title: Klotho Reduction in Alveolar Macrophages Contributes to Cigarette Smoke Extract-induced Inflammation in Chronic Obstructive Pulmonary Disease.
abstract: Abnormal inflammation and accelerated decline in lung function occur in patients with chronic obstructive pulmonary disease (COPD). Klotho, an anti-aging protein, has an anti-inflammatory function. However, the role of Klotho has never been investigated in COPD. The aim of this study is to investigate the possible role of Klotho by alveolar macrophages in airway inflammation in COPD. Klotho levels were assessed in the lung samples and peripheral blood mononuclear cells of non-smokers, smokers, and patients with COPD. The regulation of Klotho expression by cigarette smoke extract (CSE) was studied in vitro, and small interfering RNA (siRNA) and recombinant Klotho were employed to investigate the role of Klotho on CSE-induced inflammation. Klotho expression was reduced in alveolar macrophages in the lungs and peripheral blood mononuclear cells of COPD patients. CSE decreased Klotho expression and release from MH-S cells. Knockdown of endogenous Klotho augmented the expression of the inflammatory mediators, such as MMP-9, IL-6, and TNF-α, by MH-S cells. Exogenous Klotho inhibited the expression of CSE-induced inflammatory mediators. Furthermore, we showed that Klotho interacts with IκBα of the NF-κB pathway. Dexamethasone treatment increased the expression and release level of Klotho in MH-S cells. Our findings suggest that Klotho plays a role in sustained inflammation of the lungs, which in turn may have therapeutic implications in COPD.
authors.affiliation: From the Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, the Department of Respiratory Medicine, Yijishan Hospital, Wannan Medical College, Wuhu 241000, and.
authors.forename: Lingling
authors.initials: L
authors.lastname: Li
authors.affiliation: From the Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Wang
authors.affiliation: From the Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029.
authors.forename: Wei
authors.initials: W
authors.lastname: Gao
authors.affiliation: From the Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029.
authors.forename: Cheng
authors.initials: C
authors.lastname: Yuan
authors.affiliation: From the Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029.
authors.forename: Sini
authors.initials: S
authors.lastname: Zhang
authors.affiliation: the Department of Immunology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
authors.affiliation: From the Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029.
authors.forename: Mao
authors.initials: M
authors.lastname: Huang
authors.affiliation: From the Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, xyao1998@126.com.
authors.forename: Xin
authors.initials: X
authors.lastname: Yao
mesh_terms: D000368:Aged; D000818:Animals; D002460:Cell Line; D005260:Female; D055785:Gene Knockdown Techniques; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism; D000090265:Klotho Proteins; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000473:pathology; D016676:Macrophages, Alveolar / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism* / Q000473:pathology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000378:metabolism* / Q000473:pathology*; D014026:Nicotiana / Q000009:adverse effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D020672:I-kappa B Proteins; D015850:Interleukin-6; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D034741:RNA, Small Interfering; D012906:Smoke; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D005966:Glucuronidase; D000090265:Klotho Proteins; D020780:Matrix Metalloproteinase 9
keywords: Klotho; chronic obstructive pulmonary disease (COPD); cigarette smoke; inflammation; lung; macrophage