PI3K inhibitor treatment ameliorates the glucocorticoid insensitivity of PBMCs in severe asthma
PI3K inhibitor treatment ameliorates the glucocorticoid insensitivity of PBMCs in severe asthma
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PI3K 抑制剂治疗可改善严重哮喘患者 PBMC 的糖皮质激素不敏感性
DOI：
10.1186/s40169-020-0262-5
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发表时间：
2020-02-28
影响因子：
10.6
通讯作者：
Chen, Zhihong
中科院分区：
文献类型：
--
作者：
Bi, Jing;Min, Zhihui;Chen, Zhihong
背景糖皮质激素（GC）不敏感性是严重和致命性哮喘的一个重要特征。氧化应激可诱导磷脂酰肌醇-3-激酶（PI 3 K）激活，导致慢性气道疾病中GC不敏感性的发展。然而，PI 3 K在严重哮喘发病机制中的潜在分子机制仍不清楚。方法分离34例哮喘患者（轻、中度哮喘组12例，重度哮喘组10例，对照组12例）的外周血单个核细胞（PBMC）。用H2 O2刺激人巨噬细胞系U937以模拟严重哮喘时的氧化应激状态。评价候选化合物，即阿奇霉素、PI 3 K抑制剂（BEZ 235和LY 294002）和p38 MAPK抑制剂（BIRB 796）改善严重哮喘中GC不敏感性的能力。结果重度哮喘患者PBMC对GC的不敏感性呈剂量依赖性和时间依赖性，与组蛋白脱乙酰酶2（HDAC 2）活性降低（p < 0.05）和促炎基因[核因子-κ B（NF-κ B B）和激活蛋白-1（AP-1）]表达升高（p < 0.01）相关。PI 3 K抑制剂（BZE 235和LY 294002）显著恢复了重度哮喘患者PBMC的GC敏感性。在体外，PI 3 K抑制剂（BZE 235和LY 294002）通过独立地恢复HDAC 2的活性或抑制转录因子的激活来改善H2 O2/TNF α诱导的U937细胞释放IL-8中的GC不敏感性。结论PI 3 K抑制剂通过恢复HDAC 2活性和抑制核信号转录因子磷酸化，改善重度哮喘患者的GC不敏感性。
Background Glucocorticoid (GC) insensitivity is an important feature of severe and fatal asthma. Oxidative stress can induce phosphoinositide-3-kinase (PI3K) activation, contributing to the development of GC insensitivity in chronic airway diseases. However, the underlying molecular mechanism of PI3K in the pathogenesis of severe asthma remains unknown. Methods We isolated peripheral blood mononuclear cells (PBMCs) from 34 participants (12 patients with mild/moderate asthma, 10 patients with severe asthma, and 12 control subjects). H2O2 was used to stimulate the human macrophage line U937 to mimic the oxidative stress status in severe asthma. The ability of candidate compounds, namely, azithromycin, PI3K inhibitors (BEZ235 and LY294002) and a p38 MAPK inhibitor (BIRB796), to ameliorate GC insensitivity in severe asthma was evaluated. Results PBMCs from patients with severe asthma exhibited dose-dependent and time-dependent GC insensitivity, which correlated with reduced activity of histone deacetylase 2 (HDAC2) (p < 0.05) and elevated expression of proinflammatory genes [nuclear factor-kappa B (NF-kappa B) and activator protein-1 (AP-1)] (p < 0.01) compared with these parameters in the control group. The PI3K inhibitors (BZE235 and LY294002) significantly restored the GC sensitivity of PBMCs from patients with severe asthma. In vitro, the PI3K inhibitors (BZE235 and LY294002) ameliorated GC insensitivity in H2O2/TNF alpha-induced IL-8 release from U937 cells by independently restoring the activity of HDAC2 or inhibiting the activation of transcription factors. Conclusions This study demonstrates that PI3K inhibitors ameliorate GC insensitivity in severe asthma by restoring HDAC2 activity and inhibiting the phosphorylation of nuclear signaling transcription factors.