Ceramide-induced lung destruction in emphysema

肺气肿中神经酰胺引起的肺破坏

基本信息

批准号：
8115707
负责人：
Irina Petrache
金额：
$ 38.16万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8115707
关键词：
Acute Address Alveolar Alveolar Cell Alveolar Macrophages Apoptosis Apoptotic Biochemical Biological Assay Cell Death Cells Ceramides Cessation of life Characteristics Chronic Chronic Obstructive Airway Disease Cigarette smoke-induced emphysema Complement Coupled Development Endothelial Cells Enzymes Epithelial Cells Excision Figs - dietary Goals Homeostasis Impairment Injury Investigation Knowledge Laboratories Lead Link Lung Measurement Measures Metabolism Microscopy Molecular Mus Oxidative Stress Pathogenesis Pathway interactions Patients Process Pulmonary Emphysema Respiratory physiology Role Small Interfering RNA Sphingolipids Sphingosine Staging Structure of parenchyma of lung Techniques Testing Therapeutic Time Transgenic Mice Transgenic Organisms Up-Regulation Work acid sphingomyelinase base cell injury cell type cigarette smoke-induced cigarette smoking dihydroceramide enzyme pathway in vivo inhibitor/antagonist injury and repair novel paracrine public health relevance repaired response sensor tandem mass spectrometry two-photon

项目摘要

DESCRIPTION (provided by applicant): Our laboratory previously discovered a central role for ceramide in the development of emphysema. We demonstrated that ceramide is a proximal hub of amplification for apoptosis, oxidative stress, and for its own synthesis, and is both necessary and sufficient to induce airspace enlargement and functional decreases of lung elastance, fundamental characteristics of emphysema. In this application we address the novel concept that cigarette smoke (CS) exposure disrupts sphingolipid homeostasis in the lung to generate distinct acute and chronic ceramide responses, responsible for the death of structural alveolar epithelial and endothelial cells, inhibition of clearance of apoptotic cells by alveolar macrophages, and impairment of cell repair that sustain an irreversible lung destruction in emphysema. We hypothesize that CS-induced ceramides trigger alveolar cell death, impair proper removal of apoptotic bodies, and disrupt cell repair due to sequential activation of acid sphingomyelinase followed by de novo ceramide synthesis. We will test this hypothesis by using transgenic in vivo approaches complemented with pharmacological inhibition of target enzymes and by assessing structural and functional endpoints that characterize cigarette smoke-induced emphysema. Sphingolipid measurements and their effect on alveolar apoptosis and clearance of apoptotic cells will be studied by tandem mass spectrometry and intravital/time-lapse two-photon microscopy, respectively. The specific aims are: 1) To determine that the CS-activated acid sphingomyelinase triggers alveolar cell apoptosis and causes airspace enlargement in mice. 2) To establish that CS and paracellular ceramides activate the de novo pathway in alveolar macrophages causing inhibition of apoptotic body removal. 3) To elucidate if the paracrine activation of de novo ceramide synthesis causes alveolar cell apoptosis and decreased lung repair by CS. Our experimental questions and approach will address fundamental questions of emphysema pathogenesis and will provide the rationale and basis for developing a therapeutic strategy for patients with COPD.

描述（由申请人提供）：我们的实验室先前发现了神经酰胺在肺气肿发展中的核心作用。我们证明，神经酰胺是凋亡，氧化应激及其自身合成的扩增的近端枢纽，并且既需要诱导空域扩大和肺部弹性功能降低，又足够的肺部功能降低。在此应用中，我们解决了一个新的概念，即香烟烟雾（CS）暴露破坏肺中的鞘脂稳态，从而产生明显的急性和慢性神经酰胺反应，这些反应是导致结构性肺泡上皮细胞和内皮细胞的死亡，抑制肺泡细胞清除肺泡细胞的清除，并抑制肺泡型细胞，并影响势力的效果，并影响势力效果。我们假设CS诱导的神经酰胺会触发肺泡细胞死亡，损害凋亡体的适当去除以及由于酸鞘磷脂酶的顺序激活而破坏细胞修复，然后再进行神经酰胺合成。我们将通过使用与靶酶的药理学抑制的体内转基因方法以及评估表征香烟烟雾诱导的肺气肿的结构和功能终点来检验该假设。鞘脂测量及其对肺泡细胞凋亡和凋亡细胞清除的影响将分别通过串联质谱和静脉/延时两光子显微镜研究。具体目的是：1）确定CS激活的酸鞘磷脂酶会触发肺泡细胞的凋亡，并导致小鼠空域增大。 2）确定CS和细胞细胞神经酰胺在肺泡巨噬细胞中激活从头途径，从而导致抑制凋亡人体的去除。 3）阐明新神经酰胺合成的旁分泌激活是否会导致肺泡细胞凋亡并减少CS的肺修复。我们的实验性问题和方法将解决肺气肿发病机理的基本问题，并为COPD患者制定治疗策略的理由和基础。