RT Journal Article
SR Electronic
T1 Hypoxia upregulates neutrophil degranulation and potential for tissue injury
JF Thorax
JO Thorax
FD BMJ Publishing Group Ltd and British Thoracic Society
SP 1030
OP 1038
DO 10.1136/thoraxjnl-2015-207604
VO 71
IS 11
A1 Kim Hoenderdos
A1 Katharine M Lodge
A1 Robert A Hirst
A1 Cheng Chen
A1 Stefano G C Palazzo
A1 Annette Emerenciana
A1 Charlotte Summers
A1 Adri Angyal
A1 Linsey Porter
A1 Jatinder K Juss
A1 Christopher O'Callaghan
A1 Edwin R Chilvers
A1 Alison M Condliffe
YR 2016
UL http://thorax.bmj.com/content/71/11/1030.abstract
AB Background The inflamed bronchial mucosal surface is a profoundly hypoxic environment. Neutrophilic airway inflammation and neutrophil-derived proteases have been linked to disease progression in conditions such as COPD and cystic fibrosis, but the effects of hypoxia on potentially harmful neutrophil functional responses such as degranulation are unknown.Methods and results Following exposure to hypoxia (0.8% oxygen, 3 kPa for 4 h), neutrophils stimulated with inflammatory agonists (granulocyte-macrophage colony stimulating factor or platelet-activating factor and formylated peptide) displayed a markedly augmented (twofold to sixfold) release of azurophilic (neutrophil elastase, myeloperoxidase), specific (lactoferrin) and gelatinase (matrix metalloproteinase-9) granule contents. Neutrophil supernatants derived under hypoxic but not normoxic conditions induced extensive airway epithelial cell detachment and death, which was prevented by coincubation with the antiprotease α-1 antitrypsin; both normoxic and hypoxic supernatants impaired ciliary function. Surprisingly, the hypoxic upregulation of neutrophil degranulation was not dependent on hypoxia-inducible factor (HIF), nor was it fully reversed by inhibition of phospholipase C signalling. Hypoxia augmented the resting and cytokine-stimulated phosphorylation of AKT, and inhibition of phosphoinositide 3-kinase (PI3K)γ (but not other PI3K isoforms) prevented the hypoxic upregulation of neutrophil elastase release.Conclusion Hypoxia augments neutrophil degranulation and confers enhanced potential for damage to respiratory airway epithelial cells in a HIF-independent but PI3Kγ-dependent fashion.