Cigarette smoke alters chromatin remodeling and induces proinflammatory genes in rat lungs.
Cigarette smoke-triggered inflammation is considered to play a central role in the development of chronic obstructive pulmonary disease by a mechanism that may involve enhanced proinflammatory gene transcription. Histone acetylation and deacetylation is a key regulator of the specificity and duration of gene transcription. Disruption in the nuclear histone acetylation:deacetylation balance (chromatin remodeling) may result in excessive transcription of specific proinflammatory genes in the lungs. In this study we show that cigarette smoke exposure results in an influx of inflammatory cells and chromatin modifications in rat lungs. This was associated with an increase in the active phosphorylated form of p38 mitogen-activated protein kinase concomitant with increased histone 3 phospho-acetylation, histone 4 acetylation, and increased DNA binding of the redox-sensitive transcription factor nuclear factor-kappaB, independent of inhibitory protein-kappaB degradation, and activator protein 1. We also observed decreased histone deacetylase 2 activity, which is due to protein modification by aldehydes and nitric oxide products present in cigarette smoke. Furthermore, we show that corticosteroid treatment has no effect on smoke-induced proinflammatory mediator release. These findings suggest a possible molecular mechanism by which cigarette smoke drives proinflammatory gene transcription and an inflammatory response in the lungs.
Marwick
John A
JA
MRC Centre for Inflammation Research, Department of Environmental Medicine, University of Edinburgh, UK.
Kirkham
Paul A
PA
Stevenson
Christopher S
CS
Danahay
Henry
H
Giddings
June
J
Butler
Keith
K
Donaldson
Kenneth
K
Macnee
William
W
Rahman
Irfan
I
D000107:Acetylation; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D019819:Budesonide / Q000494:pharmacology; D054407:Chemokine CCL4; D054426:Chemokine CXCL2; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D019402:Macrophage Inflammatory Proteins / Q000235:genetics; D008297:Male; D015846:Monokines / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012907:Smoking / Q000235:genetics* / Q000473:pathology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D054407:Chemokine CCL4; D054426:Chemokine CXCL2; D017362:Cyclic AMP Response Element-Binding Protein; D016207:Cytokines; D006657:Histones; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D019402:Macrophage Inflammatory Proteins; D015846:Monokines; D016328:NF-kappa B; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D019819:Budesonide; D048051:p38 Mitogen-Activated Protein Kinases; D006655:Histone Deacetylases