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Published ahead of print on August 27, 2004, doi:10.1165/rcmb.2003-0290OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 31, pp. 643-649, 2004
© 2004 American Thoracic Society
DOI: 10.1165/rcmb.2003-0290OC

Cigarette Smoke Induces Senescence in Alveolar Epithelial Cells

Takao Tsuji, Kazutetsu Aoshiba and Atsushi Nagai

First Department of Medicine, Tokyo Women's Medical University, Tokyo, Japan

Address correspondence to: Kazutetsu Aoshiba, M.D., First Department of Medicine, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. E-mail: kaoshiba{at}chi.twmu.ac.jp

Cellular senescence is a state of irreversible growth arrest induced either by telomere shortening (replicative senescence) or by telomere-independent signals (stress-induced senescence). The alveolar epithelium is often injured by a variety of inhaled toxins, including cigarette smoke (CS). In the present study, we investigated whether exposure to CS induces senescence of alveolar epithelial cells. In vitro experiments showed that exposure of A549 cells or normal human alveolar epithelial cells to sublethal concentrations of aqueous CS extracts induced cellular senescence. The senescence was characterized by a dose- and time-dependent increase in senescence-associated ß-galactosidase activity, senescence-associated changes in cell morphology, an increase in cell size and lysosomal mass, accumulation of lipofuscin, overexpression of p21CIP1/WAF1/Sdi1 protein, and irreversible growth arrest. In vivo experiments in Institute for Cancer Research mice showed that inhalation of CS for 2 wk induced increases in senescence-associated ß-galactosidase activity, lipofuscin accumulation, and p21CIP1/WAF1/Sdi1 protein expression in alveolar epithelial cells. These results suggest that CS induces a phenotype that is indistinguishable from that of senescence in alveolar epithelial cells. The induction of cellular senescence by CS may contribute to impaired re-epithelialization, leading to CS-related chronic lung diseases.

Abbreviations: bromodeoxyuridine, BrdU • bovine serum albumin, BSA • cyclin-dependent kinase, CDK • CDK inhibitor, CKI • cigarette smoke, CS • CS extracts, CSE • 3,3'-diaminobenzidine, DAB • fetal calf serum, FCS • immunoglobulin, Ig • human pulmonary alveolar epithelial, HPAEpi • horseradish peroxidase, HRP • N-acetylcysteine, NAC • reactive oxygen species, ROS • phosphate-buffered saline, PBS • surfactant protein, SP • senescence-associated ß-galactosidase, SA ß-gal




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