Cigarette smoke induces senescence in alveolar epithelial cells.

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 beta-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 beta-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.

[1]  K. Aoshiba,et al.  Increased levels of cell death and proliferation in alveolar wall cells in patients with pulmonary emphysema. , 2004, Chest.

[2]  W. MacNee,et al.  Cigarette smoke prevents apoptosis through inhibition of caspase activation and induces necrosis. , 2003, American journal of respiratory cell and molecular biology.

[3]  W. MacNee,et al.  Cigarette Smoke‐Induced Oxidative Stress and TGF‐β1 Increase p21waf1/cip1 Expression in Alveolar Epithelial Cells , 2002 .

[4]  P. Hornsby,et al.  Cellular senescence and tissue aging in vivo. , 2002, The journals of gerontology. Series A, Biological sciences and medical sciences.

[5]  Eugenia Wang,et al.  Replicative senescence revisited. , 2002, The journals of gerontology. Series A, Biological sciences and medical sciences.

[6]  I. Komuro,et al.  Endothelial Cell Senescence in Human Atherosclerosis: Role of Telomere in Endothelial Dysfunction , 2002, Circulation.

[7]  P. Coates.  Markers of senescence? , 2002, The Journal of pathology.

[8]  M. Manns,et al.  Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis. , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[9]  S. Joel,et al.  DNA damage is able to induce senescence in tumor cells in vitro and in vivo. , 2002, Cancer research.

[10]  D. Romberger,et al.  Cigarette smoke inhibits human bronchial epithelial cell repair processes. , 2001, American journal of respiratory cell and molecular biology.

[11]  T. Mio,et al.  Cytotoxic effects of cigarette smoke extract on an alveolar type II cell-derived cell line. , 2001, American journal of physiology. Lung cellular and molecular physiology.

[12]  D A Lynch,et al.  Endothelial cell death and decreased expression of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in emphysema. , 2001, American journal of respiratory and critical care medicine.

[13]  P. Singhal,et al.  Tubular cell senescence and expression of TGF-beta1 and p21(WAF1/CIP1) in tubulointerstitial fibrosis of aging rats. , 2001, Experimental and molecular pathology.

[14]  A. Pardo,et al.  Idiopathic Pulmonary Fibrosis: Prevailing and Evolving Hypotheses about Its Pathogenesis and Implications for Therapy , 2001, Annals of Internal Medicine.

[15]  D. Kurz,et al.  Senescence-associated (beta)-galactosidase reflects an increase in lysosomal mass during replicative ageing of human endothelial cells. , 2000, Journal of cell science.

[16]  M. Gaxiola,et al.  Upregulation of gelatinases A and B, collagenases 1 and 2, and increased parenchymal cell death in COPD. , 2000, Chest.

[17]  S. Rennard.  Inflammation and repair processes in chronic obstructive pulmonary disease. , 1999, American journal of respiratory and critical care medicine.

[18]  U. Klotz,et al.  Does pH 6 β-galactosidase activity indicate cell senescence? , 1999, Mechanisms of Ageing and Development.

[19]  D. Givol,et al.  Induced p21waf expression in H1299 cell line promotes cell senescence and protects against cytotoxic effect of radiation and doxorubicin , 1999, Oncogene.

[20]  G. Adami,et al.  Agents that cause DNA double strand breaks lead to p16INK4a enrichment and the premature senescence of normal fibroblasts , 1998, Oncogene.

[21]  C. Harley,et al.  Extension of life-span by introduction of telomerase into normal human cells. , 1998, Science.

[22]  S. Lowe,et al.  Oncogenic ras Provokes Premature Cell Senescence Associated with Accumulation of p53 and p16INK4a , 1997, Cell.

[23]  C Roskelley,et al.  A biomarker that identifies senescent human cells in culture and in aging skin in vivo. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[24]  S. Rennard,et al.  Effects of cigarette smoke extract on bovine bronchial epithelial cell attachment and migration. , 1995, The American journal of physiology.

[25]  K. Aoshiba,et al.  Nicotine prevents a reduction in neutrophil filterability induced by cigarette smoke exposure. , 1994, American journal of respiratory and critical care medicine.

[26]  W. Pryor,et al.  Oxidants in Cigarette Smoke Radicals, Hydrogen Peroxide, Peroxynitrate, and Peroxynitrite a , 1993, Annals of the New York Academy of Sciences.

[27]  C. Baglioni,et al.  Expression of interleukin 1-inducible genes and production of interleukin 1 by aging human fibroblasts. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[28]  D. Mann,et al.  Regulation of collagenase and collagenase mRNA production in early‐ and late‐passage human diploid fibroblasts , 1989, Journal of cellular physiology.

[29]  R. Swank,et al.  Biosynthesis of two lysosomal enzymes in macrophages. Evidence for a precursor of beta-galactosidase. , 1979, The Journal of biological chemistry.

[30]  L. Hayflick.  THE LIMITED IN VITRO LIFETIME OF HUMAN DIPLOID CELL STRAINS. , 1965, Experimental cell research.

[31]  L. Hayflick,et al.  The serial cultivation of human diploid cell strains. , 1961, Experimental cell research.

[32]  P. Howarth,et al.  Increased expression of p21(waf) cyclin-dependent kinase inhibitor in asthmatic bronchial epithelium. , 2003, American journal of respiratory cell and molecular biology.

[33]  W. MacNee,et al.  Cigarette smoke-induced oxidative stress and TGF-beta1 increase p21waf1/cip1 expression in alveolar epithelial cells. , 2002, Annals of the New York Academy of Sciences.

[34]  U. Klotz,et al.  Does pH 6 beta-galactosidase activity indicate cell senescence? , 1999, Mechanisms of ageing and development.

[35]  M. Nakano,et al.  Age-related changes in the lipofuscin accumulation of brain and heart. , 1995, Gerontology.

[36]  Alho,et al.  Age-related changes in the lipofuscin accumulation of brain and heart. Discussion , 1995 .

[37]  W. MacNee,et al.  Effect of cigarette smoke and its condensates on alveolar epithelial cell injury in vitro. , 1994, The American journal of physiology.

[38]  L. Hayflick,et al.  THE LIMITED IN VITRO LIFETIME OF HUMAN DIPLOID CELL STRAINS 1 , 1964 .