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Published ahead of print on March 30, 2006, doi:10.1164/rccm.200505-725OC
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American Journal of Respiratory and Critical Care Medicine Vol 174. pp. 41-50, (2006)
© 2006 American Thoracic Society
doi: 10.1164/rccm.200505-725OC

Original Article

The Effect of Smoking on the Transcriptional Regulation of Lung Inflammation in Patients with Chronic Obstructive Pulmonary Disease

Patryk Szulakowski, Ann J. L. Crowther, Luis A. Jiménez, Kenneth Donaldson, Ruth Mayer, Thomas B. Leonard, William MacNee and Ellen M. Drost

ELEGI Colt Laboratories, MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom; and GlaxoSmithKline, King of Prussia, Pennsylvania

Correspondence and requests for reprints should be addressed to Prof. William MacNee, M.D., ELEGI Colt Laboratories, MRC Centre for Inflammation Research, University of Edinburgh, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, United Kingdom. E-mail: w.macnee{at}ed.ac.uk

Rationale: Chronic obstructive pulmonary disease (COPD) is believed to result from an abnormal inflammatory response in the lungs to noxious particles and gases usually found in cigarette smoke.

Objectives: In this study, the molecular mechanisms for the enhanced proinflammatory cytokine gene transcription in COPD were investigated.

Methods: Lung tissue was examined from 56 subjects undergoing resection for peripheral lung tumors as follows: current smokers with (n = 14) and without COPD (n = 17), ex-smokers with COPD (n = 13), and nonsmokers (n = 12). The levels of inhibitor {kappa}B-{alpha} (I{kappa}B-{alpha}), histone deacetylase 2 (HDAC2), acetylated (ac-) histone H3 and H4, the transcription factor nuclear factor-{kappa}B (NF-{kappa}B), proinflammatory cytokine messenger RNA, and 8-isoprostane were measured.

Measurements and Main Results: I{kappa}B-{alpha} levels were significantly decreased in healthy smokers and current and ex-smoking patients with COPD when compared with nonsmokers (p < 0.001), with an associated increase in NF-{kappa}B DNA binding in current smokers (p < 0.05). An increase in acetylated histone 4 (ac-H4; p < 0.01) was found in current smokers. Conversely, ex-smokers with COPD showed an increase in ac-H3 (p < 0.05). Decreased levels of cytoplasmic, but not nuclear, HDAC2 protein levels were detected. From the cytokine profiles, no significant differences were detected; however, interleukin-12p40 expression correlated with ac-H4 in current smokers with COPD (p < 0.01).

Conclusion: These data propose a role for modification of nucleosomal structure in inflammatory cytokine gene transcription in response to smoking. The imbalance between histone deacetylation and acetylation in favor of acetylation may contribute to the enhanced inflammation in smokers susceptible to the development of COPD.

Key Words: chronic obstructive pulmonary disease • histone acetylation • nuclear factor-{kappa} • B • oxidative stress • smoking




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