INFLAMMATION & CORTICOSTEROID RESPONSES IN SEVERE ASTHMA

描述（由申请人提供）： 高达5-6%的哮喘患者经历症状和恶化， 传统的治疗方法，并对医疗保健系统产生重大影响。那里 了解慢性严重哮喘的病理生理学是一个迫切的需要。 这些患者表现出对以下治疗效果的相对抗性： 皮质类固醇（CS）。在任何一个国家， 一个机构。在皇家布朗普顿医院，大约有70名严重的 每年哮喘患者被提交给一个研究方案， 管理该项目将研究炎症和细胞 反应，确定CS反应性的作用 (CR)这些反应，并阐明细胞和分子机制 受损的CR。这一假说认为，严重哮喘的炎症通路 被信号传导途径放大，特别是有丝分裂原激活的 蛋白激酶（MAPK），这反过来又减少CS的行动。CS动作可以 在受体结合水平受损，活化的 受体和抑制组蛋白乙酰化;潜在的分子 机制将被调查。从慢性重度哮喘中获得的结果 将患者与控制良好的轻中度哮喘患者进行比较 吸入中等剂量的CS痰液和血液样本 获得和肺泡巨噬细胞，上皮细胞和粘膜下组织 通过纤维支气管镜取出。急性发作和 将检查高剂量口服CS。将分析气道组织和细胞 关于炎症的类型，信号通路的激活， 细胞因子的释放、CS受体核转位和表达 和乙酰化的组蛋白，并检查CS的效果。分子 将检查CR损失的潜在机制。这些研究将导致 更有效的治疗慢性严重哮喘的方法。

DESCRIPTION (provided by applicant): Up to 5-6% of asthmatics experience symptoms and exacerbations despite conventional treatments and have a major impact on health care systems. There is a pressing need to understand the pathophysiology of chronic severe asthma. These patients demonstrate relative resistance to the therapeutic effects of corticosteroids (CS). There are only a small number of these patients at any one institution. At the Royal Brompton Hospital, approximately 70 severe asthmatics per year are referred to a protocol for investigation and management. This project will investigate the inflammatory and cellular responses in chronic severe asthma, determine the role of CS responsiveness (CR) of these responses, and elucidate the cellular and molecular mechanisms of impaired CR. The hypothesis is that inflammatory pathways in severe asthma are magnified by signalling pathways, particularly the mitogen-activated protein kinases (MAPK), which in turn diminishes CS actions. CS actions may be impaired at receptor binding level, nuclear translocation of the activated receptor and inhibition of histone acetylation; the underlying molecular mechanisms will be investigated. Results obtained from chronic severe asthma patients will be compared to those from mild-to-moderate asthma who are well-controlled on moderate doses of inhaled CS. Sputum and blood samples will be obtained and alveolar macrophages, epithelial cells and submucosal tissue retrieved by fiberoptic bronchoscopy. The effects of an exacerbation and of high-dose oral CS will be examined. Airway tissues and cells will be analysed regarding the type of inflammation, activation of signalling pathways, releasability of cytokines, CS receptor nuclear translocation, and expression and acetylation of histones, and the effect of CS examined. The molecular mechanisms underlying loss of CR will be examined. These studies should lead to more effective therapies for chronic severe asthma.