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HDAC6 regulates cigarette smoke-induced endothelial barrier dysfunction and lung injury

HDAC6 调节香烟烟雾引起的内皮屏障功能障碍和肺损伤

基本信息

批准号：
9285844
负责人：
Qing Lu
金额：
$ 32.18万
依托单位：
OCEAN STATE RESEARCH INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9285844
关键词：
Acute Lung Injury Address Adult Respiratory Distress Syndrome Adverse effects Affect Animal Model Bacterial Infections Binding Blood Circulation Blood Vessels Cell Culture Techniques Cell physiology Cessation of life Characteristics Data Deacetylase Deacetylation Disease Dynamin Endothelial Cells Endothelium Epidemiology Functional disorder Goals HDAC6 gene Human Impairment In Vitro Individual Infection Injury Knockout Mice Life Link Lung Maintenance Mediating Mediator of activation protein MicroRNAs Microtubule-Associated Proteins Microtubules Mission Mitochondria Mitochondrial DNA Modeling Molecular Morbidity - disease rate Organ Oxidants Pattern Permeability Phosphorylation Population Predisposition Preventive Proteins Pseudomonas Pseudomonas Infections Pseudomonas aeruginosa Public Health Quality Control Reactive Oxygen Species Research Research Personnel Respiratory Tract Infections Risk Factors Role Smoker Syndrome Technology Therapeutic Tubulin United States National Institutes of Health alpha Tubulin cigarette smoke-induced cigarette smoking clinical risk environmental tobacco smoke exposure epidemiology study in vivo innovation insight lung injury mitochondrial dysfunction mortality novel novel therapeutic intervention novel therapeutics oxidation pre-clinical premature prevent segregation

项目摘要

Cigarette smoke (CS) affects 1 billion people worldwide and causes 6 million premature deaths from associated diseases each year. Acute lung injury (ALI)/ acute respiratory distress syndrome (ARDS) is a life- threatening condition with 40% mortality. Emerging epidemiology studies have shown that CS predisposes lungs to infections and increases the likelihood of ALI/ ARDS. However, the mechanism of adverse effects of CS on ALI is unknown. There is an urgent need for strategies to prevent and treat ALI/ ARDS in smokers. The objectives of this application is to use human lung microvascular endothelial cells (LMVEC) and preclinical animal models to identify mechanisms by which CS impairs pulmonary endothelial barrier function and increases vulnerability to ALI after bacterial infection and to develop strategies to prevent and restore endothelial barrier function and ALI in susceptible populations. This study uses state-of-art technologies and comprehensive approaches to address a central hypothesis that CS increases endothelial cell permeability and predisposes lungs to ALI after infection by a mechanism in which oxidants from CS and mitochondria cause Akt oxidation and subsequent GSK3β-dependent activation of histone deacetylase 6 (HDAC6), this results in microtubule deacetylation, leading to translocation of dynamin-related protein (Drp)1 to mitochondria, culminating in mitochondrial fission and dysfunction and subsequent release of mitochondrial damage- associated molecular patterns (mtDAMPs). Aim 1: We will first determine the role of HDAC6 in CS priming for ALI after Pseudomonas aeruginosa infection by using global HDAC6 knockout mice, endothelium-specific lentiviral HDAC6 miRNA silencing in vivo, and LMVEC isolated from HDAC6 knockout mice; we will then determine the mechanism by which CS exposure leads to HDAC6 activation. Aim 2: We will determine the role of HDAC6 in CS-induced mitochondrial fission and dysfunction and their roles in mediating increased endothelial permeability and priming for ALI after P. aeruginosa infection. We will first characterize the effects of CS exposure on Drp1 translocation and on mitochondrial fission, fusion, function, and release of mtDNA in vitro and in vivo; we will then determine the effect of blocking HDAC6 or α-tubulin deacetylation on the adverse effects of CS on mitochondria in vitro and in vivo; finally, we will determine the roles of mitochondrial fission, mitochondrial ROS and mtDAMPs in CS-induced increased endothelial permeability in vitro and CS priming for ALI in vivo. This study will provide innovative insights into the effect of CS on lung endothelial barrier function. Establishment of the links among HDAC6, mitochondrial fission and mtDAMPs may result in new therapeutic approaches to CS-induced vascular injury in the lung and potentially also in the systemic circulation.

吸烟影响全球10亿人，并导致600万人过早死亡