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Published ahead of print on March 30, 2006, doi:10.1164/rccm.200505-725OC

Am. J. Respir. Crit. Care Med., Volume 174, Number 1, July 2006, 41-50

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Submitted on May 9, 2005
Accepted on March 30, 2006

The Effect of Smoking on the Transcriptional Regulation of Lung Inflammation in COPD Patients

Patryk Szulakowski1, Ann J.L. Crowther1, Luis A Jimenez1, Kenneth Donaldson1, Ruth Mayer2, Thomas B Leonard2, William MacNee1*, and Ellen M Drost1

1 MRC Centre for Inflammation Research, University of Edinburgh, ELEGI Colt Laboratories, Edinburgh, United Kingdom, 2 Department of Respiratory and Inflammation, GlaxoSmithKline, King of Prussia, Pennsylvania, USA

* To whom correspondence should be addressed. E-mail: w.macnee{at}ed.ac.uk.

Rationale: Chronic obstructive pulmonary disease (COPD) is thought to result from an abnormal inflammatory response in the lungs to noxious particles and gases in cigarette smoke. Objectives: In this study the molecular mechanisms for the enhanced pro-inflammatory cytokine gene transcription in COPD were investigated. Methods: Lung tissue from 56 subjects undergoing resection for peripheral lung tumors: current smokers with (n=14) and without COPD (n=17), ex-smokers with COPD (n=13) and non-smokers (n=12) were examined. 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), pro-inflammatory 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 COPD patients when compared with non-smokers (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 levels were detected. From the cytokine profiles no significant differences were detected, however, IL-12p40 expression correlated with ac-H4 in COPD current smokers (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 favour of acetylation may contribute to the enhanced inflammation in smokers susceptible to the development of COPD.
Key words: chronic obstructive pulmonary disease, histone acetylation, oxidative stress, smoking, NF-kappaB




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