Molecular mechanism of alveolar injury caused by cigarette smoke

香烟烟雾引起肺泡损伤的分子机制

• 批准号: 7876361
• 负责人: Irina Petrache
• 金额: $ 23.1万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7876361
• 关键词: Address; Alveolar; Alveolar Cell; Alveolar wall; Amplifiers; Apoptosis; Biochemical; Biomedical Research; Cause of Death; Cell Line; Cells; Cellular Membrane; Ceramides; Chronic Bronchitis; Chronic Obstructive Airway Disease; Cigarette; Complement; Data; Disease; Electric Capacitance; Epithelial Cells; Event; Exposure to; Health; Inflammatory; Inflammatory Response; Injury; Investigation; Lipid Bilayers; Lipids; Lung; Lung diseases; Mechanics; Mediating; Mediator of activation protein; Membrane Lipids; Methods; Microscopy; Modeling; Molecular; Mus; Organelles; Oxidative Stress; Pathogenesis; Patients; Peptide Hydrolases; Peripheral; Photons; Primary Cell Cultures; Property; Proteolysis; Pulmonary Emphysema; Rattus; Reactive Oxygen Species; Research; Signal Transduction; Site; Smoke; Source; Sphingolipids; Techniques; Therapeutic; Time; Work; airway inflammation; base; cell injury; cigarette smoke-induced; cigarette smoking; cigarette smoking; enzyme substrate; high risk; imaging modality; lung imaging; lung injury; molecular imaging; monolayer; multidisciplinary; novel; public health relevance; response; therapeutic target; tool; two-photon

DESCRIPTION (provided by applicant): Our previous investigations of the molecular mechanisms of dysregulated lung cell apoptosis in emphysema led us to identify a marked increase in sphingolipid ceramide species in the lungs of patients with emphysema and in cells exposed to cigarette smoke (CS). Our findings implicated ceramide as an amplifier of oxidative stress and apoptosis in the lung. We postulate that ceramide is an important proximal mediator of CS-induced oxidative stress and injury in lung alveolar cells and therefore a putative therapeutic target in emphysema. Therefore, understanding the mechanisms by which CS upregulates ceramides in the lung is of utmost importance. We hypothesize that CS stimulates ceramide synthesis by dysregulating lipid interactions within the cellular membranes. Furthermore, we hypothesize that ceramide is a mediator of early alveolar lung injury induced by cigarette smoke characterized by alterations of the alveolar barrier function. We will investigate these hypotheses with the following specific aims: Specific Aim 1. To determine the biophysical mechanism by which CS upregulates ceramides, we will conduct biophysical investigations in membrane lipid bilayer models complemented with cellular injury models; and Specific Aim 2. To establish that ceramides are mediators of the CS-induced injury of the alveolar cell barrier function, we will study the capacitance of primary alveolar cell monolayers in real-time and we will develop and utilize for the first time an intravital application of two-photon emission microscopy (TPEM) of the intact rat lung. When completed, this work will elucidate the connection between bio-mechanical changes in the lipid bilayer membrane and biochemical events leading to ceramide signaling and, by implementing intravital TPEM imaging of the lung for the first time, it will accelerate biomedical lung research by its broad application to multiple mechanisms of lung health and disease. PUBLIC HEALTH RELEVANCE: We will investigate how cigarette smoke triggers the increase in ceramides in lipid membranes which are lining the cells and important organelles within the cells and are the sites of ceramides synthesis. Besides using classical methods, we propose a novel technique of real time recording of barrier function in the intact lung utilizing an advanced imaging modality to study if the increase in ceramide is a necessary step in the earliest lung injury induced by cigarette smoke. Our work is expected to provide the rationale for a therapeutic strategy that targets ceramide in patients with COPD and will develop a new intravital molecular imaging modality of the whole lung which can be applied to the studies of all lung diseases.

描述（由申请人提供）：我们先前对肺气肿肺细胞凋亡失调的分子机制的研究，导致我们确定了肺气肿和暴露于香烟烟雾（CS）的细胞中的肺炎鞘胺神经酰胺物种明显增加。我们的发现暗示了神经酰胺是肺中氧化应激和凋亡的放大器。我们假设神经酰胺是肺肺泡细胞中CS诱导的氧化应激和损伤的重要近端介体，因此是肺气肿的假定治疗靶标。因此，了解CS上调肺中神经酰胺的机制至关重要。我们假设CS通过在细胞膜内的脂质相互作用失调来刺激神经酰胺的合成。此外，我们假设神经酰胺是由香烟烟雾引起的早期肺泡肺损伤的介体，其特征是肺泡屏障功能的改变。我们将以以下特定目的研究这些假设：具体目的1。为了确定CS上调神经酰胺的生物物理机制，我们将在膜脂质双层模型中进行生物物理研究，以补充细胞损伤模型；和特定的目的2。为了确定神经酰胺是CS诱导的肺泡细胞屏障功能损伤的介体，我们将实时研究原发性肺泡细胞单层的电容，我们将首次开发和利用两光子发射显微镜（TPEM）完整鼠（TPEM）完整鼠（TPEM）完整鼠（TPEM）完整的鼠的完整性鼠的电容。完成后，这项工作将阐明脂质双层膜的生物力学变化与生化事件之间的联系，导致神经酰胺信号传导，并通过第一次实施肺部插入式TPEM成像，它将通过对多种肺健康和疾病的多种机制来加速生物医学肺部研究。 公共卫生相关性：我们将研究香烟烟雾如何触发脂质膜中的神经酰胺的增加，脂质膜中的细胞和细胞内的重要细胞器是西酰胺合成的位置。除了使用经典方法外，我们还提出了一种新型的技术，可以利用先进的成像模态在完整肺中实时记录屏障功能，以研究神经酰胺的增加是香烟烟雾引起的最早肺损伤的必要步骤。预计我们的工作将提供针对COPD患者神经酰胺的治疗策略的基本原理，并将开发整个肺部的新型插入性分子成像方式，可以应用于所有肺部疾病的研究。