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

严重哮喘只影响到所有哮喘患者的5%，但这些不幸的患者是最难治疗的群体，因为他们没有像其他哮喘得到很好控制的患者一样从皮质类固醇药物中获得同样的好处。因此，这些患者迫切需要新的治疗方法来控制他们的哮喘。严重哮喘患者会出现持续的哮喘症状和发作，并因需要比平时更高的剂量而遭受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重度哮喘患者没有更好的效果，以及他们的肺(肺泡巨噬细胞)和血液(血液单个核细胞)的细胞如何对试管中的类固醇没有反应，而这些细胞来自轻度哮喘。我们已经发现，有一种蛋白质决定了肺细胞释放一种化学物质(简称p38MAPK，一种在许多细胞中加速反应的酶)，这种蛋白质在严重哮喘患者中会增加。我们现在希望研究这种蛋白质是如何在严重哮喘中发挥作用的，以及它是如何导致类固醇在试管中的这些细胞中效果不佳的。这项工作可能会提供严重哮喘患者迫切需要的更有效的药物，例如那些阻断p38 MAPK作用的药物。

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.