Klotho expression is reduced in COPD airway epithelial cells: effects on inflammation and oxidant injury.
Klotho expression is reduced in COPD airway epithelial cells: effects on inflammation and oxidant injury.
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COPD 气道上皮细胞中 Klotho 表达减少：对炎症和氧化损伤的影响。
DOI：
10.1042/cs20150273
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发表时间：
2015-12
期刊：
影响因子：
--
通讯作者：
Yao X
中科院分区：
文献类型：
--
作者：
Gao W;Yuan C;Zhang J;Li L;Yu L;Wiegman CH;Barnes PJ;Adcock IM;Huang M;Yao X
本研究评估了慢性阻塞性肺病患者肺中Klotho的丧失及其潜在机制。慢性阻塞性肺疾病（COPD）与持续炎症、过度损伤和肺加速老化有关。人类Klotho （KL）是一种抗衰老蛋白质，可以保护细胞免受炎症和损伤。在本研究中，我们量化了COPD患者肺部和臭氧诱导的COPD小鼠模型中KL的表达，并研究了气道中KL表达和功能的控制机制。采用免疫组织化学和免疫印迹法测定人和小鼠气道中KL的分布和水平。检测了香烟烟雾提取物对人支气管上皮细胞KL表达的影响。此外，通过sirna检测KL对cse介导的炎症和过氧化氢诱导的细胞损伤/凋亡的影响。吸烟者肺中KL表达降低，COPD患者肺中KL表达进一步降低。同样，6周的臭氧暴露降低了气道上皮细胞中的KL水平。CSE和TNFα（肿瘤坏死因子α）降低气道上皮细胞KL的表达和释放，这与促炎细胞因子的表达增强有关。此外，KL缺失增加了细胞对香烟引起的炎症和氧化应激引起的细胞损伤的敏感性。这些作用涉及NF-κB（核因子κB）、MAPK（丝裂原活化蛋白激酶）和Nrf2（核因子红细胞2相关因子2）通路。COPD气道上皮细胞中KL表达降低与氧化应激、炎症和凋亡增加有关。这些数据为COPD发展中加速肺衰老的相关机制提供了新的见解。
This study evaluated the loss of Klotho in human lungs with COPD and the underlying mechanisms. 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.