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.
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September 18 2015
Klotho expression is reduced in COPD airway epithelial cells: effects on inflammation and oxidant injury
Wei Gao;
Wei Gao
1
*Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China
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Cheng Yuan;
Cheng Yuan
1
*Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China
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Jingying Zhang;
Jingying Zhang
1
*Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China
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Lingling Li;
Lingling Li
*Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China
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Like Yu;
Like Yu
†Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing 210029, China
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Coen H. Wiegman;
Coen H. Wiegman
‡Airway Disease Section, National Heart and Lung Institute, Imperial College, Dovehouse Street, London SW3 6LY, U.K.
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Peter J. Barnes;
Peter J. Barnes
‡Airway Disease Section, National Heart and Lung Institute, Imperial College, Dovehouse Street, London SW3 6LY, U.K.
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Ian M. Adcock;
Ian M. Adcock
‡Airway Disease Section, National Heart and Lung Institute, Imperial College, Dovehouse Street, London SW3 6LY, U.K.
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Mao Huang;
Mao Huang
*Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China
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Xin Yao
*Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China
Correspondence: Dr Xin Yao (email [email protected]).
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Publisher: Portland Press Ltd
Received:
April 13 2015
Revision Received:
July 02 2015
Accepted:
July 10 2015
Accepted Manuscript online:
July 10 2015
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2015 Authors; published by Portland Press Limited
2015
Clin Sci (Lond) (2015) 129 (12): 1011–1023.
Article history
Received:
April 13 2015
Revision Received:
July 02 2015
Accepted:
July 10 2015
Accepted Manuscript online:
July 10 2015
Citation
Wei Gao, Cheng Yuan, Jingying Zhang, Lingling Li, Like Yu, Coen H. Wiegman, Peter J. Barnes, Ian M. Adcock, Mao Huang, Xin Yao; Klotho expression is reduced in COPD airway epithelial cells: effects on inflammation and oxidant injury. Clin Sci (Lond) 1 December 2015; 129 (12): 1011–1023. doi: https://doi.org/10.1042/CS20150273
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