Mechanism for dexamethasone inhibition of neutrophil migration upon exposure to lipopolysaccharide in vitro: role of neutrophil interleukin-8 release.
The mechanism by which dexamethasone (DEX) inhibits neutrophil (PMN) recruitment to a site of inflammation, such as the newborn lung with bronchopulmonary dysplasia, is not completely understood. The aim of our study was to determine whether DEX inhibits neutrophil-induced neutrophil recruitment by inhibition of interleukin- (IL) 8 release from PMNs, and if there are developmental differences. PMNs isolated from cord blood (CB) and adults (A) were studied. We first measured the effect of DEX (10(-10) to 10(-4) M) on PMN migration to an exogenous IL-8 standard (10(-8) M) using PMNs of CB (n = 3) and A (n = 3), over 1 h in a chemotaxis chamber. Second, we determined the effect of DEX (0 and 10(-10) to 10(-6) M) on IL-8 release (immunoassay) from PMNs of CB (n = 7) or A (n = 7) after incubation with lipopolysaccharide (LPS, 1 ng/mL) for 6 and 18 h. Third, the chemoattractant activity of culture media from the second experiment was studied with and without IL-8 antibody. DEX at concentrations of 10(-10) to 10(-4) M had no direct effect on PMN migration in vitro to an exogenous IL-8 standard. After LPS exposure, IL-8 release was greatly increased for PMNs from CB compared with A. DEX (10(-10) to 10(-4) M) resulted in a dose-dependent inhibition of IL-8 release from PMNs exposed to LPS for 6 and 18 h incubation. Increased PMN migration activity was only found with media of PMNs of CB with no DEX. At 18 h, media-induced migration activity was decreased if DEX (10(-7) M), IL-8 antibody, or DEX (10(-7) M) with IL-8 antibody were present during the incubation with LPS: there was an 88, 86, and 101% reduction in migration activity, respectively. We conclude that DEX inhibits PMN-induced PMN migration, predominantly via inhibition of IL-8 release for PMNs of the newborn. We suggest that a 10-fold lowering of the standard DEX dose may effectively reduce lung inflammation in bronchopulmonary dysplasia.
Zentay
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Division of Neonatal-Perinatal Medicine, Schneider Children's Hospital, LIJMC--The Long Island Campus for the Albert Einstein College of Medicine, New Hyde Park, New York 11040, USA.
Sharaf
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Qadir
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Drafta
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Davidson
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D000328:Adult; D001997:Bronchopulmonary Dysplasia / Q000188:drug therapy; D002465:Cell Movement / Q000187:drug effects; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology*; D005312:Fetal Blood / Q000166:cytology; D006801:Humans; D066298:In Vitro Techniques; D007231:Infant, Newborn; D016209:Interleukin-8 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology / Q000502:physiology
D016209:Interleukin-8; D008070:Lipopolysaccharides; D003907:Dexamethasone