title: Senescence-associated secretory phenotype in a mouse model of bleomycin-induced lung injury.
abstract: Bleomycin produces DNA damage, apoptosis and senescence, all of which play crucial roles in the development of pulmonary fibrosis. Recently, close attention has been paid to a DNA damage-induced phenotypic change (senescence-associated secretory phenotype; SASP) as a trigger for the secretion of various mediators which modify the processes of tissue injury, inflammation, repair and fibrosis. We characterized the SASP in a murine model of bleomycin-induced lung injury. Mice were intratracheally administered bleomycin or control saline, and the lungs were obtained on days 7, 14 and 21. The occurrence of DNA damage and the SASP in the lungs was examined by immunostaining. γH2AX immunostaining of the bleomycin-treated lungs revealed double-strand breaks (DSBs), largely within E-cadherin-positive, β4-integirn-positive alveolar epithelial cells. The DSBs were associated with phosphorylation of ATM/ATR, a central signal transducer mediating the DNA damage response, and upregulation of the cyclin-dependent kinase inhibitor p21(CIP1). The DSBs persisted for at least 21 days after the bleomycin exposure, although it began to wane after 7 days. A subpopulation of the γH2AX-positive, DNA-damaged cells exhibited the SASP, characterized by overexpression of IL-6, TNFα, MMP-2 and MMP-9, in association with the phosphorylation of IKKα/β and p38 MAPK. Persistent DNA damage and the SASP are induced in the process of bleomycin-induced lung injury and repair, suggesting that these events play an important role in the regulation of inflammation and tissue remodeling in bleomycin-induced pneumopathy.
authors.affiliation: Department of Respiratory Medicine, Tokyo Medical University Ibaraki Medical Center, Japan. Electronic address: kaoshiba@tokyo-med.ac.jp.
authors.forename: Kazutetsu
authors.initials: K
authors.lastname: Aoshiba
authors.forename: Takao
authors.initials: T
authors.lastname: Tsuji
authors.forename: Shinkichi
authors.initials: S
authors.lastname: Kameyama
authors.forename: Masayuki
authors.initials: M
authors.lastname: Itoh
authors.forename: Seitaro
authors.initials: S
authors.lastname: Semba
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakamura
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D001761:Bleomycin / Q000633:toxicity*; D016922:Cellular Senescence / Q000187:drug effects*; D004249:DNA Damage / Q000187:drug effects; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D055370:Lung Injury / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype
chemical_list: D000903:Antibiotics, Antineoplastic; D001761:Bleomycin
keywords: Bleomycin; Cell senescence; DNA damage; Double-strand DNA breaks; Inflammation; Lung injury; Matrix metalloproteinase; NFκB; Senescence-associated secretory phenotype