NEW YORK (Reuters Health) - Patients with chronic obstructive pulmonary disease (COPD) have progressive reductions in histone deacetylase (HDAC) activity in lung tissue and alveolar macrophages that reflect disease severity, investigators report in The New England Journal of Medicine for May 12th. This abnormality likely leads to chromatin hyperacetylation that in turn increases inflammatory gene expression in these patients.
Using reverse-transcriptase-polymerase chain reaction assays and Western blotting, Dr. Peter J. Barnes, at Imperial College in London, and his associates measured HDAC activity in lung tissue from patients with COPD and asthma and from healthy smokers and nonsmokers.
HDAC activity was significantly lower in tissue and macrophages of patients with stage 2 and 4 COPD compared with healthy subjects, and activity decreased as disease severity increased.
HDAC activity significantly correlated with percent of predicted FEV1, degree of airway obstruction as measured by the FEV1/FCV ratio, and interleukin-8 gene expression, in patients and in controls, although smokers also exhibited a smaller reduction in HDAC activity compared with nonsmokers.
However, analysis of lung biopsy sections showed that HDAC activity was not affected in patients with asthma, cystic fibrosis, or pneumonia.
Moreover, HCAD activity reduction in COPD was associated with attenuation of multiple specific HCAD isoforms (HDAC5, HDAC8, and HDAC3), which the authors note “are reported to be involved in the cell, cycle, cell differentiation, and apoptosis.”
These findings may have “therapeutic implications,” Dr. Barnes’ team notes, since “theophylline is an activator of HDAC.”
“We have recently shown that low concentrations of theophylline completely restore HDAC activity in alveolar macrophages from patients with COPD,” they write, “with reduced production of inflammatory cytokines and restoration of responsiveness to corticosteroids.”
“The challenge now is to understand the interplay between different immune and inflammatory cells and the mediators they produce that lead to tissue destruction,” writes Dr. Steven D. Shapiro, at Harvard Medical School in Boston, in an accompanying editorial.
Source: N Engl J Med 2005;352:1967-1976,2016-2019. [ Google search on this article ]
MeSH Headings:Amidohydrolases: Histone DeacetylaseCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
