; Time; Tobacco; Tobacco smoke; Trachea; Viscosity; cigarette smoking; cigarette smoking; hookah; improved; in vivo; innovation; insight; mucus hypersecretion; negative affect; novel therapeutic intervention; novel therapeutics; particle; pathogen; protein function; protein structure; respiratory; respiratory toxin; therapeutic development; toxicant; viscoelasticity

Project Summary/Abstract Chronic obstructive pulmonary disease (COPD) is a disease characterized by progressive loss of lung function and is the third leading cause of death in the US. Treatments that target the mechanisms underlying COPD pathogenesis do not currently exist and present a logical avenue for new therapeutic development. Our group and others have established that tobacco smoke, the leading cause of COPD, alters the function of the cystic fibrosis transmembrane conductance regulator (CFTR), and that this “acquired CFTR dysfunction” is also present in COPD. Genetic mutation of this ion channel is responsible for the etiology of cystic fibrosis (CF) which, like COPD, is characterized by progressive reduction in lung function due to defective mucus clearance. The FDA has identified several harmful toxicants in tobacco smoke, among which are reactive aldehydes such as acrolein, which we have shown in preliminary data are detrimental to both CFTR function and mucus clearance. Through the proposed studies, we will elucidate how specific chemicals within tobacco smoke alter CFTR function and mucus clearance in COPD. We hypothesize that acrolein and other aldehydes are principal components of tobacco smoke that inhibit CFTR function and contribute to defective mucus clearance, and that aldehyde scavengers can ameliorate these effects. To test this, we have developed three Specific Aims. In Aim 1, we will characterize how whole cigarette smoke affects CFTR-dependent ion transport and mucus clearance. In Aim 2, we will establish whether reactive aldehydes such as acrolein can recapitulate the effects of whole cigarette smoke in vitro and in vivo. In Aim 3, we will determine whether acrolein blockade using reactive aldehyde scavengers can protect against smoke-induced CFTR dysfunction and subsequent impairment of mucus clearance. These studies will advance the field by revealing the mechanistic basis underlying how tobacco smoke contributes to COPD manifestations, potentially leading to new targets and an innovative treatment approach.

项目总结/摘要 慢性阻塞性肺疾病是一种以肺功能进行性丧失为特征的疾病 是美国第三大死因针对COPD潜在机制的治疗 发病机制目前不存在，并提出了新的治疗发展的逻辑途径。我们集团 和其他人已经确定，吸烟，COPD的主要原因，改变了膀胱的功能， 纤维化跨膜传导调节因子（CFTR），这种“获得性CFTR功能障碍”也是 在COPD中。这种离子通道的基因突变是囊性纤维化（CF）的病因 与COPD一样，其特征在于由于粘液清除缺陷而导致肺功能的进行性降低。 FDA已经确定了烟草烟雾中的几种有害有毒物质，其中包括活性醛， 丙烯醛，我们已经在初步数据中表明，这是有害的CFTR功能和粘液 间隙通过拟议的研究，我们将阐明烟草烟雾中的特定化学物质如何改变 COPD患者CFTR功能和粘液清除率我们假设丙烯醛和其他醛类是主要的 烟草烟雾中抑制CFTR功能并导致粘液清除缺陷的成分，以及 醛清除剂可以改善这些影响。为了验证这一点，我们制定了三个具体目标。在 目的1，我们将描述整个香烟烟雾如何影响CFTR依赖的离子转运和粘液 间隙在目标2中，我们将确定反应性醛类（如丙烯醛）是否可以重现这些效应 在体外和体内的整体香烟烟雾。在目标3中，我们将确定是否使用丙烯醛阻断剂， 反应性醛清除剂可以防止烟雾诱导的CFTR功能障碍和随后的 粘液清除障碍。这些研究将通过揭示机械基础来推动该领域的发展 揭示了烟草烟雾如何导致COPD表现，可能导致新的目标和新的治疗方法。 创新的治疗方法。