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Cigarette Smoke Alters Chromatin Remodeling and Induces Proinflammatory Genes in Rat Lungs

Edinburgh Lung and the Environment Group Initiative Colt Laboratories, MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh; Novartis Institute for Biomedical Research, Horsham, United Kingdom; Department of Environmental Medicine, Division of Lung Biology and Disease Program, University of Rochester Medical Center, Rochester, New York

Address correspondence to: Dr. Irfan Rahman, Department of Environmental Medicine, University of Rochester Medical Center, 601 Elmwood Ave., Box 850, Rochester, NY 14642. E-mail: irfan_rahman{at}urmc.rochester.edu

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-B, independent of inhibitory protein-B 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.

Abbreviations: activator protein, AP • bronchoalveolar lavage fluid, BALF • chronic obstructive pulmonary disease, COPD • glyceraldehyde-3-phosphate dehydrogenase, GAPDH • histone deacetylase 2, HDAC2 • 4-hydroxy-2-nonenal, 4-HNE • inhibitory protein-B, IB • interleukin, IL • mitogen-activated protein kinase, MAPK • macrophage inflammatory protein, MIP • mitogen- and stress-activated protein, MSK • nuclear factor, NF • phosphate-buffered saline, PBS • reverse transcriptase–polymerase chain reaction, RT-PCR • sodium dodecyl sulfate, SDS

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