This Article Full Text Full Text (PDF) 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 Puddicombe, S. M. Articles by Davies, D. E. Search for Related Content PubMed PubMed Citation Articles by Puddicombe, S. M. Articles by Davies, D. E.

Increased Expression of p21^waf Cyclin-Dependent Kinase Inhibitor in Asthmatic Bronchial Epithelium

The Brooke Laboratory, Division of Infection, Inflammation and Repair, School of Medicine, Southampton General Hospital, Southampton, United Kingdom

Address correspondence to: Dr. S. M. Puddicombe, RCMB Division, Mailpoint 810, Southampton General Hospital, Southampton SO16 6YD, UK. E-mail: smp2{at}soton.ac.uk

Because the asthmatic bronchial epithelium is characterized by widespread damage, we postulated that this is associated with expression of cell cycle inhibitors that control proliferation. Using bronchial biopsies, the epithelium was the major site of expression of the cyclin-dependent kinase inhibitor, p21^waf. Immunostaining usually occurred in the cytoplasm of columnar cells; however, in severe asthma, nuclear staining was also evident in the proliferative, basal cell compartment. p21^waf expression was significantly higher in asthmatic versus nonasthmatic epithelium and was unaffected by corticosteroid treatment; proliferating cell nuclear antigen was not significantly different in any group. p21^waf, but not p27^kip1, mRNA and protein were induced by treatment of bronchial epithelial cells in vitro with transforming growth factor (TGF)-ß or H₂O₂, but not by dexamethasone, which induced p57^kip2. TGF-ß and dexamethasone inhibited epidermal growth factor (EGF)-induced DNA synthesis, whereas low concentrations of H₂O₂ synergized with EGF; at higher doses, growth inhibition and induction of apoptosis occurred. TGF-ß caused p21^waf to become nuclear, suggesting interaction with the replicative machinery; however, in oxidant-stressed cells, p21^waf was predominantly cytoplasmic, where it has been linked to cell survival. We conclude that p21^waf overexpression in asthma influences cell proliferation and survival. This may cause abnormal repair responses that contribute to airway inflammation and remodeling.

Abbreviations: bronchial epithelial basal medium, BEBM • bronchial epithelial growth medium, BEGM • bronchial hyperresponsiveness, BHR • cyclin-dependent kinase, CDK • cystic fibrosis, CF • chronic obstructive pulmonary disease, COPD • epidermal growth factor, EGF • fetal bovine serum, FBS • glyceraldehyde phosphate dehydrogenase, GAPDH • glycol methacrylate, GMA • poly ADP ribose polymerase, PARP • proliferating cell nuclear antigen, PCNA • serum-free medium, SFM • transforming growth factor, TGF

This article has been cited by other articles:

				A. Semlali, E. Jacques, S. Plante, S. Biardel, J. Milot, M. Laviolette, L.-P. Boulet, and J. Chakir TGF- Suppresses EGF-Induced MAPK Signaling and Proliferation in Asthmatic Epithelial Cells Am. J. Respir. Cell Mol. Biol., February 1, 2008; 38(2): 202 - 208. [Abstract] [Full Text] [PDF]

				A. D. Bird, K. H. Tan, P. F. Olsson, M. Zieba, S. J. Flecknoe, D. R. Liddicoat, R. Mollard, S. B. Hooper, and T. J. Cole Identification of glucocorticoid-regulated genes that control cell proliferation during murine respiratory development J. Physiol., November 15, 2007; 585(1): 187 - 201. [Abstract] [Full Text] [PDF]

				E. H. Walters, D. W. Reid, D. P. Johns, and C. Ward Nonpharmacological and pharmacological interventions to prevent or reduce airway remodelling Eur. Respir. J., September 1, 2007; 30(3): 574 - 588. [Abstract] [Full Text] [PDF]

				B. M. Fischer, S. Zheng, R. Fan, and J. A. Voynow Neutrophil elastase inhibition of cell cycle progression in airway epithelial cells in vitro is mediated by p27kip1 Am J Physiol Lung Cell Mol Physiol, September 1, 2007; 293(3): L762 - L768. [Abstract] [Full Text] [PDF]

				H. C. Jeong, S. Y. Lee, E. J. Lee, K. H. Jung, E. H. Kang, S. Y. Lee, J. H. Kim, E. K. Park, S. H. Lee, C. S. Uhm, et al. Proteomic Analysis of Peripheral T-Lymphocytes in Patients With Asthma Chest, August 1, 2007; 132(2): 489 - 496. [Abstract] [Full Text] [PDF]

				C. M. Lloyd and D. S. Robinson Allergen-induced airway remodelling Eur. Respir. J., May 1, 2007; 29(5): 1020 - 1032. [Abstract] [Full Text] [PDF]

				K. F. Chung Intrinsic differences of the airway epithelium in childhood allergic asthma. Am. J. Respir. Crit. Care Med., November 15, 2006; 174(10): 1066 - 1067. [Full Text] [PDF]

				C. Boxall, S. T. Holgate, and D. E. Davies The contribution of transforming growth factor-{beta} and epidermal growth factor signalling to airway remodelling in chronic asthma Eur. Respir. J., January 1, 2006; 27(1): 208 - 229. [Abstract] [Full Text] [PDF]

				P. Chanez Severe asthma is an epithelial disease Eur. Respir. J., June 1, 2005; 25(6): 945 - 946. [Full Text] [PDF]

				L. M. Hamilton, S. M. Puddicombe, R. J. Dearman, I. Kimber, T. Sandstrom, A. Wallin, P. H. Howarth, S. T. Holgate, S. J. Wilson, and D. E. Davies Altered protein tyrosine phosphorylation in asthmatic bronchial epithelium Eur. Respir. J., June 1, 2005; 25(6): 978 - 985. [Abstract] [Full Text] [PDF]

				I A Fedorov, S J Wilson, D E Davies, and S T Holgate Epithelial stress and structural remodelling in childhood asthma Thorax, May 1, 2005; 60(5): 389 - 394. [Abstract] [Full Text] [PDF]

				P. A.B. Wark, S. L. Johnston, F. Bucchieri, R. Powell, S. Puddicombe, V. Laza-Stanca, S. T. Holgate, and D. E. Davies Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus J. Exp. Med., March 21, 2005; 201(6): 937 - 947. [Abstract] [Full Text] [PDF]

				C. M. Lilly, H. Tateno, T. Oguma, E. Israel, and L. A. Sonna Effects of Allergen Challenge on Airway Epithelial Cell Gene Expression Am. J. Respir. Crit. Care Med., March 15, 2005; 171(6): 579 - 586. [Abstract] [Full Text] [PDF]

				T. Tsuji, K. Aoshiba, and A. Nagai Cigarette Smoke Induces Senescence in Alveolar Epithelial Cells Am. J. Respir. Cell Mol. Biol., December 1, 2004; 31(6): 643 - 649. [Abstract] [Full Text] [PDF]

				H. Yoshisue, S. M. Puddicombe, S. J. Wilson, H. M. Haitchi, R. M. Powell, D. I. Wilson, A. Pandit, A. E. Berger, D. E. Davies, S. T. Holgate, et al. Characterization of Ciliated Bronchial Epithelium 1, a Ciliated Cell-Associated Gene Induced During Mucociliary Differentiation Am. J. Respir. Cell Mol. Biol., November 1, 2004; 31(5): 491 - 500. [Abstract] [Full Text] [PDF]

				N. S. Undevia, D. R. Dorscheid, B. A. Marroquin, W. L. Gugliotta, R. Tse, and S. R. White Smad and p38-MAPK signaling mediates apoptotic effects of transforming growth factor-{beta}1 in human airway epithelial cells Am J Physiol Lung Cell Mol Physiol, September 1, 2004; 287(3): L515 - L524. [Abstract] [Full Text] [PDF]

				S.T. Holgate Lessons learnt from the epidemic of asthma QJM, May 1, 2004; 97(5): 247 - 257. [Full Text] [PDF]

				S. T. Holgate, J. Holloway, S. Wilson, F. Bucchieri, S. Puddicombe, and D. E. Davies Epithelial-Mesenchymal Communication in the Pathogenesis of Chronic Asthma Proceedings of the ATS, April 1, 2004; 1(2): 93 - 98. [Abstract] [Full Text] [PDF]

				G Caramori and A Papi Oxidants and asthma Thorax, February 1, 2004; 59(2): 170 - 173. [Abstract] [Full Text] [PDF]

				S.T. Holgate, D. E. Davies, S. Puddicombe, A. Richter, P. Lackie, J. Lordan, and P. Howarth Mechanisms of airway epithelial damage: epithelial-mesenchymal interactions in the pathogenesis of asthma Eur. Respir. J., September 20, 2003; 22(44_suppl): 24S - 29s. [Full Text] [PDF]

				M. P. O'Sullivan, J. W. Tyner, and M. J. Holtzman Apoptosis in the Airways: Another Balancing Act in the Epithelial Program Am. J. Respir. Cell Mol. Biol., July 1, 2003; 29(1): 3 - 7. [Full Text] [PDF]