HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS REGISTER		Author Keyword(s) Vol Page [Advanced]

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this link to a friend Similar articles in this journal Similar articles in PubMed Add article to my folders Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mata, M Articles by Morcillo, E J Search for Related Content PubMed PubMed Citation Articles by Mata, M Articles by Morcillo, E J

Phosphodiesterase 4 inhibition decreases MUC5AC expression induced by epidermal growth factor in human airway epithelial cells

¹ Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain
² Research Foundation, University General Hospital, University of Valencia, Valencia, Spain
³ Department of Pathology, Faculty of Medicine, University of Valencia, Valencia, Spain

Correspondence to:
Correspondence to:
Dr E J Morcillo
Department of Pharmacology, Faculty of Medicine, Av. Blasco Ibanez 15, E-46010 Valencia, Spain; Esteban.Morcillo{at}uv.es

Background: A common pathological feature of chronic inflammatory airway diseases such as asthma and chronic obstructive pulmonary disease (COPD) is mucus hypersecretion. MUC5AC is the predominant mucin gene expressed in healthy airways and is increased in asthmatic and COPD patients. Recent clinical trials indicate that phosphodiesterase type 4 (PDE4) inhibitors may have therapeutic value for COPD and asthma. However, their direct effects on mucin expression have been scarcely investigated.

Methods: MUC5AC mRNA and protein expression were examined in cultured human airway epithelial cells (A549) and in human isolated bronchial tissue stimulated with epidermal growth factor (EGF; 25 ng/ml). MUC5AC mRNA was measured by real time RT-PCR and MUC5AC protein by ELISA (cell lysates and tissue homogenates), Western blotting (tissue homogenates) and immunohistochemistry.

Results: EGF increased MUC5AC mRNA and protein expression in A549 cells. PDE4 inhibitors produced a concentration dependent inhibition of the EGF induced MUC5AC mRNA and protein expression with potency values (–log IC₅₀): roflumilast (7.5) > rolipram (6.5) > cilomilast (5.5). Roflumilast also inhibited the EGF induced expression of phosphotyrosine proteins, EGF receptor, and phospho-p38- and p44/42-MAPK measured by Western blot analysis in A549 cells. In human isolated bronchus, EGF induced MUC5AC mRNA and protein expression was inhibited by roflumilast (1 µM) as well as the MUC5AC positive staining shown by immunohistochemistry.

Conclusion: Selective PDE4 inhibition is effective in decreasing EGF induced MUC5AC expression in human airway epithelial cells. This effect may contribute to the clinical efficacy of this new drug category in mucus hypersecretory diseases.

Keywords: Asthma; chronic obstructive pulmonary disease; phosphodiesterase 4; mucin; epithelial growth factor

This article has been cited by other articles:

				T. Mateo, Y. Naim Abu Nabah, M. Losada, R. Estelles, C. Company, B. Bedrina, J. M. Cerda-Nicolas, S. Poole, P. J. Jose, J. Cortijo, et al. A critical role for TNF{alpha} in the selective attachment of mononuclear leukocytes to angiotensin-II-stimulated arterioles Blood, September 15, 2007; 110(6): 1895 - 1902. [Abstract] [Full Text] [PDF]

				M. Martinez-Losa, J. Cortijo, G. Juan, M. Ramon, M. J. Sanz, and E. J. Morcillo Modulatory effects of N-acetyl-L-cysteine on human eosinophil apoptosis Eur. Respir. J., September 1, 2007; 30(3): 436 - 442. [Abstract] [Full Text] [PDF]

				R. A. McIvor Future options for disease intervention: important advances in phosphodiesterase 4 inhibitors Eur. Respir. Rev., September 1, 2007; 16(105): 105 - 112. [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]

				S. D Martina, M. S Ismail, and K. S Vesta Cilomilast: Orally Active Selective Phosphodiesterase-4 Inhibitor for Treatment of Chronic Obstructive Pulmonary Disease Ann. Pharmacother., October 1, 2006; 40(10): 1822 - 1828. [Abstract] [Full Text] [PDF]

				H. J. Kwak, J. S. Song, J. Y. Heo, S. D. Yang, J.-Y. Nam, and H. G. Cheon Roflumilast Inhibits Lipopolysaccharide-Induced Inflammatory Mediators via Suppression of Nuclear Factor-{kappa}B, p38 Mitogen-Activated Protein Kinase, and c-Jun NH2-Terminal Kinase Activation J. Pharmacol. Exp. Ther., December 1, 2005; 315(3): 1188 - 1195. [Abstract] [Full Text] [PDF]