Effects of glucocorticoids on lymphocyte activation in patients with steroid-sensitive and steroid-resistant asthma
Effects of glucocorticoids on lymphocyte activation in patients with steroid-sensitive and steroid-resistant asthma
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DOI：
10.1016/s0091-6749(96)80194-1
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发表时间：
1996-12-01
影响因子：
14.2
通讯作者：
Szefler, SJ
中科院分区：
文献类型：
--
作者：
Spahn, JD;Landwehr, LP;Szefler, SJ
背景：糖皮质激素是控制哮喘相关气道炎症的重要药物。合成糖皮质激素的糖皮质激素受体（GCR）的结合亲和力不同：我们比较了氢化可的松，丙酸倍氯米松，曲安奈德，氟尼缩松，布地奈德方面的能力，以抑制植物血凝素诱导的外周血单核细胞增殖6例激素敏感性哮喘和7例激素抵抗性哮喘。外周血单个核细胞GCR结合亲和力地塞米松和布地奈德也确定了两个患者组通过使用放射性配体结合试验和Scatchard analysis.Results：剂量依赖性抑制证明了所有糖皮质激素在两个患者组，与类固醇耐药组需要约2个对数倍以上的糖皮质激素的同等程度的抑制。类固醇敏感组导致淋巴细胞增殖50%抑制所需的平均浓度（IC（50）s）范围为布地奈德的2 x 10（-10）mol/L至氢化可的松的7 x 10（-8）mol/L，而类固醇耐药组的平均IC 50范围从布地奈德的约2 × 10 - 8 mol/L到氢化可的松的大于10 - 6 mol/L。此外，淋巴细胞增殖抑制程度（IC 50）和地塞米松对GCR的结合亲和力之间存在显著相关性。已显示激素抵抗性哮喘患者GCR结合亲和力降低。两组中布地奈德的GCR结合亲和力均显著较高（即，结论：这些数据表明，糖皮质激素，如布地奈德，凭借其高GCR结合亲和力和更大的能力，抑制淋巴细胞增殖，因此可能是有益的管理难以控制的哮喘。
Background: Glucocorticoids are important medications used to control the airway inflammation associated with asthma. Synthetic glucocorticoids vary in their binding affinity for the glucocorticoid receptor (GCR).Methods: We compared hydrocortisone, beclomethasone dipropionate, triamcinolone acetonide, flunisolide, and budesonide with regard to their capacity to inhibit phytohemagglutinin-induced peripheral blood mononuclear cell proliferation from six patients with steroid-sensitive asthma and seven patients with steroid-resistant asthma. Peripheral blood mononuclear cell GCR binding affinities for dexamethasone and budesonide were also determined for both patient groups by using a radioligand binding assay and Scatchard analysis.Results: Dose-dependent inhibition was demonstrated for all glucocorticoids in both patient groups, with the steroid-resistant group requiring approximately 2 log-fold more glucocorticoids for an equivalent degree of inhibition. The mean concentrations necessary to cause 50% inhibition of lymphocyte proliferation (IC(50)s) for the steroid-sensitive group ranged from 2 x 10(-10) mol/L for budesonide to 7 x 10(-8) mol/L for hydrocortisone, whereas the mean IC50 for the steroid-resistant group ranged from approximately 2 x 10(-8) mol/L for budesonide to greater than 10(-6) mol/L for hydrocortisone. In addition, a significant correlation was noted between the degree of inhibition of lymphocyte proliferation (IC50) and the binding affinity of dexamethasone to the GCR Patients with steroid-resistant asthma have been shown to have a reduced GCR binding affinity. The GCR binding affinity fdr budesonide was significantly higher in both groups (i.e., lower dissociation constant) than that obtained for dexamethasone.Conclusion: These data suggest that glucocorticoids such as budesonide, by virtue of their high GCR binding affinities and greater ability to suppress lymphocyte proliferation, may therefore be beneficial in the management of difficult-to-control asthma.