Section of Airways Disease, National Heart & Lung Institute, Imperial College & Royal Brompton and Harefield NHS Trust Hospital, London, UK.
Eur Respir J. 2010 Apr;35(4):750-6. doi: 10.1183/09031936.00071309. Epub 2009 Oct 19.
Patients with severe asthma respond less well to corticosteroids than those with non-severe asthma. Increased p38 mitogen-activated protein kinase (MAPK) activation in alveolar macrophages (AMs) from severe asthma patients has been associated with a reduced inhibition of cytokine release by dexamethasone. We determined whether p38 MAPK inhibitors would modulate corticosteroid suppression of cytokine release from AMs and peripheral blood mononuclear cells (PBMCs). PBMCs were isolated from venous blood and AMs by bronchoalveolar lavage in severe and non-severe asthma patients. PBMCs and AMs were exposed to lipopolysaccharide (LPS) with and without the p38 MAPK inhibitor, SD282, or dexamethasone. We determined the concentration-dependent effects of another p38 MAPK inhibitor, GW-A, on dexamethasone-induced inhibition of interleukin (IL)-8 release from PBMCs. Cytokines were assayed using an ELISA-based method. SD282 (10(-7) M), with dexamethasone (10( -6) M), caused a greater inhibition of release of IL-1beta, IL-6, macrophage inflammatory protein-1alpha and IL-10, than with dexamethasone alone in AMs from severe and non-severe asthma. At 10(-9) and 10(-10) M, GW-A, that had no direct effects, increased the inhibitory activity of dexamethasone (10(-8) and 10( -6) M) on LPS-induced IL-8 release in PBMCs from severe asthma. Corticosteroid insensitivity in severe asthma patients may be improved by inhibitors of p38 MAPK.
严重哮喘患者对皮质类固醇的反应不如非严重哮喘患者。严重哮喘患者肺泡巨噬细胞（AMs）中 p38 有丝分裂原激活蛋白激酶（MAPK）的激活增加与地塞米松抑制细胞因子释放的能力降低有关。我们确定 p38 MAPK 抑制剂是否会调节皮质类固醇对 AMs 和外周血单核细胞（PBMCs）中细胞因子释放的抑制作用。严重和非严重哮喘患者通过支气管肺泡灌洗从静脉血和 AMs 中分离 PBMCs。将 PBMCs 和 AMs 暴露于脂多糖（LPS）中，同时使用 p38 MAPK 抑制剂 SD282 或地塞米松。我们确定了另一种 p38 MAPK 抑制剂 GW-A 对地塞米松诱导的 PBMCs 中白细胞介素（IL）-8 释放抑制作用的浓度依赖性影响。使用基于 ELISA 的方法测定细胞因子。SD282（10（-7）M）与地塞米松（10（-6）M）联合使用时，与单独使用地塞米松相比，可引起 AMs 中 IL-1β、IL-6、巨噬细胞炎症蛋白-1α和 IL-10 的释放抑制作用更强，来自严重和非严重哮喘。在 10（-9）和 10（-10）M 时，GW-A 没有直接作用，增加了地塞米松（10（-8）和 10（-6）M）对 LPS 诱导的 PBMCs 中 IL-8 释放的抑制活性。严重哮喘患者的皮质类固醇不敏感可能通过 p38 MAPK 抑制剂得到改善。
