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Histone acetylation status depends on the equilibrium between the activities of histone acetyltransferase (HAT) and histone deacetylase (HDAC). Acetylation prompts unwinding of histone and allows DNA transcription and production of cytokines. In alveolar macrophages HDAC is a key molecule in repressing the production of pro-inflammatory cytokines.
In this study the authors attempted to correlate changes in HDAC activity and expression with the severity of chronic obstructive pulmonary disease (COPD) as measured by spirometry. HDAC and HAT activities were measured in nuclear extracts of surgical lung specimens from non-smokers and patients with pneumonia, cystic fibrosis, or COPD. Alveolar macrophages from non-smokers, healthy smokers, and patients with COPD or asthma were also examined. RNA was used for quantitative reverse transcriptase polymerase chain reaction assay of HDAC1-8 and interleukin-8 (IL-8). Histone-4 acetylation at the IL-8 promoter was evaluated with chromatin immunoprecipitation.
HDAC activity was decreased in the peripheral lung tissue, alveolar macrophages, and bronchial biopsy specimens of COPD patients compared with healthy non-smokers. Lung HDAC activity was reduced in more severe COPD. Increases in histone-4 acetylation at the IL-8 promoter and expression of IL-8 messenger RNA were correlated with increased severity. However, there was no relationship between total HAT activity and severity of COPD. Bronchial biopsy specimens from mild asthmatics and healthy smokers had lower HDAC activity than those from non-smokers. There were further reductions in patients with COPD. Asthmatic patients had increased HAT activity compared with non-smokers, but there was no change in HAT activity in those with COPD.
The authors conclude that patients with COPD have progressive reduction in total HDAC activity that reflects the severity of the disease. In both asthma and COPD the balance between HAT and HDAC is shifted towards hyperacetylation, but by different mechanisms. These findings may have therapeutic implications.