Hew Mark, Bhavsar Pankaj, Torrego Alfons, Meah Sally, Khorasani Nadia, Barnes Peter J, Adcock Ian, Chung Kian Fan
National Heart and Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, UK.
Am J Respir Crit Care Med. 2006 Jul 15;174(2):134-41. doi: 10.1164/rccm.200512-1930OC. Epub 2006 Apr 13.
Patients with severe asthma have a poor therapeutic response to corticosteroid therapy, and corticosteroid responsiveness cannot be easily measured in these patients. We hypothesized that this poor response is associated with a reduced effect of corticosteroids to inhibit cytokine release from activated peripheral blood mononuclear cells (PBMCs).
Patients with severe asthma were defined by American Thoracic Society criteria. We compared the suppression of LPS-induced cytokine release (monocyte chemotactic protein-1 [MCP-1], macrophage inflammatory protein [MIP] 1alpha, RANTES, tumor necrosis factor alpha, interleukin 1beta (IL-1beta), IL-8, IFN-gamma, IL-6, IL-10, and granulocyte-macrophage colony-stimulating factor [GM-CSF]) by dexamethasone from PBMCs of patients with severe asthma (n = 16), patients with nonsevere asthma (n = 19), and normal volunteers (n = 10).
There was no difference in baseline spontaneous or stimulated release of these cytokines among groups. LPS-induced release of 10 cytokines was less suppressed by dexamethasone (10(-6) M) in patients with severe asthma compared with patients with nonsevere asthma, with statistical significance achieved for IL-1beta (p < 0.03), IL-8 (p < 0.03), and MIP-1alpha (p < 0.003), and borderline significance for IL-6 (p = 0.054). There was less difference between the two groups for dexamethasone at 10(-8) M. Nuclear histone deacetylase (HDAC) and histone acetyltransferase activities were reduced in patients with severe asthma compared with patients with nonsevere asthma (p < 0.01). HDAC activity reduction correlated directly to the degree of steroid insensitivity of GM-CSF (r = 0.57, p < 0.01) and IFN-gamma (r = 0.56, p < 0.05) release. Reduction in histone acetyltransferase activity related to corticosteroid use rather than asthma severity.
Patients with severe asthma have diminished corticosteroid sensitivity of PBMCs when compared with patients with nonsevere asthma, associated with a reduction in HDAC activity that parallels the impaired corticosteroid sensitivity.
重度哮喘患者对皮质类固醇治疗的反应较差，且这些患者的皮质类固醇反应性难以轻易测定。我们推测这种较差的反应与皮质类固醇抑制活化外周血单个核细胞（PBMC）释放细胞因子的作用减弱有关。
根据美国胸科学会标准定义重度哮喘患者。我们比较了地塞米松对重度哮喘患者（n = 16）、非重度哮喘患者（n = 19）和正常志愿者（n = 10）的PBMC中脂多糖诱导的细胞因子释放（单核细胞趋化蛋白-1 [MCP-1]、巨噬细胞炎性蛋白 [MIP] 1α、调节激活正常T细胞表达和分泌因子 [RANTES]、肿瘤坏死因子α、白细胞介素1β [IL-1β]、IL-8、干扰素-γ [IFN-γ]、IL-6、IL-10和粒细胞-巨噬细胞集落刺激因子 [GM-CSF]）的抑制作用。
各组间这些细胞因子的基线自发或刺激释放无差异。与非重度哮喘患者相比，重度哮喘患者中地塞米松（10⁻⁶ M）对脂多糖诱导的10种细胞因子释放的抑制作用较小，IL-1β（p < 0.03）、IL-8（p < 0.03）和MIP-1α（p < 0.003）具有统计学意义，IL-6具有临界意义（p = 0.054）。对于10⁻⁸ M的地塞米松，两组间差异较小。与非重度哮喘患者相比，重度哮喘患者的核组蛋白去乙酰化酶（HDAC）和组蛋白乙酰转移酶活性降低（p < 0.01）。HDAC活性降低与GM-CSF（r = 0.57，p < 0.01）和IFN-γ（r = 0.56，p < 0.05）释放的类固醇不敏感性程度直接相关。组蛋白乙酰转移酶活性降低与皮质类固醇使用有关，而非哮喘严重程度。
与非重度哮喘患者相比，重度哮喘患者的PBMC对皮质类固醇的敏感性降低，这与HDAC活性降低有关，且HDAC活性降低与皮质类固醇敏感性受损平行。
