This Article Full Text Full Text (PDF) All Versions of this Article: 2003-0290OCv1 31/6/643    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tsuji, T. Articles by Nagai, A. Search for Related Content PubMed PubMed Citation Articles by Tsuji, T. Articles by Nagai, A.

Cigarette Smoke Induces Senescence in Alveolar Epithelial Cells

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 p21^{CIP1/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 p21^{CIP1/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

This article has been cited by other articles:

				H. Yao, S.-R. Yang, I. Edirisinghe, S. Rajendrasozhan, S. Caito, D. Adenuga, M. A. O'Reilly, and I. Rahman Disruption of p21 Attenuates Lung Inflammation Induced by Cigarette Smoke, LPS, and fMLP in Mice Am. J. Respir. Cell Mol. Biol., July 1, 2008; 39(1): 7 - 18. [Abstract] [Full Text] [PDF]

				K. F. Chung and I. M. Adcock Multifaceted mechanisms in COPD: inflammation, immunity, and tissue repair and destruction Eur. Respir. J., June 1, 2008; 31(6): 1334 - 1356. [Abstract] [Full Text] [PDF]

				S. A. Perera, R. S. Maser, H. Xia, K. McNamara, A. Protopopov, L. Chen, A. F.Hezel, C. F. Kim, R. T. Bronson, D. H. Castrillon, et al. Telomere dysfunction promotes genome instability and metastatic potential in a K-ras p53 mouse model of lung cancer Carcinogenesis, April 1, 2008; 29(4): 747 - 753. [Abstract] [Full Text] [PDF]

				H. Mori, T. Nose, K. Ishitani, S. Kasagi, S. Souma, T. Akiyoshi, Y. Kodama, T. Mori, M. Kondo, S. Sasaki, et al. Phosphodiesterase 4 inhibitor GPD-1116 markedly attenuates the development of cigarette smoke-induced emphysema in senescence-accelerated mice P1 strain Am J Physiol Lung Cell Mol Physiol, February 1, 2008; 294(2): L196 - L204. [Abstract] [Full Text] [PDF]

				T. Yoshida and R. M. Tuder Pathobiology of Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease Physiol Rev, July 1, 2007; 87(3): 1047 - 1082. [Abstract] [Full Text] [PDF]

				T. Nyunoya, M. M. Monick, A. Klingelhutz, T. O. Yarovinsky, J. R. Cagley, and G. W. Hunninghake Cigarette Smoke Induces Cellular Senescence Am. J. Respir. Cell Mol. Biol., December 1, 2006; 35(6): 681 - 688. [Abstract] [Full Text] [PDF]

				R. M. Tuder, T. Yoshida, I. Fijalkowka, S. Biswal, and I. Petrache Role of Lung Maintenance Program in the Heterogeneity of Lung Destruction in Emphysema Proceedings of the ATS, November 1, 2006; 3(8): 673 - 679. [Abstract] [Full Text] [PDF]

				T. Tsuji, K. Aoshiba, and A. Nagai Alveolar Cell Senescence in Patients with Pulmonary Emphysema Am. J. Respir. Crit. Care Med., October 15, 2006; 174(8): 886 - 893. [Abstract] [Full Text] [PDF]

				R. M. Tuder Aging and Cigarette Smoke: Fueling the Fire Am. J. Respir. Crit. Care Med., September 1, 2006; 174(5): 490 - 491. [Full Text] [PDF]

				R. M. Tuder, T. Yoshida, W. Arap, R. Pasqualini, and I. Petrache State of the Art. Cellular and Molecular Mechanisms of Alveolar Destruction in Emphysema: An Evolutionary Perspective Proceedings of the ATS, August 1, 2006; 3(6): 503 - 510. [Abstract] [Full Text] [PDF]

				C.-Y. Zhong, Y.-M. Zhou, G. C. Douglas, H. Witschi, and K. E. Pinkerton MAPK/AP-1 signal pathway in tobacco smoke-induced cell proliferation and squamous metaplasia in the lungs of rats Carcinogenesis, December 1, 2005; 26(12): 2187 - 2195. [Abstract] [Full Text] [PDF]