title: Passive smoking impairs histone deacetylase-2 in children with severe asthma.
abstract: BACKGROUND
  Parental smoking is known to worsen asthma symptoms in children and to make them refractory to asthma treatment, but the molecular mechanism is unclear. Oxidative stress from tobacco smoke has been reported to impair histone deacetylase-2 (HDAC2) via phosphoinositide-3-kinase (PI3K)/Akt activation and, thus, to reduce corticosteroid sensitivity. The aim of this study was to investigate passive smoking-dependent molecular abnormalities in alveolar macrophages (AMs) by comparing passive smoke-exposed children and non-passive smoke-exposed children with uncontrolled severe asthma.
  
  
  METHODS
  BAL fluid (BALF) was obtained from 19 children with uncontrolled severe asthma (10 non-passive smoking-exposed subjects and nine passive smoking-exposed subjects), and HDAC2 expression/activity, Akt/HDAC2 phosphorylation levels, and corticosteroid responsiveness in AMs were evaluated.
  
  
  RESULTS
  Parental smoking reduced HDAC2 protein expression by 54% and activity by 47%, with concomitant enhancement of phosphorylation of Akt1 and HDAC2. In addition, phosphorylation levels of Akt1 correlated positively with HDAC2 phosphorylation levels and negatively with HDAC2 activity. Furthermore, passive smoke exposure reduced the inhibitory effects of dexamethasone on tumor necrosis factor-α-induced CXCL8 release in AMs. There were relatively higher neutrophil counts and CXCL8 concentrations in BALF and lower Asthma Control Test scores compared with non-passive smoke-exposed children with uncontrolled severe asthma.
  
  
  CONCLUSIONS
  Passive smoking impairs HDAC2 function via PI3K signaling activation, which could contribute to corticosteroid-insensitive inflammation in children with severe asthma. This novel mechanism will be a treatment target in children with severe asthma and stresses the need for a smoke-free environment for asthmatic children.
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London; Department of Respiratory Paediatrics, Royal Brompton Hospital, London, England.
authors.forename: Cara
authors.initials: C
authors.lastname: Bossley
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London; Department of Respiratory Paediatrics, Royal Brompton Hospital, London, England.
authors.forename: Atul
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Akashi
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London; Department of Respiratory Paediatrics, Royal Brompton Hospital, London, England.
authors.forename: Lemonia
authors.initials: L
authors.lastname: Tsartsali
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Mercado
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Barnes
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London; Department of Respiratory Paediatrics, Royal Brompton Hospital, London, England.
authors.forename: Andrew
authors.initials: A
authors.lastname: Bush
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London. Electronic address: k.ito@imperial.ac.uk.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ito
mesh_terms: D000293:Adolescent; D001249:Asthma / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D016022:Case-Control Studies; D002648:Child; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use; D056464:Histone Deacetylase 2 / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D018384:Oxidative Stress / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000502:physiology; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
chemical_list: D005938:Glucocorticoids; D016209:Interleukin-8; D014028:Tobacco Smoke Pollution; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D056464:Histone Deacetylase 2
references.citation: Allergy. 2009 Dec;64(12):1722-7
references.pmid: 19832738
references.citation: Mediators Inflamm. 2011;2011:891752
references.pmid: 21772668
references.citation: Lancet. 2009 May 30;373(9678):1905-17
references.pmid: 19482216
references.citation: Chest. 2012 Feb;141(2):330-338
references.pmid: 21636667
references.citation: Am J Respir Cell Mol Biol. 2009 Apr;40(4):464-73
references.pmid: 18927347
references.citation: Ann Allergy Asthma Immunol. 2010 May;104(5):385-93
references.pmid: 20486328
references.citation: Thorax. 2007 Dec;62(12):1074-80
references.pmid: 17526676
references.citation: Chest. 2009 Jul;136(1):163-170
references.pmid: 19225056
references.citation: PLoS One. 2011;6(12):e27627
references.pmid: 22205926
references.citation: Trends Pharmacol Sci. 2010 Jul;31(7):335-43
references.pmid: 20554041
references.citation: J Exp Med. 2006 Jan 23;203(1):7-13
references.pmid: 16380507
references.citation: Am J Respir Crit Care Med. 2004 Jul 15;170(2):141-7
references.pmid: 15087294
references.citation: Clin Chem Lab Med. 2011 Sep 13;49(12):2007-12
references.pmid: 21913795
references.citation: Eur Respir J. 2004 Nov;24(5):822-33
references.pmid: 15516679
references.citation: Arch Biochem Biophys. 2010 Jun 1;498(1):62-73
references.pmid: 20388487
references.citation: Chem Biol Interact. 2008 Nov 25;176(2-3):79-87
references.pmid: 18793622
references.citation: Am J Respir Crit Care Med. 2002 Aug 1;166(3):392-6
references.pmid: 12153977
references.citation: Am J Respir Crit Care Med. 2010 Oct 1;182(7):897-904
references.pmid: 20224070
references.citation: FASEB J. 2001 Apr;15(6):1110-2
references.pmid: 11292684
references.citation: Lancet. 2010 Sep 4;376(9743):814-25
references.pmid: 20816548
references.citation: J Exp Med. 2004 Sep 6;200(5):689-95
references.pmid: 15337792
references.citation: Am J Respir Crit Care Med. 2009 Apr 1;179(7):542-8
references.pmid: 19164702
references.citation: Am J Respir Crit Care Med. 2007 Apr 15;175(8):783-90
references.pmid: 17204725
references.citation: COPD. 2009 Aug;6(4):291-7
references.pmid: 19811389
references.citation: J Allergy Clin Immunol. 2006 Mar;117(3):549-56
references.pmid: 16522452
references.citation: Eur Respir J. 1997 Jul;10(7):1683-93
references.pmid: 9230267
references.citation: J Allergy Clin Immunol. 2010 May;125(5):1146-53
references.pmid: 20381852
references.citation: Eur Respir J. 2009 Nov;34(5):1052-9
references.pmid: 19541710
references.citation: N Engl J Med. 2005 May 12;352(19):1967-76
references.pmid: 15888697
references.citation: J Biol Chem. 2010 Jun 4;285(23):17417-24
references.pmid: 20385560
references.citation: Arch Dis Child. 2009 Oct;94(10):780-4
references.pmid: 19546102
references.citation: Biochem Biophys Res Commun. 2009 Jul 3;384(3):366-71
references.pmid: 19410558
references.citation: Am J Respir Crit Care Med. 2006 Jul 15;174(2):134-41
references.pmid: 16614347
references.citation: Expert Opin Ther Targets. 2009 Sep;13(9):1053-67
references.pmid: 19659447
references.citation: J Am Board Fam Med. 2011 May-Jun;24(3):313-22
references.pmid: 21551404