The effect of smoking on the transcriptional regulation of lung inflammation in patients with chronic obstructive pulmonary disease.
BACKGROUND
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.


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


RESULTS
IkappaB-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-kappaB 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).


CONCLUSIONS
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.
Szulakowski
Patryk
P
ELEGI Colt Laboratories, MRC Centre for Inflammation Research, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, United Kingdom.
Crowther
Ann J L
AJ
Jiménez
Luis A
LA
Donaldson
Kenneth
K
Mayer
Ruth
R
Leonard
Thomas B
TB
MacNee
William
W
Drost
Ellen M
EM
D000368:Aged; D016022:Case-Control Studies; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015237:Dinoprost / Q000031:analogs & derivatives / Q000378:metabolism; D005260:Female; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D012907:Smoking / Q000378:metabolism* / Q000473:pathology
D016207:Cytokines; D006657:Histones; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D012333:RNA, Messenger; D012097:Repressor Proteins; D000072000:NF-KappaB Inhibitor alpha; C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases