p38 MAPK activation as the basis for corticosteroid insensitivity in severe asthma

p38 MAPK 激活是严重哮喘皮质类固醇不敏感的基础

• 批准号: G0700900/1
• 负责人: Kian Fan Chung
• 金额: $ 64.42万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0700900%2F1
• 关键词: p38; MAPK; activation; basis; corticosteroid

Severe asthma affects only ~5% of all asthmatics, but these unfortunate patients are the most difficult group to treat because they do not get the same amount of benefit from corticosteroid medicines as other patients whose asthma remains well-controlled. These patients therefore desperately need newer treatments to control their asthma. Severe asthmatics suffer from persistent asthma symptoms and attacks and suffer from more side-effects of corticosteroid treatment because they need higher doses than usual. We have been studying how the steroids do not seem to provide more beneficial effects on patients with severe asthma and how cells from their lung (alveolar macrophages) and blood (blood mononuclear cells) are not responding to steroids in the test-tub, as those cells from a mild type of asthma. We have found that there is a protein that determines the release of a chemical from lung cells (called p38 MAPK for short, an enzyme that accelerates reactions in many cells) that is increased in severe asthma. We now wish to study how this protein gets to be active in severe asthma, and how it causes the steroids to be less effective in these cells in the test-tube. This work may provide more effective medicines that patients with severe asthma desperately need such as those medicines that block the effect of the p38 MAPK.

重度哮喘仅影响所有哮喘患者的约5%，但这些不幸的患者是最难治疗的群体，因为他们不能像其他哮喘控制良好的患者那样从皮质类固醇药物中获得相同的益处。因此，这些患者迫切需要新的治疗方法来控制他们的哮喘。严重的哮喘患者患有持续的哮喘症状和发作，并且由于他们需要比平常更高的剂量，因此患有皮质类固醇治疗的更多副作用。我们一直在研究类固醇似乎对严重哮喘患者没有更有益的影响，以及他们的肺细胞（肺泡巨噬细胞）和血液细胞（血液单核细胞）如何在试管中对类固醇没有反应，因为这些细胞来自轻度哮喘。我们发现，有一种蛋白质决定了肺细胞释放一种化学物质（简称p38 MAPK，一种加速许多细胞反应的酶），这种蛋白质在严重哮喘中增加。我们现在希望研究这种蛋白质是如何在严重哮喘中变得活跃的，以及它是如何导致类固醇在试管中的这些细胞中不那么有效的。这项工作可能会为严重哮喘患者提供更有效的药物，例如阻断p38 MAPK作用的药物。