Role of PPAR-gamma in Smoking-induced COPD Progression and Steroid Resistance

PPAR-γ 在吸烟引起的 COPD 进展和类固醇耐药中的作用

• 批准号: 8680001
• 负责人: RAJU C REDDY
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8680001
• 关键词: Accounting; Adverse effects; Agonist; Alveolar; Alveolar Cell; Alveolar Macrophages; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Binding; Biological; Cause of Death; Cells; Chromatin Structure; Chronic; Chronic Obstructive Airway Disease; Clinical; Clinical Management; Competitive Binding; Complex; DNA-Directed RNA Polymerase; Data; Development; Disease; Disease Progression; Disease Resistance; Dose; Exposure to; Functional disorder; Gases; Gene Activation; Genes; Genetic Transcription; Glucocorticoid Receptor; Glucocorticoids; Goals; Histone Acetylation; Histone Deacetylase; Histone H4; Immune response; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Intervention; Knock-out; Ligand Binding; Lung; Matrix Metalloproteinases; Mechanics; Mediating; Mediator of activation protein; Modeling; Morbidity - disease rate; Mus; NF-kappa B; Nuclear; Nuclear Hormone Receptors; Obstruction; Oxidative Stress; PPAR gamma; Particulate; Patients; Peroxisome Proliferator-Activated Receptors; Pneumonia; Production; Pulmonary Emphysema; Reactive Oxygen Species; Research; Resistance; Risk; Risk Factors; Role; Smoke; Smoking; Source; Steroid Resistance; Steroids; Structure of parenchyma of lung; Testing; Tissues; Transcription Coactivator; Transcription Factor AP-1; Treatment Efficacy; United States; Up-Regulation; Veterans; base; chemokine; cigarette smoking; cigarette smoking; cytokine; economic cost; effective therapy; histone deacetylase 2; improved; in vivo; inflammatory marker; innovation; macrophage; mouse model; neutrophil; novel; novel strategies; prevent; public health relevance; response; smoking cessation; standard care; therapeutic target; toxicant; transcription factor

DESCRIPTION (provided by applicant): This research will test whether a novel approach based on activation of PPAR-g can inhibit progression of chronic obstructive pulmonary disease (COPD) and possibly restore glucocorticoid responsiveness. COPD, the 4th-leading cause of death in the US, is characterized by chronic pulmonary inflammation and longer-term progressive lung destruction that severely limits gas exchange. The major risk factor is cigarette smoking, but smoking cessation does not halt disease progression. There is currently no effective therapy for COPD. Using a murine model of smoking-induced COPD, we will test whether activating the nuclear hormone receptor peroxisome proliferator-activated receptor-g (PPAR-g) blocks disease progression and improves responses to glucocorticoids. Glucocorticoids, a standard treatment for most inflammatory diseases, have only modest effects in COPD. This steroid insensitivity may be due to reduced levels of histone deacetylase 2 (HDAC2), which is required for a major mechanism through which activated glucocorticoid receptors (GRs) block transcription of inflammation-related genes. Smoking has been shown to reduce HDAC2 expression and activity in alveolar macrophages, key cells in COPD pathophysiology. This reduction of HDAC2 is believed to result from oxidative stress caused by both inflammation and cigarette smoke. PPAR-g inhibits transcription of inflammatory genes, by mechanisms not involving HDAC2, and our preliminary data show that PPAR-g activation reduces pulmonary inflammation in smoke-exposed mice. The anti-inflammatory and antioxidant effects of PPAR-g activation may thus restore glucocorticoid sensitivity by restoring HDAC2 levels. We therefore hypothesize that PPAR-g activation inhibits disease progression and restores glucocorticoid sensitivity in COPD. The Specific Aims of this proposal are: 1) To determine in vivo whether PPAR-g reduces emphysematous changes and restores glucocorticoid sensitivity following cigarette smoke exposure; and 2) To determine in macrophages from smoke-exposed mice and COPD patients whether the mechanisms by which PPAR-g promotes synergy with glucocorticoids involves upregulation of HDAC2 expression/activity, and whether PPAR-g agonists and glucocorticoids synergistically suppress inflammatory markers. Confirming our hypothesis would establish the role of a new potential therapeutic target in COPD progression. It would also establish the feasibility of an innovative approach to restoring therapeutic glucocorticoid sensitivity, thereby promoting PPAR-g-glucocorticoid synergy, in COPD and potentially in other steroid-resistant diseases.

描述（由申请人提供）：