Respiratory Inflammation and Autoimmune (RIA) Precision Medicine Unit, Precision Medicine, Oncology R&D, AstraZeneca, Gothenburg, Sweden.
Microbial Sciences, Medimmune, Gaithersburg, MD, USA.
Int J Chron Obstruct Pulmon Dis. 2019 Nov 26;14:2611-2624. doi: 10.2147/COPD.S211619. eCollection 2019.
Unlike p38 mitogen-activated protein Kinases (MAPK) that has been extensively studied in the context of lung-associated pathologies in COPD, the role of the dual-specificity mitogen-activated protein kinase kinase (MEK1/2) or its downstream signaling molecule extracellular signal-regulated kinases 1/2 (ERK1/2) in COPD is poorly understood.
The aim of this study was to address whether MEK1/2 pathway activation is linked to COPD and that targeting this pathway can improve lung inflammation through decreased immune-mediated inflammatory responses without compromising bacterial clearance.
Association of MEK1/2 pathway activation to COPD was investigated by immunohistochemistry using lung tissue biopsies from COPD and healthy individuals and through analysis of sputum gene expression data from COPD patients. The anti-inflammatory effect of MEK1/2 inhibition was assessed on cytokine release from lipopolysaccharide-stimulated alveolar macrophages. The effect of MEK1/2 inhibition on bacterial clearance was assessed using killing assays with RAW 264.7 macrophage cell line and human neutrophils.
We report here MEK1/2 pathway activation demonstrated by increased pERK1/2 staining in bronchial epithelium and by the presence of MEK gene activation signature in sputum samples from COPD patients. Inhibition of MEK1/2 resulted in a superior anti-inflammatory effect in human alveolar macrophages in comparison to a p38 inhibitor. Furthermore, MEK1/2 inhibition led to an increase in bacterial killing in human neutrophils and RAW 264.7 cells that was not observed with the p38 inhibitor.
Our data demonstrate the activation of MEK1/2 pathway in COPD and highlight a dual function of MEK1/2 inhibition in improving host defense responses whilst also controlling inflammation.
与在 COPD 相关肺病理学中广泛研究的 p38 丝裂原活化蛋白激酶（MAPK）不同，双重特异性丝裂原活化蛋白激酶激酶（MEK1/2）或其下游信号分子细胞外信号调节激酶 1/2（ERK1/2）在 COPD 中的作用知之甚少。
本研究旨在探讨 MEK1/2 通路激活是否与 COPD 相关，以及靶向该通路是否可以通过减少免疫介导的炎症反应来改善肺部炎症，而不损害细菌清除。
通过 COPD 和健康个体的肺组织活检进行免疫组织化学分析，以及通过 COPD 患者的痰基因表达数据进行分析，研究 MEK1/2 通路激活与 COPD 的关联。通过测定 LPS 刺激的肺泡巨噬细胞细胞因子释放来评估 MEK1/2 抑制的抗炎作用。使用 RAW 264.7 巨噬细胞系和人中性粒细胞进行杀伤测定，评估 MEK1/2 抑制对细菌清除的影响。
我们在此报告 MEK1/2 通路的激活，表现为支气管上皮细胞中 pERK1/2 染色增加，以及 COPD 患者痰样本中存在 MEK 基因激活特征。与 p38 抑制剂相比，MEK1/2 抑制在人肺泡巨噬细胞中具有更好的抗炎作用。此外，与 p38 抑制剂相比，MEK1/2 抑制导致人中性粒细胞和 RAW 264.7 细胞中的细菌杀伤增加。
我们的数据表明 MEK1/2 通路在 COPD 中被激活，并强调 MEK1/2 抑制在改善宿主防御反应的同时控制炎症具有双重功能。
