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Am J Physiol Lung Cell Mol Physiol 287: L332-L343, 2004. First published March 26, 2004; doi:10.1152/ajplung.00384.2003
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Differential expression of PDE4 cAMP phosphodiesterase isoforms in inflammatory cells of smokers with COPD, smokers without COPD, and nonsmokers

Rachael Barber,1 George S. Baillie,2 Reinhard Bergmann,3 Malcolm C. Shepherd,4 Ruth Sepper,5 Miles D. Houslay,2 and Gino Van Heeke1

1Respiratory Disease Area, Novartis Institutes for BioMedical Research, Horsham RH12 5AB; 2Molecular Pharmacology Group, Division of Biochemistry & Molecular Biology, Institute of Biomedical & Life Sciences and 4Department of Medicine, University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom; 3Informatics and Knowledge Management, Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland; and 5The Unit for Lung Investigations, Institute of Experimental and Clinical Medicine, Tallinn, 13419 Estonia

Submitted 10 November 2003 ; accepted in final form 16 March 2004

The expression profile of a panel of 15 cAMP phosphodiesterase isoforms was determined for inflammatory cell types of relevance to chronic obstructive pulmonary disease (COPD). In particular, the expression profiles for bronchoalveolar macrophages, peripheral blood monocytes, T lymphocytes, and neutrophils from smokers with and without COPD were compared. The phosphodiesterase expression profile was also analyzed for peripheral blood monocytes, T lymphocytes, and neutrophils from nonsmokers and compared with smokers. Qualitative RT-PCR identified transcripts for PDE4A10, PDE4A7, PDE4B1, PDE4B2, PDE4D1, and PDE4D2 isoforms as well as transcripts for both PDE3B and PDE7A in T cells, monocytes, and macrophages in all subjects. Transcripts for PDE4B3 and PDE4D4 were not observed in any of the cell types investigated. PDE4C was detected in all cells analyzed except for T cells. The long PDE4A4, PDE4D3, and PDE4D5 isoforms exhibited cell type-specific expression patterns. Semiquantitative and real-time quantitative RT-PCR were used to analyze differential expression between disease states and between cell types. PDE4A4 was found significantly upregulated in lung macrophages from smokers with COPD when compared with control smokers. Furthermore, PDE4A4 as well as PDE4B2 transcripts were detected in higher amounts in peripheral blood monocytes of smokers when compared with nonsmokers. Finally, PDE4D5 and PDE4C were differentially regulated in lung macrophages when compared with monocytes of the same subjects, irrespective of the disease state. The data obtained suggest that PDE4A4 may be relevant as a macrophage-specific anti-inflammatory target for COPD.

cAMP-specific phosphodiesterase family type 4; chronic obstructive pulmonary disease; inflammation


Address for reprint requests and other correspondence: G. Van Heeke, Respiratory Disease Area, Novartis Horsham Research Center, Wimblehurst Road, Horsham RH12 5AB, United Kingdom (E-mail: gino.van_heeke{at}pharma.novartis.com)




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