title: Long-acting β2 agonists and corticosteroids restore the reduction of histone deacetylase activity and inhibit H2O2-induced mediator release from alveolar macrophages.
abstract: BACKGROUND
  Treatment of COPD with a combination of long-acting β(2) agonists and corticosteroids is currently used worldwide. The mechanisms of the anti-inflammatory effects and their associations with histone deacetylase (HDAC) activity remain unclear.
  
  
  METHODS
  Human alveolar macrophages were isolated and stimulated with H(2)O(2) in the presence of varying concentrations of long-acting β(2) agonists and corticosteroids. Supernatants were collected for IL-8 and MMP-9 measurements. Cell lysates were analyzed for HDAC (mainly HDAC1/HDAC2) activity. Quantitative real-time PCR was performed to determine the levels of IL-8 and MMP-9 mRNA.
  
  
  RESULTS
  Both long-acting β(2) agonists, salmeterol and formoterol, and corticosteroids, fluticasone and budesonide, showed anti-inflammatory effects to a certain extent on H(2)O(2)-induced IL-8 and MMP-9 release in alveolar macrophages. Combinations of long-acting β(2) agonists and corticosteroids exerted greater effects to suppress mediator release, and both transcription and translation of IL-8 and MMP-9 were inhibited. It seemed that the levels of IL-8 and MMP-9 after H(2)O(2) stimulation were inversely associated with the activity of HDAC. H(2)O(2) stimulation resulted in a significant decrease in HDAC activity and was associated with an increase in mediator release. In contrast, treatment with long-acting β(2) agonists, corticosteroids or theophylline restored the H(2)O(2)-induced decrease in HDAC activity and inhibited mediator release.
  
  
  CONCLUSIONS
  Combinations of long-acting β(2) agonists and corticosteroids exerted greater effects on the suppression of mediator release in relation to the enhancement of HDAC activity. This supports at least in part the likely contribution of anti-inflammatory effects of long-acting β(2) agonists and corticosteroids to the clinical benefits seen in COPD patients.
authors.affiliation: Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC. dwperng@vghtpe.gov.tw
authors.forename: Diahn-Warng
authors.initials: DW
authors.lastname: Perng
authors.forename: Kang-Cheng
authors.initials: KC
authors.lastname: Su
authors.forename: Kun-Ta
authors.initials: KT
authors.lastname: Chou
authors.forename: Yu-Chung
authors.initials: YC
authors.lastname: Wu
authors.forename: Chun-Sheng
authors.initials: CS
authors.lastname: Chen
authors.forename: Yi-Han
authors.initials: YH
authors.lastname: Hsiao
authors.forename: Ching-Min
authors.initials: CM
authors.lastname: Tseng
authors.forename: Yu-Hsuan
authors.initials: YH
authors.lastname: Chen
authors.forename: Tun-Yun
authors.initials: TY
authors.lastname: Hsueh
authors.forename: Yu-Chin
authors.initials: YC
authors.lastname: Lee
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000368:Aged; D000369:Aged, 80 and over; D000420:Albuterol / Q000031:analogs & derivatives / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D019819:Budesonide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004983:Ethanolamines / Q000494:pharmacology; D005260:Female; D000068298:Fluticasone; D000068759:Formoterol Fumarate; D005938:Glucocorticoids / Q000008:administration & dosage / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D016209:Interleukin-8 / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D016877:Oxidants / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D000068299:Salmeterol Xinafoate
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D000730:Androstadienes; D000893:Anti-Inflammatory Agents; D004983:Ethanolamines; D005938:Glucocorticoids; D016209:Interleukin-8; D016877:Oxidants; D012333:RNA, Messenger; D019819:Budesonide; D000068299:Salmeterol Xinafoate; D006861:Hydrogen Peroxide; D000068298:Fluticasone; D020780:Matrix Metalloproteinase 9; D006655:Histone Deacetylases; D000420:Albuterol; D000068759:Formoterol Fumarate