title: The effect of phosphatidylinositol-3 kinase inhibition on matrix metalloproteinase-9 and reactive oxygen species release from chronic obstructive pulmonary disease neutrophils.
abstract: BACKGROUND
  Chronic Obstructive Pulmonary Disease (COPD) is characterised by increased neutrophilic inflammation. A potential novel anti-inflammatory target in COPD is phosphatidylinositol-3 kinase (PI3 kinase), which targets neutrophil function. This study evaluated the effects of selective PI3Kδ inhibition on COPD blood and sputum neutrophils both in the stable state and during exacerbations.
  
  
  METHODS
  Blood and sputum neutrophils from stable and exacerbating COPD patients were cultured with the corticosteroid dexamethasone, a pan PI3 kinase inhibitor (ZSTK474), a δ selective PI3 kinase inhibitor (GSK045) and a p38 mitogen activated protein (MAP) kinase inhibitor (BIRB 796); matrix metalloproteinase (MMP)-9 and reactive oxygen species (ROS) release were analysed.
  
  
  RESULTS
  PI3Kδ inhibition significantly reduced MMP-9, intracellular ROS and extracellular ROS release from blood neutrophils (45.6%, 30.1% and 47.4% respectively; p<0.05) and intracellular ROS release from sputum neutrophils (16.6%; p<0.05) in stable patients. PI3Kδ selective inhibition significantly reduced stimulated MMP-9 (36.4%; p<0.05) and unstimulated and stimulated ROS release (12.6 and 26.7%; p<0.05) from blood neutrophils from exacerbating patients. The effects of the p38 MAP kinase inhibitor and dexamethasone in these experiments were generally lower than PI3Kδ inhibition.
  
  
  CONCLUSIONS
  PI3Kδ selective inhibition is a potential strategy for targeting glucocorticoid insensitive MMP-9 and ROS secretion from COPD neutrophils, both in the stable state and during exacerbations.
authors.affiliation: University of Manchester, Medicines Evaluation Unit, Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, University Hospital of South Manchester, NHS Foundation Trust, Manchester M23 9LT, UK. Electronic address: vgupta@meu.org.uk.
authors.forename: V
authors.initials: V
authors.lastname: Gupta
authors.affiliation: University of Manchester, Medicines Evaluation Unit, Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, University Hospital of South Manchester, NHS Foundation Trust, Manchester M23 9LT, UK.
authors.forename: A
authors.initials: A
authors.lastname: Khan
authors.affiliation: University of Manchester, Medicines Evaluation Unit, Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, University Hospital of South Manchester, NHS Foundation Trust, Manchester M23 9LT, UK.
authors.forename: A
authors.initials: A
authors.lastname: Higham
authors.affiliation: University of Manchester, Medicines Evaluation Unit, Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, University Hospital of South Manchester, NHS Foundation Trust, Manchester M23 9LT, UK.
authors.forename: J
authors.initials: J
authors.lastname: Lemon
authors.affiliation: Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, UK.
authors.forename: S
authors.initials: S
authors.lastname: Sriskantharajah
authors.affiliation: Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, UK.
authors.forename: A
authors.initials: A
authors.lastname: Amour
authors.affiliation: Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, UK.
authors.forename: E M
authors.initials: EM
authors.lastname: Hessel
authors.affiliation: University of Manchester, Medicines Evaluation Unit, Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, University Hospital of South Manchester, NHS Foundation Trust, Manchester M23 9LT, UK.
authors.forename: T
authors.initials: T
authors.lastname: Southworth
authors.affiliation: University of Manchester, Medicines Evaluation Unit, Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, University Hospital of South Manchester, NHS Foundation Trust, Manchester M23 9LT, UK.
authors.forename: D
authors.initials: D
authors.lastname: Singh
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D003907:Dexamethasone; D020780:Matrix Metalloproteinase 9
keywords: COPD; COPD exacerbations; MMP-9; Neutrophil PI3 kinase; ROS