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.

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.

Keywords: COPD; COPD exacerbations; MMP-9; Neutrophil PI3 kinase; ROS.