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）： 这项研究将测试基于PPAR-G激活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反应性。 COPD是美国第四个领先的死亡原因，其特征是慢性肺部炎症和长期进行性肺部破坏，严重限制了气体交换。主要危险因素是吸烟，但戒烟不会阻止疾病的进展。目前尚无针对COPD的有效疗法。使用吸烟引起的COPD的鼠模型，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的受体-G（PPAR-G）会阻止疾病进展并改善对糖皮质激素的反应。糖皮质激素是大多数炎症性疾病的标准治疗方法，在COPD中仅具有适度的影响。这种类固醇不敏感的可能是由于组蛋白脱乙酰基酶2（HDAC2）的水平降低，这是一种主要机制所必需的，该机制通过该机制激活了糖皮质激素受体（GRS）阻断炎症相关基因的转录。已证明吸烟可降低肺泡巨噬细胞中的HDAC2表达和活性，COPD病理生理学中的关键细胞。 HDAC2的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HDAC2的机制抑制炎症基因的转录，我们的初步数据表明，PPAR-G激活减少了暴露于烟雾的小鼠的肺部炎症。因此，PPAR-G活化的抗炎和抗氧化作用可以通过恢复HDAC2水平来恢复糖皮质激素的敏感性。因此，我们假设PPAR-G激活抑制疾病进展并恢复COPD中的糖皮质激素敏感性。该提案的具体目的是：1）确定体内PPAR-G是否会减少卷烟烟雾后的质量变化并恢复糖皮质激素敏感性； 2）要确定来自烟雾暴露的小鼠和COPD患者的巨噬细胞中，PPAR-G促进糖皮质激素的协同作用是否涉及HDAC2表达/活性的上调，以及PPAR-G-G激动剂和糖皮质激素是否协同抑制炎症标记。确认我们的假设将确定新的潜在治疗靶标在COPD进展中的作用。它还将建立一种创新方法来恢复治疗性糖皮质激素敏感性的可行性，从而在COPD中促进PPAR-G-G-糖皮质激素协同作用，并可能在其他耐药疾病中进行。