title: Hypoxia upregulates neutrophil degranulation and potential for tissue injury.
abstract: 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.
  
  
  
  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.
  
  
  
  Hypoxia augments neutrophil degranulation and confers enhanced potential for damage to respiratory airway epithelial cells in a HIF-independent but PI3Kγ-dependent fashion.
authors: Department of Medicine, University of Cambridge, Cambridge, UK.
authors: Kim
authors: K
authors: Hoenderdos
authors: Department of Medicine, University of Cambridge, Cambridge, UK.
authors: Katharine M
authors: KM
authors: Lodge
authors: Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK.
authors: Robert A
authors: RA
authors: Hirst
authors: Department of Medicine, University of Cambridge, Cambridge, UK.
authors: Cheng
authors: C
authors: Chen
authors: Department of Medicine, University of Cambridge, Cambridge, UK.
authors: Stefano G C
authors: SG
authors: Palazzo
authors: Department of Medicine, University of Cambridge, Cambridge, UK.
authors: Annette
authors: A
authors: Emerenciana
authors: Department of Medicine, University of Cambridge, Cambridge, UK.
authors: Charlotte
authors: C
authors: Summers
authors: Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK.
authors: Adri
authors: A
authors: Angyal
authors: Department of Medicine, University of Cambridge, Cambridge, UK.
authors: Linsey
authors: L
authors: Porter
authors: Department of Medicine, University of Cambridge, Cambridge, UK.
authors: Jatinder K
authors: JK
authors: Juss
authors: Department of Respiratory Medicine, Portex Unit, Institute of Child Health, University College London, Cambridge, UK.
authors: Christopher
authors: C
authors: O'Callaghan
authors: Department of Medicine, University of Cambridge, Cambridge, UK.
authors: Edwin R
authors: ER
authors: Chilvers
authors: Department of Medicine, University of Cambridge, Cambridge, UK Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK.
authors: Alison M
authors: 0000-0002-9912-1966
authors: AM
authors: Condliffe
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D015550:Cell Degranulation / Q000187:drug effects*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology*; D007150:Immunohistochemistry; D007781:Lactoferrin / Q000378:metabolism; D019272:Leukocyte Elastase / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008854:Microscopy, Electron; D018375:Neutrophil Activation / Q000187:drug effects*; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism; D010972:Platelet Activating Factor / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D044042:Receptors, Formyl Peptide / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D010972:Platelet Activating Factor; D044042:Receptors, Formyl Peptide; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D009195:Peroxidase; D007781:Lactoferrin; D019272:Leukocyte Elastase; D020780:Matrix Metalloproteinase 9
keywords: Airway Epithelium; COPD ÀÜ Mechanisms; Cystic Fibrosis; Innate Immunity; Neutrophil Biology; Respiratory Infection