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Hypoxia upregulates neutrophil degranulation and potential for tissue injury
  1. Kim Hoenderdos1,
  2. Katharine M Lodge1,
  3. Robert A Hirst2,
  4. Cheng Chen1,
  5. Stefano G C Palazzo1,
  6. Annette Emerenciana1,
  7. Charlotte Summers1,
  8. Adri Angyal3,
  9. Linsey Porter1,
  10. Jatinder K Juss1,
  11. Christopher O'Callaghan4,
  12. Edwin R Chilvers1,
  13. Alison M Condliffe1,3
  1. 1Department of Medicine, University of Cambridge, Cambridge, UK
  2. 2Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK
  3. 3Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK
  4. 4Department of Respiratory Medicine, Portex Unit, Institute of Child Health, University College London, Cambridge, UK
  1. Correspondence to Professor Alison Condliffe, Department of Infection and Immunity, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, UK; a.m.condliffe{at}


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.

  • Neutrophil Biology
  • Airway Epithelium
  • COPD ÀÜ Mechanisms
  • Innate Immunity
  • Cystic Fibrosis
  • Respiratory Infection

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