This Article Full Text Full Text (PDF) Online Supplement All Versions of this Article: 200505-725OCv1 174/1/41    most recent 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 Szulakowski, P. Articles by Drost, E. M. Search for Related Content PubMed PubMed Citation Articles by Szulakowski, P. Articles by Drost, E. M.

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

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 B- (IB-), histone deacetylase 2 (HDAC2), acetylated (ac-) histone H3 and H4, the transcription factor nuclear factor-B (NF-B), proinflammatory cytokine messenger RNA, and 8-isoprostane were measured.

Measurements and Main Results: IB- 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-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- • B • oxidative stress • smoking

This article has been cited by other articles:

				C. C. Leung, T. H. Lam, W. M. Chan, W. W. Yew, K. S. Ho, G. M. Leung, W. S. Law, C. M. Tam, C. K. Chan, and K. C. Chang Diabetic Control and Risk of Tuberculosis: A Cohort Study Am. J. Epidemiol., June 15, 2008; 167(12): 1486 - 1494. [Abstract] [Full Text] [PDF]

				K. F. Chung and I. M. Adcock Multifaceted mechanisms in COPD: inflammation, immunity, and tissue repair and destruction Eur. Respir. J., June 1, 2008; 31(6): 1334 - 1356. [Abstract] [Full Text] [PDF]

				S.-R. Yang, S. Valvo, H. Yao, A. Kode, S. Rajendrasozhan, I. Edirisinghe, S. Caito, D. Adenuga, R. Henry, G. Fromm, et al. IKK{alpha} Causes Chromatin Modification on Pro-Inflammatory Genes by Cigarette Smoke in Mouse Lung Am. J. Respir. Cell Mol. Biol., June 1, 2008; 38(6): 689 - 698. [Abstract] [Full Text] [PDF]

				C. C. Leung, W. C. Yam, W. W. Yew, P. L. Ho, C. M. Tam, W. S. Law, M. Y. Wong, M. Leung, and D. Tsui Comparison of T-Spot.TB and tuberculin skin test among silicotic patients Eur. Respir. J., February 1, 2008; 31(2): 266 - 272. [Abstract] [Full Text] [PDF]

				T. Yoshida and R. M. Tuder Pathobiology of Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease Physiol Rev, July 1, 2007; 87(3): 1047 - 1082. [Abstract] [Full Text] [PDF]

				K. F. Rabe, B. Beghe, F. Luppi, and L. M. Fabbri Update in Chronic Obstructive Pulmonary Disease 2006 Am. J. Respir. Crit. Care Med., June 15, 2007; 175(12): 1222 - 1232. [Full Text] [PDF]

				J. H. J. Vernooy, G. M. Moller, R. J. van Suylen, M. P. van Spijk, R. H. E. Cloots, P. H. Hoet, H. J. Pennings, and E. F. M. Wouters Increased Granzyme A Expression in Type II Pneumocytes of Patients with Severe Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., March 1, 2007; 175(5): 464 - 472. [Abstract] [Full Text] [PDF]

				R. de Marco, S. Accordini, I. Cerveri, A. Corsico, J. M. Anto, N. Kunzli, C. Janson, J. Sunyer, D. Jarvis, S. Chinn, et al. Incidence of Chronic Obstructive Pulmonary Disease in a Cohort of Young Adults According to the Presence of Chronic Cough and Phlegm Am. J. Respir. Crit. Care Med., January 1, 2007; 175(1): 32 - 39. [Abstract] [Full Text] [PDF]

				E. M. Drost, C. A. Poland, K. Donaldson, and W. MacNee Diminished peroxisome proliferator-activated receptor (PPAR) regulation as a potential mechanism for the persistent inflammation in chronic obstructive pulmonary disease Eur. Respir. Rev., December 1, 2006; 15(101): 211 - 212. [Abstract] [Full Text] [PDF]

				G. Caramori and A. Papi Smoking history effect on peripheral lung inflammation and gene transcription in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med., July 1, 2006; 174(1): 2 - 3. [Full Text] [PDF]