Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; Pulmonary Cell Research & Clinic of Respiratory Medicine, Dept. Biomedicine University of Basel & University Hospital of Basel, CH-4031, Basel, Switzerland.
Pulmonary Cell Research & Clinic of Respiratory Medicine, Dept. Biomedicine University of Basel & University Hospital of Basel, CH-4031, Basel, Switzerland.
Free Radic Biol Med. 2021 Aug 20;172:541-549. doi: 10.1016/j.freeradbiomed.2021.07.004. Epub 2021 Jul 3.
Airway epithelial mitochondrial oxidative stress and damage is an important pathology in chronic obstructive pulmonary disease (COPD). Mitophagy involves MAPK15-ULK1 signaling, the role of which is unknown in COPD. This study investigated MAPK15-ULK1 signaling in airway epithelial cells of COPD patients and its activation by cigarette smoke extract (CSE) in isolated human airway epithelial cells. Significant increased phosphorylation of MAPK15 and ULK1 (Ser555) was detected in the airway epithelium of COPD patients. This pathology was maintained in isolated primary COPD-epithelial cells. Compared to control cells, the protein expression of Beclin1 and the ratio of LC3II to LC3I were both significantly increased in COPD-epithelial cells. In human airway epithelial cells, CSE significantly increased the phosphorylation of MAPK15, ULK1 (Ser555), the expression of Beclin1, and the LC3II/LC3I ratio in a concentration- and time-dependent manner. Transfection with MAPK15 siRNA significantly inhibited the CSE-induced ULK1 (Ser555) phosphorylation in airway epithelial cells. Silencing of MAPK15 or ULK1 significantly reduced CSE-induced mitophagy and mitochondrial oxidative stress, thereby improving cell viability. In summary, cigarette smoke activated MAPK15-ULK1 signaling, thereby promoting mitophagy and mitochondrial oxidative stress in airway epithelial cells. This signaling pathway is activated in COPD-epithelial cells and therefore might present a novel therapeutic target for COPD.
气道上皮细胞的线粒体氧化应激和损伤是慢性阻塞性肺疾病（COPD）的重要病理学特征。自噬涉及 MAPK15-ULK1 信号通路，但其在 COPD 中的作用尚不清楚。本研究调查了 COPD 患者气道上皮细胞中的 MAPK15-ULK1 信号通路及其在分离的人气道上皮细胞中被香烟烟雾提取物（CSE）激活的情况。在 COPD 患者的气道上皮中，检测到 MAPK15 和 ULK1（Ser555）的磷酸化显著增加。这种病理学在分离的原发性 COPD-上皮细胞中得以维持。与对照细胞相比，COPD-上皮细胞中的 Beclin1 蛋白表达和 LC3II/LC3I 比值均显著增加。在人气道上皮细胞中，CSE 以浓度和时间依赖的方式显著增加 MAPK15 的磷酸化、ULK1（Ser555）的磷酸化、Beclin1 的表达和 LC3II/LC3I 的比值。MAPK15 siRNA 的转染显著抑制了 CSE 诱导的气道上皮细胞中 ULK1（Ser555）的磷酸化。MAPK15 或 ULK1 的沉默显著减少了 CSE 诱导的自噬和线粒体氧化应激，从而提高了细胞活力。总之，香烟烟雾激活了 MAPK15-ULK1 信号通路，从而促进了气道上皮细胞中的自噬和线粒体氧化应激。该信号通路在 COPD-上皮细胞中被激活，因此可能成为 COPD 的一个新的治疗靶点。
