Decreased histone deacetylase activity in chronic obstructive pulmonary disease.
BACKGROUND
Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation that is greater in patients with advanced disease. We asked whether there is a link between the severity of disease and the reduction in histone deacetylase (HDAC) activity in the peripheral lung tissue of patients with COPD of varying severity. HDAC is a key molecule in the repression of production of proinflammatory cytokines in alveolar macrophages.


METHODS
HDAC activity and histone acetyltransferase (HAT) activity were determined in nuclear extracts of specimens of surgically resected lung tissue from nonsmokers without COPD, patients with COPD of varying severity, and patients with pneumonia or cystic fibrosis. Alveolar macrophages from nonsmokers, smokers, and patients with COPD and bronchial-biopsy specimens from nonsmokers, healthy smokers, patients with COPD, and those with mild asthma were also examined. Total RNA extracted from lung tissue and macrophages was used for quantitative reverse-transcriptase-polymerase-chain-reaction assay of HDAC1 through HDAC8 and interleukin-8. Expression of HDAC2 protein was quantified with the use of Western blotting. Histone-4 acetylation at the interleukin-8 promoter was evaluated with the use of a chromatin immunoprecipitation assay.


RESULTS
Specimens of lung tissue obtained from patients with increasing clinical stages of COPD had graded reductions in HDAC activity and increases in interleukin-8 messenger RNA (mRNA) and histone-4 acetylation at the interleukin-8 promoter. The mRNA expression of HDAC2, HDAC5, and HDAC8 and expression of the HDAC2 protein were also lower in patients with increasing severity of disease. HDAC activity was decreased in patients with COPD, as compared with normal subjects, in both the macrophages and biopsy specimens, with no changes in HAT activity, whereas HAT activity was increased in biopsy specimens obtained from patients with asthma. Neither HAT activity nor HDAC activity was changed in lung tissue from patients with cystic fibrosis or pneumonia.


CONCLUSIONS
Patients with COPD have a progressive reduction in total HDAC activity that reflects the severity of the disease.
Ito
Kazuhiro
K
Airway Disease Section, National Heart and Lung Institute, Imperial College, London, United Kingdom.
Ito
Misako
M
Elliott
W Mark
WM
Cosio
Borja
B
Caramori
Gaetano
G
Kon
Onn Min
OM
Barczyk
Adam
A
Hayashi
Shizu
S
Adcock
Ian M
IM
Hogg
James C
JC
Barnes
Peter J
PJ
D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism; D000368:Aged; D001249:Asthma / Q000201:enzymology; D015153:Blotting, Western; D001980:Bronchi / Q000201:enzymology; D002843:Chromatin / Q000378:metabolism; D003550:Cystic Fibrosis / Q000201:enzymology; D005260:Female; D005541:Forced Expiratory Volume; D015971:Gene Expression Regulation, Enzymologic; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000201:enzymology*; D016676:Macrophages, Alveolar / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D011014:Pneumonia / Q000201:enzymology; D029424:Pulmonary Disease, Chronic Obstructive / Q000145:classification / Q000201:enzymology* / Q000503:physiopathology; D012333:RNA, Messenger / Q000096:biosynthesis; D012720:Severity of Illness Index; D012907:Smoking / Q000378:metabolism
D002843:Chromatin; D007527:Isoenzymes; D012333:RNA, Messenger; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases