Boehme Stefen A, Franz-Bacon Karin, Ludka John, DiTirro Danielle N, Ly Tai Wei, Bacon Kevin B
Axikin Pharmaceuticals, Inc., San Diego, California, United States of America.
DNA Consulting, Inc., San Diego, California, United States of America.
PLoS One. 2016 Dec 9;11(12):e0167169. doi: 10.1371/journal.pone.0167169. eCollection 2016.
Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation and lung inflammation resulting in a progressive decline in lung function whose principle cause is cigarette smoke. MAP3K19 is a novel kinase expressed predominantly by alveolar and interstitial macrophages and bronchial epithelial cells in the lung. We found that MAP3K19 mRNA was overexpressed in a limited sampling of lung tissue from COPD patients, and a closer examination found it to be overexpressed in bronchoalveolar macrophages from COPD patients, as well as the bronchial epithelium and inflammatory cells in the lamina propria. We further found MAP3K19 to be induced in various cell lines upon environmental stress, such as cigarette smoke, oxidative and osmotic stress. Exogenous expression of MAP3K19 in cells caused an upregulation of transcriptionally active NF-κB, and secretion of the chemokines CXCL-8, CCL-20 and CCL-7. Inhibition of MAP3K19 activity by siRNA or small molecular weight inhibitors caused a decrease in cigarette smoke-induced inflammation in various murine models, which included a decrease in pulmonary neutrophilia and KC levels. In a chronic cigarette smoke model, inhibition of MAP3K19 significantly attenuated emphysematous changes in airway parenchyma. Finally, in a viral exacerbation model, mice exposed to cigarette smoke and influenza A virus showed a decrease in pulmonary neutrophilia, pro-inflammatory cytokines and viral load upon inhibition of MAP3K19. Collectively, these results suggest that inhibition of MAP3K19 may represent a novel strategy to target COPD that promises to have a potential therapeutic benefit for patients.
慢性阻塞性肺疾病（COPD）的特征是持续性气流受限和肺部炎症，导致肺功能逐渐下降，其主要原因是吸烟。MAP3K19是一种新型激酶，主要由肺中的肺泡和间质巨噬细胞以及支气管上皮细胞表达。我们发现，在慢性阻塞性肺疾病患者的有限肺组织样本中，MAP3K19 mRNA过表达，进一步检查发现它在慢性阻塞性肺疾病患者的支气管肺泡巨噬细胞、支气管上皮以及固有层中的炎症细胞中均过表达。我们还发现，在香烟烟雾、氧化应激和渗透压应激等环境压力下，各种细胞系中都会诱导MAP3K19表达。细胞中外源表达MAP3K19会导致转录活性NF-κB上调，以及趋化因子CXCL-8、CCL-20和CCL-7的分泌。在各种小鼠模型中，通过小干扰RNA（siRNA）或小分子抑制剂抑制MAP3K19活性，可减少香烟烟雾诱导的炎症，包括肺部中性粒细胞增多和KC水平降低。在慢性香烟烟雾模型中，抑制MAP3K19可显著减轻气道实质的肺气肿变化。最后，在病毒加重模型中，抑制MAP3K19后，暴露于香烟烟雾和甲型流感病毒的小鼠肺部中性粒细胞增多、促炎细胞因子和病毒载量均有所下降。总体而言，这些结果表明，抑制MAP3K19可能是一种针对慢性阻塞性肺疾病的新策略，有望为患者带来潜在的治疗益处。
