title: Accelerated epithelial cell senescence in IPF and the inhibitory role of SIRT6 in TGF-β-induced senescence of human bronchial epithelial cells.
abstract: Reepithelialization of remodeled air spaces with bronchial epithelial cells is a prominent pathological finding in idiopathic pulmonary fibrosis (IPF) and is implicated in IPF pathogenesis. Recent studies suggest that epithelial senescence is a risk factor for development of IPF, indicating such reepithelialization may be influenced by the acceleration of cellular senescence. Among the sirtuin (SIRT) family, SIRT6, a class III histone deacetylase, has been demonstrated to antagonize senescence. We evaluated the senescence of bronchiolization in association with SIRT6 expression in IPF lung. Senescence-associated β-galactosidase staining and immunohistochemical detection of p21 were performed to evaluate cellular senescence. As a model for transforming growth factor (TGF)-β-induced senescence of abnormal reepithelialization, we used primary human bronchial epithelial cells (HBEC). The changes of SIRT6, p21, and interleukin (IL)-1β expression levels in HBEC, as well as type I collagen expression levels in fibroblasts, were evaluated. In IPF lung samples, an increase in markers of senescence and SIRT6 expression was found in the bronchial epithelial cells lining cystically remodeled air spaces. We found that TGF-β induced senescence in primary HBEC by increasing p21 expression, and, whereas TGF-β also induced SIRT6, it was not sufficient to inhibit cellular senescence. However, overexpression of SIRT6 efficiently inhibited TGF-β-induced senescence via proteasomal degradation of p21. TGF-β-induced senescent HBEC secreted increased amounts of IL-1β, which was sufficient to induce myofibroblast differentiation in fibroblasts. These findings suggest that accelerated epithelial senescence plays a role in IPF pathogenesis through perpetuating abnormal epithelial-mesenchymal interactions, which can be antagonized by SIRT6.
authors.affiliation: Division of Respiratory Diseases, Dept. of Internal Medicine, Jikei Univ. School of Medicine, Tokyo, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Minagawa
authors.forename: Jun
authors.initials: J
authors.lastname: Araya
authors.forename: Takanori
authors.initials: T
authors.lastname: Numata
authors.forename: Satoko
authors.initials: S
authors.lastname: Nojiri
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Hara
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yumino
authors.forename: Makoto
authors.initials: M
authors.lastname: Kawaishi
authors.forename: Makoto
authors.initials: M
authors.lastname: Odaka
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Morikawa
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Nishimura
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Nakayama
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kuwano
mesh_terms: D001980:Bronchi / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000378:metabolism / Q000473:pathology*; D053583:Interleukin-1beta / Q000378:metabolism; D058628:Myofibroblasts / Q000166:cytology / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D037761:Sirtuins / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D053583:Interleukin-1beta; D053773:Transforming Growth Factor beta1; D001616:beta-Galactosidase; D046988:Proteasome Endopeptidase Complex; C516592:SIRT6 protein, human; D037761:Sirtuins