Effects of formoterol and salmeterol on cytokine release from monocyte-derived macrophages

被引:50
作者
Donnelly, L. E. [1 ]
Tudhope, S. J. [1 ]
Fenwick, P. S. [1 ]
Barnes, P. J. [1 ]
机构
[1] Univ London Imperial Coll Sci Technol & Med, Airway Dis Natl Heart & Lung Inst, London SW3 6LY, England
关键词
Budesonide; inflammation; long-acting beta(2)-agonists; macrophage; tumour necrosis factor-alpha; OBSTRUCTIVE PULMONARY-DISEASE; SMOOTH-MUSCLE-CELLS; BRONCHIAL EPITHELIAL-CELLS; LONG-ACTING BETA(2)-AGONISTS; INHALED COMBINATION THERAPY; NECROSIS-FACTOR-ALPHA; NF-KAPPA-B; GLUCOCORTICOID-RECEPTOR; ALVEOLAR MACROPHAGE; PROTEIN-KINASE;
D O I
10.1183/09031936.00158008
中图分类号
R56 [呼吸系及胸部疾病];
学科分类号
摘要
Pulmonary macrophages are a target for inhaled therapies. Combinations of long-acting beta(2)-agonists (LABA) and glucocorticosteroids have been developed for asthma and chronic obstructive pulmonary disease (COPD). This study examined two LABA, salmeterol and formoterol, and the glucocorticosteroid, budesonide, on cytokine release from monocyte-derived macrophages (MDM) to determine whether anti-inflammatory effects observed in patients are due to inhibition of macrophages. MDM were incubated in the absence or presence of LABA or budesonide prior to stimulation with lipopolysaccharide (LPS). Tumour necrosis factor (TNF)-alpha, granulocyte macrophage-colony stimulating factor (GM-CSF) and CXC chemokine ligand (CXCL) 8 were measured by ELISA. Formoterol and salmeterol inhibited LPS-stimulated release of TNF-alpha (mean effective concentration (EC50) 2.4 +/- 1.8 and 3.5 +/- 2.7 nM, respectively; n=11-16), GM-CSF (EC50 24.6 +/- 2.1 and 52.4 +/- 40.8 nM, respectively, n=11-12) but not CXCL8 from LPS-stimulated MDM. Budesonide inhibited release of all three cytokines (EC50 TNF-alpha: 1.2 +/- 0.4 nM; GM-CSF: 0.4 +/- 0.2 nM; CXCL8: 0.4 +/- 0.1 nM; n=3-4). Formoterol but not salmeterol elevated cAMP in these cells. These effects were attenuated by beta-adrenoceptor antagonists, propranolol and ICI118551. Salmeterol (10(-7) M) also inhibited formoterol-induced cAMP and formoterol-mediated attenuation of cytokine release. Combining budesonide (0.3 nM) with formoterol, inhibited TNF-alpha release additively. LABA may inhibit inflammatory cytokine release from macrophages in a cAMP-independent manner and act additively with budesonide.
引用
收藏
页码:178 / 186
页数:9
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