title: Klotho expression is reduced in COPD airway epithelial cells: effects on inflammation and oxidant injury.
abstract: 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.
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Gao
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Yuan
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China.
authors.forename: Jingying
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing 210029, China.
authors.forename: Like
authors.initials: L
authors.lastname: Yu
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College, Dovehouse Street, London SW3 6LY, U.K.
authors.forename: Coen H
authors.initials: CH
authors.lastname: Wiegman
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College, Dovehouse Street, London SW3 6LY, U.K.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Barnes
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College, Dovehouse Street, London SW3 6LY, U.K.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Adcock
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China.
authors.forename: Mao
authors.initials: M
authors.lastname: Huang
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China yaoxin@njmu.edu.cn.
authors.forename: Xin
authors.initials: X
authors.lastname: Yao
mesh_terms: D000818:Animals; D017209:Apoptosis; D016022:Case-Control Studies; D002460:Cell Line; D004195:Disease Models, Animal; D015536:Down-Regulation; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000633:toxicity; D000090265:Klotho Proteins; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D016877:Oxidants / Q000633:toxicity; D018384:Oxidative Stress; D010126:Ozone; D011014:Pneumonia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011656:Pulmonary Emphysema / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D015398:Signal Transduction; D012906:Smoke / Q000009:adverse effects; D013997:Time Factors; D014162:Transfection
chemical_list: D018836:Inflammation Mediators; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495635:NFE2L2 protein, human; D016877:Oxidants; D012906:Smoke; D010126:Ozone; D020928:Mitogen-Activated Protein Kinases; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: bronchial epithelial cells; chronic obstructive pulmonary disease (COPD); cytokines; klotho protein; oxidative stress; smoke