INFLAMMATION & CORTICOSTEROID RESPONSES IN SEVERE ASTHMA

描述(由申请人提供)： 高达5%-6%的哮喘患者出现症状和加重，尽管 常规治疗，并对卫生保健系统产生重大影响。那里 迫切需要了解慢性重症哮喘的病理生理学。 这些患者对阿司匹林的治疗效果表现出相对的抵抗性 皮质类固醇(CS)。这些患者中只有一小部分人 一家机构。在皇家布朗普顿医院，大约70名重症患者 每年的哮喘患者都会被转介到一个方案进行调查和 管理层。该项目将研究炎症和细胞 慢性重症哮喘患者的反应，确定CS反应性的作用 (Cr)，并阐明其细胞和分子机制 对于受损的CR。假设重症哮喘中的炎症途径 被信号通路放大，特别是有丝分裂原激活的 蛋白激酶(MAPK)，进而减弱CS的作用。CS操作可能 在受体结合水平受损，激活的核转位 受体与组蛋白乙酰化抑制；潜在分子 将对机制进行调查。慢性重度哮喘的结果 患者将与控制良好的轻度至中度哮喘患者进行比较。 吸入中等剂量的CS。痰和血样将会是 获得的肺泡巨噬细胞、上皮细胞和粘膜下组织 通过纤维支气管镜检查。病情恶化的影响和 对大剂量口服CS进行检查。将对呼吸道组织和细胞进行分析 关于炎症的类型，信号通路的激活， 细胞因子的释放、CS受体的核转位和表达 组蛋白的乙酰化，以及CS的作用。分子 我们将研究CR丢失的潜在机制。这些研究应该引领 更有效的治疗慢性重度哮喘的方法。

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.