title: 27-Hydroxycholesterol accelerates cellular senescence in human lung resident cells.
abstract: Cellular senescence is reportedly involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). We previously showed that 27-hydroxycholesterol (27-OHC) is elevated in the airways of COPD patients compared with those in healthy subjects. The aim of this study was to investigate whether lung fibroblasts of COPD patients are senescent and to determine the effects of 27-OHC on senescence of lung resident cells, including fibroblasts and airway epithelial cells. Localization of senescence-associated proteins and sterol 27-hydroxylase was investigated in the lungs of COPD patients by immunohistochemical staining. To evaluate whether 27-OHC accelerates cellular senescence, lung resident cells were exposed to 27-OHC. Senescence markers and fibroblast-mediated tissue repair were investigated in the 27-OHC-treated cells. Expression of senescence-associated proteins was significantly enhanced in lung fibroblasts of COPD patients. Similarly, expression of sterol 27-hydroxylase was significantly upregulated in lung fibroblasts and alveolar macrophages in these patients. Treatment with the concentration of 27-OHC detected in COPD airways significantly augmented expression of senescence-associated proteins and senescence-associated β-galactosidase activity, and delayed cell growth through the prostaglandin E2-reactive nitrogen species pathway. The 27-OHC-treated fibroblasts impaired tissue repair function. Fibroblasts from lungs of COPD patients showed accelerated senescence and were more susceptible to 27-OHC-induced cellular senescence compared with those of healthy subjects. In conclusion, 27-OHC accelerates cellular senescence in lung resident cells and may play a pivotal role in cellular senescence in COPD.
authors.affiliation: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan;
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Hashimoto
authors.affiliation: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; sugiura@rm.med.tohoku.ac.jp.
authors.forename: Hisatoshi
authors.initials: H
authors.lastname: Sugiura
authors.affiliation: Department of Respiratory Medicine, Juntendo University School of Medicine, Tokyo, Japan;
authors.forename: Shinsaku
authors.initials: S
authors.lastname: Togo
authors.affiliation: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan;
authors.forename: Akira
authors.initials: A
authors.lastname: Koarai
authors.affiliation: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan;
authors.forename: Kyoko
authors.initials: K
authors.lastname: Abe
authors.affiliation: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan;
authors.forename: Mitsuhiro
authors.identifier: 0000-0002-0832-1939
authors.initials: M
authors.lastname: Yamada
authors.affiliation: Third Department of Internal Medicine, Wakayama Medical University School of Medicine, Wakayama, Japan;
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Ichikawa
authors.affiliation: Third Department of Internal Medicine, Wakayama Medical University School of Medicine, Wakayama, Japan;
authors.forename: Takashi
authors.initials: T
authors.lastname: Kikuchi
authors.affiliation: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan;
authors.forename: Tadahisa
authors.initials: T
authors.lastname: Numakura
authors.affiliation: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan;
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Onodera
authors.affiliation: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan;
authors.forename: Rie
authors.initials: R
authors.lastname: Tanaka
authors.affiliation: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan;
authors.forename: Kei
authors.initials: K
authors.lastname: Sato
authors.affiliation: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan;
authors.forename: Satoru
authors.initials: S
authors.lastname: Yanagisawa
authors.affiliation: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan;
authors.forename: Tatsuma
authors.initials: T
authors.lastname: Okazaki
authors.affiliation: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan;
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Tamada
authors.affiliation: Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; and.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kikuchi
authors.affiliation: Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Hoshikawa
authors.affiliation: Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan;
authors.forename: Masakazu
authors.initials: M
authors.lastname: Ichinose
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000187:drug effects*; D053493:Cholestanetriol 26-Monooxygenase / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology*; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology*; D008168:Lung / Q000473:pathology; D016676:Macrophages, Alveolar / Q000201:enzymology; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism / Q000473:pathology; D026361:Reactive Nitrogen Species / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D006888:Hydroxycholesterols; D026361:Reactive Nitrogen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C076996:27-hydroxycholesterol; D053493:Cholestanetriol 26-Monooxygenase
keywords: chronic obstructive pulmonary disease; oxysterols; senescence