title: Oxygen levels determine the ability of glucocorticoids to influence neutrophil survival in inflammatory environments.
abstract: GCs are highly effective in treating a wide range of inflammatory diseases but are limited in their ability to control neutrophilic lung inflammation in conditions such as COPD. Neutrophil apoptosis, a central feature of inflammation resolution, is delayed in response to microenvironmental cues, such as hypoxia and inflammatory cytokines, present at inflamed sites. GCs delay neutrophil apoptosis in vitro, and this may therefore limit the ability of GCs to control neutrophilic inflammation. This study assesses the effect GCs have on hypoxia- and inflammatory cytokine-induced neutrophil survival. Human neutrophils were treated with GCs in the presence or absence of GM-CSF or inflammatory macrophage-CM at a range of oxygen concentrations (21-1% oxygen). Neutrophil apoptosis and survival were assessed by flow cytometry and morphological analysis and neutrophil function, by stimulus-induced shape change and respiratory burst. Dexamethasone promoted neutrophil survival at 21%, 10%, and 5% oxygen but not at 1% oxygen. Interestingly, GM-CSF and inflammatory CM increased neutrophil survival significantly, even at 1% oxygen, with cells remaining functionally active at 96 h. Dexamethasone was able to reduce the prosurvival effect of GM-CSF and inflammatory CM in a hypoxic environment. In conclusion, we found that GCs do not augment neutrophil survival in the presence of severe hypoxia or proinflammatory mediators. This suggests that GCs would not promote neutrophil survival at sites of inflammation under these conditions.
authors: 1.The Queen's Medical Research Institute, University of Edinburgh Medical School, 47 Little France Crescent, Edinburgh, EH16 4TJ, Scotland, UK. John.Marwick@ed.ac.uk.
authors: John A
authors: JA
authors: Marwick
authors: David A
authors: DA
authors: Dorward
authors: Christopher D
authors: CD
authors: Lucas
authors: Katie O
authors: KO
authors: Jones
authors: Tara A
authors: TA
authors: Sheldrake
authors: Sarah
authors: S
authors: Fox
authors: Carol
authors: C
authors: Ward
authors: Joanna
authors: J
authors: Murray
authors: Mairi
authors: M
authors: Brittan
authors: Nik
authors: N
authors: Hirani
authors: Rodger
authors: R
authors: Duffin
authors: Ian
authors: I
authors: Dransfield
authors: Christopher
authors: C
authors: Haslett
authors: Adriano G
authors: AG
authors: Rossi
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D002470:Cell Survival; D003907:Dexamethasone / Q000494:pharmacology*; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D008297:Male; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D010100:Oxygen / Q000276:immunology* / Q000378:metabolism
chemical_list: D005938:Glucocorticoids; D018836:Inflammation Mediators; D003907:Dexamethasone; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D010100:Oxygen
keywords: apoptosis; hypoxia; inflammation; steroids
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