Lung and Allergy Research Centre, School of Medicine, The University of Queensland, Princess Alexandra Hospital Clinical Division, Woolloongabba, Queensland, Australia.
PLoS One. 2011;6(11):e27898. doi: 10.1371/journal.pone.0027898. Epub 2011 Nov 18.
Asthma is a chronic inflammatory airways disease in which respiratory viral infections frequently trigger exacerbations. Current treatment of asthma with combinations of inhaled corticosteroids and long acting beta2 agonists improves asthma control and reduces exacerbations but what impact this might have on innate anti-viral immunity is unclear. We investigated the in vitro effects of asthma drugs on innate anti-viral immunity. Peripheral blood mononuclear cells (PBMC) from healthy and asthmatic donors were cultured for 24 hours with the Toll-like receptor 7 agonist, imiquimod, or rhinovirus 16 (RV16) in the presence of budesonide and/or formoterol. Production of proinflammatory cytokines and expression of anti-viral intracellular signalling molecules were measured by ELISA and RT-PCR respectively. In PBMC from healthy donors, budesonide alone inhibited IP-10 and IL-6 production induced by imiquimod in a concentration-dependent manner and the degree of inhibition was amplified when budesonide and formoterol were used in combination. Formoterol alone had little effect on these parameters, except at high concentrations (10⁻⁶ M) when IL-6 production increased. In RV16 stimulated PBMC, the combination of budesonide and formoterol inhibited IFNα and IP-10 production in asthmatic as well as healthy donors. Combination of budesonide and formoterol also inhibited RV16-stimulated expression of the type I IFN induced genes myxovirus protein A and 2', 5' oligoadenylate synthetise. Notably, RV16 stimulated lower levels of type Myxovirus A and oligoadenylate synthase in PBMC of asthmatics than control donors. These in vitro studies demonstrate that combinations of drugs commonly used in asthma therapy inhibit both early pro-inflammatory cytokines and key aspects of the type I IFN pathway. These findings suggest that budesonide and formoterol curtail excessive inflammation induced by rhinovirus infections in patients with asthma, but whether this inhibits viral clearance in vivo remains to be determined.
哮喘是一种慢性炎症性气道疾病，呼吸道病毒感染常引发其恶化。目前，采用皮质类固醇吸入剂和长效β2 受体激动剂联合治疗哮喘，可改善哮喘控制并减少恶化，但这种治疗对固有抗病毒免疫的影响尚不清楚。我们研究了哮喘药物对固有抗病毒免疫的体外作用。用 Toll 样受体 7 激动剂咪喹莫特或鼻病毒 16（RV16）刺激健康供体和哮喘供体的外周血单个核细胞（PBMC）24 小时，同时加入布地奈德和/或福莫特罗。通过 ELISA 和 RT-PCR 分别测量促炎细胞因子的产生和抗病毒细胞内信号分子的表达。在健康供体的 PBMC 中，布地奈德可浓度依赖性地抑制咪喹莫特诱导的 IP-10 和 IL-6 的产生，而布地奈德与福莫特罗联合使用时抑制程度增强。福莫特罗单独对这些参数几乎没有影响，除了在高浓度（10⁻⁶ M）时会增加 IL-6 的产生。在 RV16 刺激的 PBMC 中，布地奈德和福莫特罗联合抑制了哮喘患者和健康供体的 IFNα 和 IP-10 的产生。联合用药还抑制了布地奈德和福莫特罗刺激的 I 型干扰素诱导基因的表达，包括粘液病毒蛋白 A 和 2'，5'寡聚腺苷酸合成酶。值得注意的是，RV16 刺激哮喘患者的 PBMC 产生的 I 型干扰素诱导基因 Myxovirus A 和寡聚腺苷酸合成酶的水平低于对照供体。这些体外研究表明，常用于哮喘治疗的药物联合抑制了早期促炎细胞因子和 I 型干扰素途径的关键方面。这些发现表明，布地奈德和福莫特罗抑制了哮喘患者鼻病毒感染引起的过度炎症，但这种抑制是否能抑制体内病毒清除仍有待确定。
