title: Inhibition of PI3Kdelta restores glucocorticoid function in smoking-induced airway inflammation in mice.
abstract: BACKGROUND
  There is an increasing prevalence of reduced responsiveness to glucocorticoid therapy in severe asthma and chronic obstructive pulmonary disease (COPD). The molecular mechanism of this remains unknown. Recent studies have shown that histone deacetylase activity, which is critical to glucocorticoid function, is altered by oxidant stress and may be involved in the development of glucocorticoid insensitivity.
  
  
  OBJECTIVE
  To determine the role of phosphoinositol-3-kinase (PI3K) in the development of cigarette smoke-induced glucocorticoid insensitivity.
  
  
  METHODS
  Wild-type, PI3Kgamma knock-out and PI3Kdelta kinase dead knock-in transgenic mice were used in a model of cigarette smoke-induced glucocorticoid insensitivity. Peripheral lung tissue was obtained from six healthy nonsmokers, nine smokers with normal lung function, and eight patients with COPD.
  
  
  RESULTS
  In vitro oxidative stress activates PI3K and induced a relative glucocorticoid resistance, which is restored by PI3K inhibition. In vivo, cigarette smoke exposure in mice increased tyrosine nitration of histone deacetylase 2 in the lung, correlating with reduced histone deacetylase 2 activity and reduced glucocorticoid function. Histone deacetylase 2 activity and the antiinflammatory effects of glucocorticoids were restored in PI3Kdelta kinase dead knock-in but not PI3Kgamma knock-out smoke-exposed mice compared with wild type mice, correlating with reduced histone deacetylase 2 tyrosine nitration. Glucocorticoid receptor expression was significantly reduced in smoke-exposed mice, in smokers with normal lung function, and in patients with COPD.
  
  
  CONCLUSIONS
  These data show that therapeutic inhibition of PI3Kdelta may restore glucocorticoid function in oxidative stress-induced glucocorticoid insensitivity.
authors.affiliation: Airways Disease Section, National Heart & Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, UK. j.marwick@imperial.ac.uk
authors.forename: John A
authors.initials: JA
authors.lastname: Marwick
authors.forename: Gaetano
authors.initials: G
authors.lastname: Caramori
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Stevenson
authors.forename: Paolo
authors.initials: P
authors.lastname: Casolari
authors.forename: Elen
authors.initials: E
authors.lastname: Jazrawi
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Barnes
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ito
authors.forename: Ian M
authors.initials: IM
authors.lastname: Adcock
authors.forename: Paul A
authors.initials: PA
authors.lastname: Kirkham
authors.forename: Alberto
authors.initials: A
authors.lastname: Papi
mesh_terms: D000280:Administration, Inhalation; D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D002478:Cells, Cultured; D058534:Class I Phosphatidylinositol 3-Kinases; D004351:Drug Resistance; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage*; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000276:immunology; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000378:metabolism; D012097:Repressor Proteins / Q000187:drug effects / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects* / Q000276:immunology*
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D005938:Glucocorticoids; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011965:Receptors, Glucocorticoid; D012097:Repressor Proteins; C411470:glucocorticoid receptor alpha; C421683:Pik3cd protein, mouse; C533424:Hdac2 protein, mouse