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

描述(由申请人提供)： 这项研究将测试一种基于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的反应性。慢性阻塞性肺疾病是美国第四大死因，其特点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。吸烟是主要的危险因素，但戒烟并不能阻止疾病的发展。目前还没有有效的治疗COPD的方法。利用吸烟诱导的COPD小鼠模型，我们将测试激活核激素受体过氧化体增殖物激活受体-g(PPAR-g)是否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，对COPD只有轻微的影响。这种类固醇不敏感可能是由于组蛋白脱乙酰酶2(HDAC2)水平降低，这是激活的糖皮质激素受体(GRs)阻止炎症相关基因转录的主要机制所必需的。吸烟可降低肺泡巨噬细胞中HDAC2的表达和活性，肺泡巨噬细胞是COPD病理生理过程中的关键细胞。HDAC2的这种减少被认为是由炎症和香烟烟雾引起的氧化应激所致。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的激活减少了烟雾暴露小鼠的肺部炎症。因此，PPAR-g激活的抗炎和抗氧化作用可能通过恢复HDAC2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。该建议的具体目的是：1)在体内确定PPAR-g是否减少了香烟烟雾暴露后的肺气肿变化，并恢复了糖皮质激素的敏感性；以及2)在烟雾暴露的小鼠和COPD患者的巨噬细胞中，确定PPAR-g促进与糖皮质激素的协同作用的机制是否涉及上调HDAC2的表达/活性，以及PPAR-g激动剂和糖皮质激素是否协同抑制炎症标志物。证实我们的假设将确立新的潜在治疗靶点在COPD进展中的作用。它还将确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-糖皮质激素在慢性阻塞性肺疾病和其他类固醇耐药疾病中的协同作用。

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.