title: Decreased histone deacetylase activity in chronic obstructive pulmonary disease.
abstract: 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.
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College, London, United Kingdom.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ito
authors.forename: Misako
authors.initials: M
authors.lastname: Ito
authors.forename: W Mark
authors.initials: WM
authors.lastname: Elliott
authors.forename: Borja
authors.initials: B
authors.lastname: Cosio
authors.forename: Gaetano
authors.initials: G
authors.lastname: Caramori
authors.forename: Onn Min
authors.initials: OM
authors.lastname: Kon
authors.forename: Adam
authors.initials: A
authors.lastname: Barczyk
authors.forename: Shizu
authors.initials: S
authors.lastname: Hayashi
authors.forename: Ian M
authors.initials: IM
authors.lastname: Adcock
authors.forename: James C
authors.initials: JC
authors.lastname: Hogg
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Barnes
mesh_terms: 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
chemical_list: D002843:Chromatin; D007527:Isoenzymes; D012333:RNA, Messenger; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases