Antiasthmatic activity of a macrolide antibiotic, roxithromycin: analysis of possible mechanisms in vitro and in vivo.
This study was designed to examine the possible mechanisms by which macrolide antibiotics favorably influence the clinical course of asthmatic patients. In the first set of experiments, we investigated the effect of roxithromycin (RXM), a newly synthesized macrolide antibiotic, on in vitro cytokine secretion by mitogen-activated human peripheral blood leukocytes. RXM suppressed the secretion of T cell cytokine interleukins (IL) 2-4 and monocyte cytokine tumor necrosis factor alpha. This inhibitory effects on cytokine secretion was dose dependent and firstly noted at a concentration of as little as 0.5 microgram/ml which is much lower than therapeutic blood levels. In the second part of experiments, we examined the influence of RXM on cytokine appearance in mouse lung extract induced by lipopolysaccharide (LPS) inhalation and on bronchial responsiveness to methacholine in LPS-treated mice. As compared with mice pretreated with phosphate-buffered saline, RXM administered orally at a single dose of 5 mg/kg once a day for 21 days inhibited the appearance of IL-3, IL-4, IL-5, and tumor necrosis factor alpha in aqueous lung extracts. Pretreatment with RXM also decreased the bronchial responsiveness to methacholine induced by intratracheal injection of LPS. We conclude that the attenuating effect of macrolide antibiotics on asthmatic syndromes might be explained partially by their inhibitory effects on cytokine secretion from leukocytes.
Konno
S
S
1st Department of Internal Medicine, School of Medicine, Showa University, Tokyo, Japan.
Asano
K
K
Kurokawa
M
M
Ikeda
K
K
Okamoto
K
K
Adachi
M
M
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology; D002478:Cells, Cultured; D002794:Choline / Q000031:analogs & derivatives; D016207:Cytokines / Q000187:drug effects*; D004731:Endotoxins; D006801:Humans; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides; D008168:Lung / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D012129:Respiratory Function Tests; D015575:Roxithromycin / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D000906:Antibodies; D016207:Cytokines; D004731:Endotoxins; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C017506:methylcholine; D015575:Roxithromycin; D002794:Choline