Airway Disease, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London, SW3 6LY, UK.
Eur Respir J. 2010 Jul;36(1):178-86. doi: 10.1183/09031936.00158008. Epub 2009 Nov 19.
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 (EC(50)) 2.4+/-1.8 and 3.5+/-2.7 nM, respectively; n = 11-16), GM-CSF (EC(50) 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 (EC(50) 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.
肺巨噬细胞是吸入疗法的靶标。长效β2-激动剂（LABA）和糖皮质激素的组合已被开发用于治疗哮喘和慢性阻塞性肺疾病（COPD）。本研究检测了两种 LABA，沙美特罗和福莫特罗，以及糖皮质激素布地奈德，观察它们对单核细胞衍生的巨噬细胞（MDM）释放细胞因子的影响，以确定在患者中观察到的抗炎作用是否归因于对巨噬细胞的抑制。在 LPS 刺激之前，将 MDM 在不存在或存在 LABA 或布地奈德的情况下孵育。通过 ELISA 测量肿瘤坏死因子（TNF）-α、粒细胞巨噬细胞集落刺激因子（GM-CSF）和 CXC 趋化因子配体（CXCL）8。福莫特罗和沙美特罗抑制 LPS 刺激的 TNF-α释放（平均有效浓度（EC50）分别为 2.4+/-1.8 和 3.5+/-2.7 nM；n = 11-16）、GM-CSF（EC50）分别为 24.6+/-2.1 和 52.4+/-40.8 nM，n = 11-12），但不抑制 LPS 刺激的 MDM 释放 CXCL8。布地奈德抑制所有三种细胞因子的释放（TNF-α：EC50 为 1.2+/-0.4 nM；GM-CSF：0.4+/-0.2 nM；CXCL8：0.4+/-0.1 nM；n = 3-4）。福莫特罗但不是沙美特罗增加了这些细胞中的 cAMP。这些作用被β-肾上腺素能受体拮抗剂普萘洛尔和 ICI118551 减弱。沙美特罗（10(-7) M）还抑制了福莫特罗诱导的 cAMP 和福莫特罗介导的细胞因子释放抑制作用。将布地奈德（0.3 nM）与福莫特罗联合使用可相加抑制 TNF-α释放。LABA 可能以 cAMP 非依赖性方式抑制巨噬细胞炎症细胞因子的释放，并与布地奈德相加作用。
