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Hypoxia upregulates neutrophil degranulation and potential for tissue injury.

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journal contribution
posted on 2017-01-03, 15:05 authored by K. Hoenderdos, K. M. Lodge, Robert A. Hirst, C. Chen, S. G. Palazzo, A. Emerenciana, C. Summers, A. Angyal, L. Porter, J. K. Juss, C. O'Callaghan, E. R. Chilvers, A. M. Condliffe
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.

Funding

Supported by the British Lung Foundation, Papworth Hospital NHS Foundation Trust, BBSRC and the Cambridge NIHR-Biomedical Research Centre. CS was funded by Wellcome Trust Early Postdoctoral Research Fellowship for Clinician Scientists (WT101692MA).

History

Citation

Thorax, 2016, 71 (11), pp. 1030-1038

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Infection, Immunity and Inflammation

Version

  • VoR (Version of Record)

Published in

Thorax

Publisher

BMJ Publishing Group, British Thoracic Society (BTS)

issn

0040-6376

eissn

1468-3296

Acceptance date

2016-04-04

Available date

2017-01-03

Publisher version

http://thorax.bmj.com/content/71/11/1030

Notes

Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/thoraxjnl-2015-207604)

Language

en

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