Gao Wei, Yuan Cheng, Zhang Jingying, Li Lingling, Yu Like, Wiegman Coen H, Barnes Peter J, Adcock Ian M, Huang Mao, Yao Xin
Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China.
Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing 210029, China.
Clin Sci (Lond). 2015 Dec;129(12):1011-23. doi: 10.1042/CS20150273. Epub 2015 Jul 10.
COPD (chronic obstructive pulmonary disease) is associated with sustained inflammation, excessive injury, and accelerated lung aging. Human Klotho (KL) is an anti-aging protein that protects cells against inflammation and damage. In the present study, we quantified KL expression in the lungs of COPD patients and in an ozone-induced mouse model of COPD, and investigated the mechanisms that control KL expression and function in the airways. KL distribution and levels in human and mouse airways were measured by immunohistochemistry and Western blotting. The effect of CSE (cigarette smoke extract) on KL expression was detected in human bronchial epithelial cells. Moreover, the effect of KL on CSE-mediated inflammation and hydrogen peroxide-induced cellular injury/apoptosis was determined using siRNAs. KL expression was decreased in the lungs of smokers and further reduced in patients with COPD. Similarly, 6 weeks of exposure to ozone decreased KL levels in airway epithelial cells. CSE and TNFα (tumour necrosis factor α) decreased KL expression and release from airway epithelial cells, which was associated with enhanced pro-inflammatory cytokine expression. Moreover, KL depletion increased cell sensitivity to cigarette smoke-induced inflammation and oxidative stress-induced cell damage. These effects involved the NF-κB (nuclear factor κB), MAPK (mitogen-activated protein kinase) and Nrf2 (nuclear factor erythroid 2-related factor 2) pathways. Reduced KL expression in COPD airway epithelial cells was associated with increased oxidative stress, inflammation and apoptosis. These data provide new insights into the mechanisms associated with the accelerated lung aging in COPD development.
慢性阻塞性肺疾病（COPD）与持续性炎症、过度损伤及肺部加速衰老相关。人Klotho（KL）是一种抗衰老蛋白，可保护细胞免受炎症和损伤。在本研究中，我们对COPD患者肺部及臭氧诱导的COPD小鼠模型肺部中的KL表达进行了定量，并研究了控制气道中KL表达和功能的机制。通过免疫组织化学和蛋白质印迹法检测人和小鼠气道中KL的分布及水平。在人支气管上皮细胞中检测香烟烟雾提取物（CSE）对KL表达的影响。此外，使用小干扰RNA（siRNAs）确定KL对CSE介导的炎症及过氧化氢诱导的细胞损伤/凋亡的影响。吸烟者肺部的KL表达降低，COPD患者中进一步降低。同样，暴露于臭氧6周可降低气道上皮细胞中的KL水平。CSE和肿瘤坏死因子α（TNFα）可降低气道上皮细胞中KL的表达和释放，这与促炎细胞因子表达增强相关。此外，KL缺失增加了细胞对香烟烟雾诱导的炎症和氧化应激诱导的细胞损伤的敏感性。这些效应涉及核因子κB（NF-κB）、丝裂原活化蛋白激酶（MAPK）和核因子红细胞2相关因子2（Nrf2）信号通路。COPD气道上皮细胞中KL表达降低与氧化应激、炎症和凋亡增加相关。这些数据为COPD发生发展过程中肺部加速衰老相关机制提供了新的见解。
