Exposure to systemic prednisolone for 4 hours reduces ex vivo synthesis of GM-CSF by bronchoalveolar lavage cells and blood mononuclear cells of mild allergic asthmatics.
BACKGROUND
In acute severe asthma, the earliest clinical effects of glucocorticosteroids occur from 4 to 5 h after systemic administration, but the mechanisms are unclear. In persistent asthma, corticosteroids are thought to suppress airway inflammation by modulating the expression of adhesion molecules, enzymes, and leucotactic cytokines, including granulocyte-macrophage colony stimulating factor (GM-CSF). GM-CSF is also overexpressed in the airways of symptomatic asthmatics.


OBJECTIVE
To examine the early effects of systemic corticosteroids on cytokine expression, we investigated whether ex vivo synthesis of GM-CSF is suppressed in the bronchoalveolar lavage (BAL) cells and peripheral blood mononuclear cells (PBMCs) of normal and mild allergic asthmatic subjects obtained 4 h after a single intravenous dose of prednisolone.


METHODS
In a randomized, double-blind, placebo-controlled study, BAL cells and PBMCs were obtained from mild atopic asthmatic patients (n = 9) and normal subjects (n = 9) 4 h after an intravenous bolus dose of 80 mg prednisolone, and cultured for 0-18 h in the presence or absence of lipopolysaccharide (LPS; 10 microg/mL). Enzyme immunoassay was used to assess GM-CSF levels in BAL cell and PBMC culture supernatants, and in BAL fluid.


RESULTS
After placebo, GM-CSF synthesis tended to be higher in BAL cells from asthmatics than in normals. LPS stimulation significantly increased median (interquartile range) GM-CSF synthesis by BAL cells ex vivo from 16.4 (23 to 74) to 35.8 (3-148) pg/106 cells in normals (P < 0.05), and from 59 (9 to 204) to 134 (24-288) pg/106 cells in asthmatics (P < 0.01). After intravenous prednisolone, the rise in GM-CSF production induced in BAL cells by LPS was completely abolished in both subject groups. In PBMCs of placebo-treated asthmatics (but not normals), LPS stimulated median GM-CSF synthesis from 164 (110 to 300) to 314 (235-485) pg/106 cells (P = 0.02), and this was blocked by intravenous prednisolone.


CONCLUSIONS
LPS-stimulated GM-CSF synthesis ex vivo is abolished in BAL cells of mild asthmatic and normal subjects, and in PBMCs of asthmatics, obtained 4 h after a single intravenous dose of prednisolone. Suppression of GM-CSF synthesis in airway and blood leucocytes may contribute to the early clinical efficacy of systemic glucocorticoids in acute allergic asthma.
Cotter
T P
TP
Sackler Institute of Pulmonary Pharmacology, Department of Respiratory Medicine, Kings College School of Medicine and Dentistry, London, UK.
Hood
P P
PP
Costello
J F
JF
Sampson
A P
AP
D000328:Adult; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology* / Q000276:immunology; D001999:Bronchoscopy; D004311:Double-Blind Method; D005938:Glucocorticoids / Q000627:therapeutic use*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism*; D008214:Lymphocytes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D011239:Prednisolone / Q000627:therapeutic use*
D005938:Glucocorticoids; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011239:Prednisolone