Khorasani Nadia, Baker Josephine, Johnson Malcolm, Chung Kian Fan, Bhavsar Pankaj K
Experimental Studies, Airway Disease Section, National Heart and Lung Institute, Imperial College and Biomedical Research Unit, Royal Brompton and Harefield NHS Trust Hospital, London, UK.
GlaxoSmithKline, Uxbridge, UK.
Int J Chron Obstruct Pulmon Dis. 2015 Feb 4;10:283-91. doi: 10.2147/COPD.S72403. eCollection 2015.
Corticosteroids (CS) have limited efficacy in the treatment of chronic obstructive pulmonary disease (COPD). p38 mitogen-activated protein kinase (MAPK) activation is increased in lung macrophages of COPD. We investigated whether p38 MAPK inhibition can modulate CS insensitivity of peripheral blood mononuclear cells (PBMCs) from patients with COPD.
PBMCs from patients with COPD (n=8) or healthy smokers (n=8) were exposed to lipopolysaccharide (LPS) with a selective p38 MAPK inhibitor (GW856553; 10(-10)-10(-6) M), with dexamethasone (10(-10)-10(-6) M), or with both. Phosphorylated glucocorticoid receptor (GR) was measured by Western blot.
Baseline (P<0.01) and LPS-induced (P<0.05) CXCL8 release was greater in PBMCs from COPD compared to healthy smokers. Inhibition of LPS-induced CXCL8 release by dexamethasone (10(-6) M) was reduced, and baseline and LPS-induced p38 MAPK activation increased in PBMCs of COPD. GW856553 (10(-9) and 10(-10) M) synergistically increased the inhibitory effect of dexamethasone (10(-8) and 10(-6) M) on LPS-induced CXCL8 release in COPD. Similar results were obtained for IL-6 release. GW856553 inhibited dexamethasone- and LPS-activated phosphorylation of serine 211 on GR. CS insensitivity in COPD PBMCs is reversed by inhibition of p38 MAPK activity, partly by preventing phosphorylation of GR at serine 211.
p38 MAPK inhibition may be beneficial in COPD by restoring CS sensitivity.
皮质类固醇（CS）在慢性阻塞性肺疾病（COPD）治疗中的疗效有限。COPD患者肺巨噬细胞中p38丝裂原活化蛋白激酶（MAPK）的激活增加。我们研究了抑制p38 MAPK是否能调节COPD患者外周血单核细胞（PBMC）对CS的不敏感性。
将COPD患者（n = 8）或健康吸烟者（n = 8）的PBMC暴露于脂多糖（LPS），同时加入选择性p38 MAPK抑制剂（GW856553；10⁻¹⁰ - 10⁻⁶ M）、地塞米松（10⁻¹⁰ - 10⁻⁶ M）或两者。通过蛋白质免疫印迹法检测磷酸化糖皮质激素受体（GR）。
与健康吸烟者相比，COPD患者PBMC的基线（P < 0.01）和LPS诱导的（P < 0.05）CXCL8释放量更高。地塞米松（10⁻⁶ M）对LPS诱导的CXCL8释放的抑制作用减弱，COPD患者PBMC的基线和LPS诱导的p38 MAPK激活增加。GW856553（10⁻⁹和10⁻¹⁰ M）协同增强了地塞米松（10⁻⁸和10⁻⁶ M）对COPD患者LPS诱导的CXCL8释放的抑制作用。IL - 6释放也得到了类似结果。GW856553抑制了地塞米松和LPS激活的GR丝氨酸211的磷酸化。抑制p38 MAPK活性可逆转COPD患者PBMC对CS的不敏感性，部分原因是阻止GR丝氨酸211的磷酸化。
抑制p38 MAPK可能通过恢复CS敏感性对COPD有益。
