Corticosteroid suppression of lipoxin A4 and leukotriene B4 from alveolar macrophages in severe asthma.
BACKGROUND
An imbalance in the generation of pro-inflammatory leukotrienes, and counter-regulatory lipoxins is present in severe asthma. We measured leukotriene B4 (LTB4), and lipoxin A4 (LXA4) production by alveolar macrophages (AMs) and studied the impact of corticosteroids.


METHODS
AMs obtained by fiberoptic bronchoscopy from 14 non-asthmatics, 12 non-severe and 11 severe asthmatics were stimulated with lipopolysaccharide (LPS,10 microg/ml) with or without dexamethasone (10(-6)M). LTB4 and LXA4 were measured by enzyme immunoassay.


RESULTS
LXA4 biosynthesis was decreased from severe asthma AMs compared to non-severe (p < 0.05) and normal subjects (p < 0.001). LXA4 induced by LPS was highest in normal subjects and lowest in severe asthmatics (p < 0.01). Basal levels of LTB4 were decreased in severe asthmatics compared to normal subjects (p < 0.05), but not to non-severe asthma. LPS-induced LTB4 was increased in severe asthma compared to non-severe asthma (p < 0.05). Dexamethasone inhibited LPS-induced LTB4 and LXA4, with lesser suppression of LTB4 in severe asthma patients (p < 0.05). There was a significant correlation between LPS-induced LXA4 and FEV1 (% predicted) (r(s) = 0.60; p < 0.01).


CONCLUSIONS
Decreased LXA4 and increased LTB4 generation plus impaired corticosteroid sensitivity of LPS-induced LTB4 but not of LXA4 support a role for AMs in establishing a pro-inflammatory balance in severe asthma.
Experimental Studies, Airways Disease Section, National Heart & Lung Institute, Imperial College London & Royal Brompton NHS Trust, London, UK.
Pankaj K
PK
Bhavsar
Bruce D
BD
Levy
Mark J
MJ
Hew
Michael A
MA
Pfeffer
Shamsah
S
Kazani
Elliot
E
Israel
Kian Fan
KF
Chung
D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000328:Adult; D001249:Asthma / Q000276:immunology* / Q000503:physiopathology; D001999:Bronchoscopy; D016022:Case-Control Studies; D003907:Dexamethasone / Q000494:pharmacology*; D015536:Down-Regulation; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D007124:Immunoenzyme Techniques; D018836:Inflammation Mediators / Q000378:metabolism*; D007975:Leukotriene B4 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D044045:Lipoxins / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index; D055815:Young Adult
D000305:Adrenal Cortex Hormones; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D044045:Lipoxins; C040527:lipoxin A4; D007975:Leukotriene B4; D003907:Dexamethasone