The RAGE of COPD

慢性阻塞性肺病的愤怒

• 批准号: 8971959
• 负责人: John R Hoidal
• 金额: --
• 依托单位: VA SALT LAKE CITY HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8971959
• 关键词: Ablation; Address; Advanced Glycosylation End Products; Alveolar; Alveolar Macrophages; Animal Model; Apoptosis; Biochemical; Cause of Death; Cells; Chronic; Chronic Obstructive Airway Disease; Cigarette Smoker; Complement; Data; Development; Diagnosis; Disease; Epithelial Cells; Epithelial Receptor Cell; Family; Generations; Genetic; HMGB1 Protein; Hospitals; Inflammation; Inflammatory; Inflammatory Response; Lead; Leukocyte L1 Antigen Complex; Ligands; Lung; Lung Inflammation; Lung diseases; Mediating; Medical; Modeling; Mononuclear; Mus; Mutant Strains Mice; NADPH Oxidase; Outcome; Pathogenesis; Pathway interactions; Peptide Hydrolases; Publications; Pulmonary Emphysema; Reactive Oxygen Species; Receptor Inhibition; Research Design; Role; Signal Pathway; Signal Transduction; Source; Stress; Testing; Validation; abstracting; alveolar epithelium; base; cigarette smoking; cigarette smoking; clinical application; cytokine; environmental tobacco smoke exposure; macrophage; member; mouse model; novel strategies; oxidant stress; prevent; public health relevance; receptor; receptor expression; transcription factor

DESCRIPTION (provided by applicant): Abstract: Objective: To determine the pathogenic mechanisms of COPD and to define new ways to prevent or treat the disorder. Hypotheses: We propose a new paradigm for a central role of the receptor for advanced glycation end products (RAGE) and its ligands in the emphysema pathogenesis. We hypothesize that RAGE and its ligands through distinct signaling pathways that include NADPH oxidase(s) (Nox)-generated reactive oxygen species (ROS) activate key transcription factors including NF-B and EGR-1 to propagate the inflammation, apoptosis and lung destruction leading to emphysema. Background: Chronic obstructive pulmonary disease (COPD) is a devastating disorder characterized by chronic airflow limitation. It is among the most common discharge diagnoses from VA hospitals and will be the third leading cause of death worldwide by the year 2020. In part, due to the still poorly elucidated or undiscovered mechanisms causing COPD, treatment options are very limited. COPD is associated with chronic inflammation, apoptosis and emphysema. This proposal is aimed at defining the biochemical mechanisms for the inflammation, apoptosis and emphysema. Aims: Aim 1 will determine the ability of RAGE and its ligands to promote inflammation, apoptosis and lung destruction leading to the development of emphysema. It will test the hypothesis that advanced glycation end products (AGEs) or other ligands interact with RAGE to amplify the inflammatory response and apoptosis that mediate the lung destruction leading to the development of emphysema. Aim 2 will determine the role of signaling intermediates in RAGE-induced lung inflammation, apoptosis and destruction leading to the development of emphysema. It will test the hypothesis that RAGE and its ligands acting through Nox(s) and NF-B or Egr-1, cause synthesis and release of pro-inflammatory cytokines and additional RAGE ligands, which further perpetuate RAGE expression, inflammation, oxidative and/or proteinase stress and apoptosis with resulting lung destruction. Aim 3 will determine whether lung macrophage RAGE or alveolar epithelial cell RAGE is primarily responsible for propagating inflammation, apoptosis and lung destruction leading to the development of emphysema. These studies will take advantage of unique mouse models with mononuclear or alveolar epithelial cell specific deletion of RAGE to test the hypothesis that lung macrophage RAGE is the primary effector of RAGE-mediated inflammation and lung destruction. Research Design: We will study the expression of RAGE and its ligands during the development of emphysema using a model of cigarette smoke exposure to mice. Mutant mice exposed to cigarette smoke will be used to determine the importance of RAGE and specific signaling pathways in emphysema development. Studies in isolated cells exposed to cigarette smoke extract will complement those proposed in mouse models to aide in delineating signaling pathways. A particular focus will be the role(s) of RAGE expressed on lung macrophages and alveolar epithelium since these are the primary sources of RAGE expression in the lungs of cigarette smokers. Significance: Successful outcome of this proposal will transform basic understanding of the pathobiochemistry of emphysema by focusing on pathways currently only tangentially mentioned in discussions of the mechanisms for development of the disorder. It will impact our ability to prevent or reduce the enormous medical burden caused by cigarette smoking. Nowhere is the need for new approaches with clinical application more important in pulmonary diseases than in COPD.

描述（由申请人提供）：

项目成果

RAGE is a Critical Mediator of Pulmonary Oxidative Stress, Alveolar Macrophage Activation and Emphysema in Response to Cigarette Smoke.

RAGE 是香烟烟雾引起的肺氧化应激、肺泡巨噬细胞激活和肺气肿的关键调节因子。

• DOI: 10.1038/s41598-018-36163-z
• 发表时间: 2019
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Sanders,KarlA;Delker,DonA;Huecksteadt,Tom;Beck,Emily;Wuren,Tanna;Chen,Yuntian;Zhang,Yuxia;Hazel,MarkW;Hoidal,JohnR
• 通讯作者: Hoidal,JohnR