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: 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. CONCLUSION: 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.
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Authors | V Gupta, A Khan, A Higham, J Lemon, S Sriskantharajah, A Amour, E M Hessel, T Southworth, D Singh |
Journal | International immunopharmacology
(Int Immunopharmacol)
Vol. 35
Pg. 155-162
(Jun 2016)
ISSN: 1878-1705 [Electronic] Netherlands |
PMID | 27049289
(Publication Type: Journal Article)
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Copyright | Copyright © 2016 Elsevier B.V. All rights reserved. |
Chemical References |
- Anti-Inflammatory Agents
- Enzyme Inhibitors
- Phosphoinositide-3 Kinase Inhibitors
- Protein Kinase Inhibitors
- Reactive Oxygen Species
- Dexamethasone
- Matrix Metalloproteinase 9
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Topics |
- Aged
- Aged, 80 and over
- Anti-Inflammatory Agents
(pharmacology)
- Cells, Cultured
- Dexamethasone
(pharmacology)
- Enzyme Inhibitors
(pharmacology)
- Female
- Humans
- Male
- Matrix Metalloproteinase 9
(metabolism)
- Middle Aged
- Neutrophils
(drug effects, physiology)
- Phosphoinositide-3 Kinase Inhibitors
- Protein Kinase Inhibitors
(pharmacology)
- Pulmonary Disease, Chronic Obstructive
(drug therapy)
- Reactive Oxygen Species
(metabolism)
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