Mechanisms of Steroid Resistant Asthma

描述（由申请人提供）：气道炎症在慢性哮喘的发病机制中起关键作用。糖皮质激素（GC）是这种疾病抗炎治疗的基石。然而，并不是所有的哮喘患者在GC治疗后都能改善他们的肺功能。这些患者遭受长期全身GC治疗的不良副作用，通常是在没有证据表明它发挥任何明显益处的情况下。最近对哮喘的经济负担的分析表明，哮喘的费用主要归因于不受控制的疾病。虽然严重哮喘患者占哮喘患者的少数，但由于使用昂贵的药物，急诊室就诊和频繁住院，他们占疾病发病率和费用的大部分。 我们最近发现，皮质类固醇抵抗性哮喘患者外周血单核细胞和BAL巨噬细胞中磷酸化p38丝裂原活化蛋白激酶（p-p38 MAPK）激活的基线水平增加。目前的建议将检查潜在的机制增加p-p38 MAPK和它的作用，在翻译后修饰的GCR α功能在CR哮喘。我们假设p38激活通过干扰GCR α核转位而导致皮质类固醇激素抵抗，而GCR α核转位是最佳的反式激活和反式抑制所必需的。初步数据表明，哮喘控制的丧失与在正常微生物组中看不到的独特生物体的扩张有关。 我们的具体目标是：1）确定p-p38 MAPK在单核细胞/巨噬细胞皮质类固醇不敏感性中的作用; 2）表征具有持续气道阻塞的哮喘患者中的微生物组，以确定CR哮喘中细胞p38活化的潜在触发因素; 3）确定维生素D的临床类固醇节省作用是否是由于其诱导促分裂原活化激酶磷酸酶-1（MKP-1）的能力，一种下调单核细胞/巨噬细胞中p38活化的关键磷酸酶; 4）检查导致CR哮喘患者中MKP-1半衰期缩短的机制。 阐明类固醇耐药的潜在机制将对开发诊断和监测类固醇耐药的生物标志物以及开发治疗CR哮喘以及其他慢性炎症性疾病（其中GC反应性改变导致持续性组织炎症）的新治疗方式产生重要影响。

DESCRIPTION (provided by applicant): Airway inflammation plays a critical role in the pathogenesis of chronic asthma. Glucocorticoid (GC)s are the cornerstone of anti-inflammatory therapy in this disease. However, not all asthmatics improve their pulmonary function following GC therapy. These patients are subjected to the unwanted side effects of prolonged systemic GC therapy, often in situations where there is no evidence that it is exerting any appreciable benefit. Recent analyses of the economic burden of asthma suggest that the costs of asthma are largely attributable to uncontrolled disease. Although patients with severe asthma represent a minority of asthmatics, they account for much of the morbidity and cost of the disease due to use of costly medications, emergency room visits and frequent hospitalizations. We have recently found that peripheral blood monocytes and BAL macrophages of corticosteroid-resistant asthmatics have increased baseline levels of phospho-p38 mitogen-activated protein kinase (p-p38 MAPK) activation in their monocyte/macrophages. The current proposal will examine the mechanisms underlying increased p-p38 MAPK and its role in posttranslational modifications of GCR alpha function in CR asthma. We hypothesize that p38 activation results in corticosteroid resistance by interfering with GCR alpha nuclear translocation required for optimal transactivation and transrepression. Preliminary data indicates that loss of asthma control is associated with the expansion of unique organisms not seen in the normal microbiome. Our specific aims will be: 1) to determine the role of p-p38 MAPK in monocyte/macrophage corticosteroid insensitivity; 2) to characterize the microbiome in asthmatics with persistent airway obstruction to determine the potential trigger for cell p38 activation in CR asthma; 3) to determine whether the clinical steroid sparing effects of vitamin D result from its ability to induce mitogen activated kinase phosphatase-1 (MKP-1), a critical phosphatase that downregulates p38 activation in monocytes/macrophages; 4) to examine the mechanisms leading to reduced half-life of MKP-1 in CR asthmatics. The elucidation of mechanisms underlying steroid resistance will have important consequences for development of biomarkers to diagnose and monitor steroid resistance, as well as develop novel therapeutic modalities in the treatment of CR asthma as well as other chronic inflammatory conditions where altered GC responsiveness contributes to persistent tissue inflammation.