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: 8333651
• 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/8333651
• 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）： 这项研究将测试一种基于激活PPAR-g的新方法是否可以抑制慢性阻塞性肺疾病（COPD）的进展，并可能恢复糖皮质激素的反应性。COPD是美国的第四大死因，其特征是慢性肺部炎症和长期进行性肺破坏，严重限制了气体交换。主要的危险因素是吸烟，但戒烟并不能阻止疾病的进展。目前还没有有效的治疗COPD的方法。使用吸烟诱导的COPD小鼠模型，我们将测试是否激活核激素受体过氧化物酶体增殖物激活受体-g（PPAR-g）阻断疾病进展和改善对糖皮质激素的反应。糖皮质激素是大多数炎性疾病的标准治疗方法，但对COPD的影响不大。这种类固醇不敏感性可能是由于组蛋白去乙酰化酶2（HDAC 2）水平降低，这是激活的糖皮质激素受体（GR）阻断炎症相关基因转录的主要机制所必需的。吸烟已显示降低肺泡巨噬细胞（COPD病理生理学中的关键细胞）中的HDAC 2表达和活性。HDAC 2的这种减少被认为是由炎症和香烟烟雾引起的氧化应激引起的。PPAR-g通过不涉及HDAC 2的机制抑制炎症基因的转录，我们的初步数据显示PPAR-g激活减少了烟雾暴露小鼠的肺部炎症。PPAR-g活化的抗炎和抗氧化作用因此可以通过恢复HDAC 2水平来恢复糖皮质激素敏感性。因此，我们假设PPAR-g激活抑制了COPD的疾病进展，并恢复了糖皮质激素的敏感性。本发明的具体目的是：1）在体内确定PPAR-g是否减少香烟烟雾暴露后的肺气肿变化和恢复糖皮质激素敏感性;和2）为了确定来自烟雾暴露小鼠和COPD患者的巨噬细胞中PPAR-g促进与糖皮质激素协同作用的机制是否涉及HDAC 2表达/活性的上调，以及PPAR-g激动剂和糖皮质激素是否协同抑制炎性标志物。证实我们的假设将确立一个新的潜在治疗靶点在COPD进展中的作用。它还将建立一种创新方法的可行性，以恢复治疗性糖皮质激素的敏感性，从而促进PPAR-g-糖皮质激素协同作用，在COPD和潜在的其他类固醇耐药疾病。