Deng Tang, Huang Qifeng, Lin Kaiwen, Qian Jin, Li Qi, Li Lihua, Xu Shuangqin, Yun Hongfang, Wang Hangfei, Wu Xinxin, Liu Heng, Jin Guiyun, Liu Xiaoran
Department of Interventional radiology and vascular surgery, The First Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou, China.
Key Laboratory of Emergency and Trauma of Hainan Medical University, Ministry of Education, Key Laboratory of Hainan Trauma and Disaster Rescue, Hainan Medical University, Haikou, China.
Front Pharmacol. 2022 Jun 14;13:794952. doi: 10.3389/fphar.2022.794952. eCollection 2022.
Inflammation-induced proliferation of airway smooth muscle cells (ASMCs) and subsequent airway remodeling is a hallmark of chronic obstructive lung disease (COPD). The role of midkine (MK) in COPD is unclear. In this work, we explored the role of MK-Notch2 signaling in COPD by inhibiting the expression of MK using lentivirus shRNA in ASMCs and instillation of AAV9-MK in the airway of a COPD rat model . The results demonstrated that LPS decreased ASMC migration and proliferation, increased apoptosis and induced the expression of MK and Notch2 signaling molecules. Inhibition of MK exacerbated the changes in migration and proliferation but decreased the expression of MK and Notch2 signaling molecules. Rats treated with smoke fumigation and LPS showed features of COPD. The small airways of COPD rats were remodeled and lung function was significantly reduced. The expressions of TGF-β, ICAM-1, HA, MMP-9, PC-III, and LN in BALF and the expression of MK and Notch2 signaling molecules were significantly increased in the COPD rats compared with controls. Inhibition of MK reversed these changes. In conclusion the MK-Notch2 pathway plays a key role in airway remodeling induced by ASMC proliferation. Targeting the MK-Notch2 pathway may be a new strategy for improving airway remodeling and preventing progressive decline of pulmonary function in COPD.
炎症诱导的气道平滑肌细胞（ASMCs）增殖及随后的气道重塑是慢性阻塞性肺疾病（COPD）的一个标志。中期因子（MK）在COPD中的作用尚不清楚。在这项研究中，我们通过在ASMCs中使用慢病毒shRNA抑制MK的表达以及在COPD大鼠模型气道中注入AAV9-MK，探讨了MK-Notch2信号通路在COPD中的作用。结果表明，脂多糖（LPS）降低了ASMC的迁移和增殖，增加了细胞凋亡，并诱导了MK和Notch2信号分子的表达。抑制MK会加剧迁移和增殖的变化，但会降低MK和Notch2信号分子的表达。烟熏和LPS处理的大鼠表现出COPD的特征。COPD大鼠的小气道发生重塑，肺功能显著降低。与对照组相比，COPD大鼠支气管肺泡灌洗液（BALF）中转化生长因子-β（TGF-β）、细胞间黏附分子-1（ICAM-1）、透明质酸（HA）、基质金属蛋白酶-9（MMP-9）、Ⅲ型前胶原（PC-III）和层粘连蛋白（LN）的表达以及MK和Notch2信号分子的表达均显著增加。抑制MK可逆转这些变化。总之，MK-Notch2通路在ASMC增殖诱导的气道重塑中起关键作用。靶向MK-Notch2通路可能是改善气道重塑和预防COPD患者肺功能进行性下降的一种新策略。
