PMID- 27049289 OWN - NLM STAT- MEDLINE DCOM- 20170404 LR - 20191210 IS - 1878-1705 (Electronic) IS - 1567-5769 (Linking) VI - 35 DP - 2016 Jun TI - The effect of phosphatidylinositol-3 kinase inhibition on matrix metalloproteinase-9 and reactive oxygen species release from chronic obstructive pulmonary disease neutrophils. PG - 155-162 LID - S1567-5769(16)30113-8 [pii] LID - 10.1016/j.intimp.2016.03.027 [doi] AB - 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 PI3Kdelta 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 delta 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: PI3Kdelta 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. PI3Kdelta 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 PI3Kdelta inhibition. CONCLUSION: PI3Kdelta 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. CI - Copyright (c) 2016 Elsevier B.V. All rights reserved. FAU - Gupta, V AU - Gupta V AD - 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. FAU - Khan, A AU - Khan A AD - 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. FAU - Higham, A AU - Higham A AD - 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. FAU - Lemon, J AU - Lemon J AD - 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. FAU - Sriskantharajah, S AU - Sriskantharajah S AD - Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, UK. FAU - Amour, A AU - Amour A AD - Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, UK. FAU - Hessel, E M AU - Hessel EM AD - Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, UK. FAU - Southworth, T AU - Southworth T AD - 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. FAU - Singh, D AU - Singh D AD - 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. LA - eng PT - Journal Article DEP - 20160416 PL - Netherlands TA - Int Immunopharmacol JT - International immunopharmacology JID - 100965259 RN - 0 (Anti-Inflammatory Agents) RN - 0 (Enzyme Inhibitors) RN - 0 (Phosphoinositide-3 Kinase Inhibitors) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Reactive Oxygen Species) RN - 7S5I7G3JQL (Dexamethasone) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) SB - IM MH - Aged MH - Aged, 80 and over MH - Anti-Inflammatory Agents/*pharmacology MH - Cells, Cultured MH - Dexamethasone/pharmacology MH - Enzyme Inhibitors/*pharmacology MH - Female MH - Humans MH - Male MH - Matrix Metalloproteinase 9/metabolism MH - Middle Aged MH - Neutrophils/*drug effects/physiology MH - *Phosphoinositide-3 Kinase Inhibitors MH - Protein Kinase Inhibitors/*pharmacology MH - Pulmonary Disease, Chronic Obstructive/*drug therapy MH - Reactive Oxygen Species/metabolism OTO - NOTNLM OT - COPD OT - COPD exacerbations OT - MMP-9 OT - Neutrophil PI3 kinase OT - ROS EDAT- 2016/04/07 06:00 MHDA- 2017/04/05 06:00 CRDT- 2016/04/07 06:00 PHST- 2015/07/08 00:00 [received] PHST- 2016/03/01 00:00 [revised] PHST- 2016/03/21 00:00 [accepted] PHST- 2016/04/07 06:00 [entrez] PHST- 2016/04/07 06:00 [pubmed] PHST- 2017/04/05 06:00 [medline] AID - S1567-5769(16)30113-8 [pii] AID - 10.1016/j.intimp.2016.03.027 [doi] PST - ppublish SO - Int Immunopharmacol. 2016 Jun;35:155-162. doi: 10.1016/j.intimp.2016.03.027. Epub 2016 Apr 16.