重症哮喘时p38 MAPK对激素抑制细胞因子释放的抑制作用
2010/08/20
关键词：肺泡巨噬细胞；激素抵抗性哮喘；细胞因子；p38 MAPK；重症哮喘
临床上与非重症哮喘患者相比，重症哮喘患者对激素的反应较差。重症哮喘患者肺泡巨噬细胞（alveolar macrophages, AM）的p38 MAPK活性增强，而p38 MAPK活性与地塞米松对细胞因子释放的抑制有关。
为了确定p38 MAPK抑制子能否调节皮质激素对AM和外周血单核细胞（peripheral blood mononuclear cells, PBMCs)细胞因子释放的抑制。研究者分别从重症哮喘和非重症哮喘患者分离到外周血单核细胞（PBMCs）和支气管灌洗液AM。将细胞至于含脂多糖（LPS）的培养基上，分别不添加SD282（p38 MAPK抑制剂）、添加SD282或者添加地塞米松。ELISA方法测定AM和PBMC所释放的各种细胞因子。
研究发现，无论重症哮喘或非重症哮喘者，SD282（10–7 M）联合地塞米松(10–6 M)能明显抑制AM细胞因子的释放，如IL-1β、IL-6、 单核细胞炎症蛋白-1（macrophage inflammatory protein-1，MIP-1）和IL-10, 其抑制作用比单用地塞米松更显著。
为了研究p38 MAPK抑制子的浓度依赖作用，研究者观察了不同浓度的GW-A（另一种p38 MAPK抑制子）和地塞米松对LPS诱导的IL-8释放的影响。研究发现在重症哮喘患者PBMC中，GW-A（10–9M和10–10M）虽然不能直接影响LPS诱导的IL-8释放，但能增加地塞米松(10–8M和10–6M)对LPS诱导的IL-8释放的抑制作用。
根据研究结果，作者认为，鉴于p38 MAPK抑制子能够增强激素对细胞因子释放的抑制作用（即抗炎作用），p38 MAPK抑制剂可望成为改善重症哮喘患者的激素不敏感问题的方法之一。
（韩伟 青岛大学附属青岛市立医院东院 266071 摘译）
（Eur Respir J 2010; 35:750-756）
Effect of p38 MAPK inhibition on corticosteroid suppression of cytokine release in severe asthma
P. Bhavsar1, N. Khorasani1, M. Hew1, et al.
Keywords: Alveolar macrophages, corticosteroid-resistant asthma, cytokines, p38 mitogen-activated protein kinase, severe asthma
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-1β, IL-6, macrophage inflammatory protein-1 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.
