Hypoxia upregulates neutrophil degranulation and potential for tissue injury.
BMJ Publishing Group
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Hoenderdos, K., Lodge, K., Hirst, R., Chen, C., Palazzo, S., Emerenciana, A., Summers, C., et al. (2016). Hypoxia upregulates neutrophil degranulation and potential for tissue injury.. Thorax, 71 (11), 1030-1038. https://doi.org/10.1136/thoraxjnl-2015-207604
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 chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF), 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 hours) neutrophils stimulated with inflammatory agonists (granulocyte-macrophage activating factor (GM-CSF) or platelet activating factor (PAF), and formylated peptide (fMLP)) displayed a markedly augmented (2-6 fold) release of azurophilic (neutrophil elastase, myeloperoxidase), specific (lactoferrin) and gelatinase (matrix metalloproteinase-9, MMP-9) granule contents. Neutrophil supernatants derived under hypoxic but not normoxic conditions induced extensive airway epithelial cell detachment and death, which was prevented by co-incubation with the anti-protease alpha-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 (PLC) signaling. Hypoxia augmented the resting and cytokinestimulated phosphorylation of Akt, and inhibition of phosphoinositide 3-kinase (PI3K)γ 3 (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.
Airway Epithelium, COPD ÀÜ Mechanisms, Cystic Fibrosis, Innate Immunity, Neutrophil Biology, Respiratory Infection
Supported by the British Lung Foundation, Papworth Hospital NHS Foundation Trust, BBSRC and the Cambridge NIHR-Biomedical Research Centre. CS is in receipt of a Wellcome Trust Early Postdoctoral Research Fellowship for Clinician Scientists [WT101692MA].
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External DOI: https://doi.org/10.1136/thoraxjnl-2015-207604
This record's URL: https://www.repository.cam.ac.uk/handle/1810/255802
Attribution 4.0 International
Licence URL: http://creativecommons.org/licenses/by/4.0/