Research Centre on Asthma and COPD, University of Ferrara, Ferrara, Italy.
National Heart and Lung Institute, Imperial College London, London, UK.
Eur J Pharmacol. 2021 Feb 15;893:173839. doi: 10.1016/j.ejphar.2020.173839. Epub 2020 Dec 24.
Inhaled corticosteroids (ICS) are recommended treatments for all degrees of asthma severity and in combination with bronchodilators are indicated for COPD patients with a history of frequent exacerbations. However, the long-term side effects of glucocorticoids (GCs) may include increased risk of respiratory infections, including viral triggered exacerbations. Rhinovirus (RV) infection is the main trigger of asthma and COPD exacerbations. Thus, we sought to explore the influence of GCs on viral replication. We demonstrate the ICS fluticasone propionate (FP) and two selective non-steroidal (GRT7) and steroidal (GRT10) glucocorticoid receptor (GR) agonists significantly suppress pro-inflammatory (IL-6 and IL-8) and antiviral (IFN-λ1) cytokine production and the expression of the interferon-stimulated genes (ISGs) OAS and viperin in RV-infected bronchial epithelial cells, with a consequent increase of viral replication. We also show that FP, GRT7 and GRT10 inhibit STAT1 Y701 and/or STAT2 Y690 phosphorylation and ISG mRNA induction following cell stimulation with recombinant IFN-β. In addition, we investigated the effects of the ICS budesonide (BD) and the long-acting β2 agonist (LABA) formoterol, alone or as an ICS/LABA combination, on RV-induced ISG expression and viral replication. Combination of BD/formoterol increases the suppression of OAS and viperin mRNA observed with both BD and formoterol alone, but an increase in viral RNA was only observed with BD treatment and not with formoterol. Overall, we provide evidence of an impairment of the innate antiviral immune response by GC therapy and the potential for GCs to enhance viral replication. These findings could have important clinical implications.
吸入性皮质类固醇（ICS）被推荐用于治疗所有严重程度的哮喘，并且与支气管扩张剂联合用于有频繁恶化史的 COPD 患者。然而，糖皮质激素（GCs）的长期副作用可能包括增加呼吸道感染的风险，包括病毒诱发的恶化。鼻病毒（RV）感染是哮喘和 COPD 恶化的主要诱因。因此，我们试图探索 GCs 对病毒复制的影响。我们证明 ICS 丙酸氟替卡松（FP）和两种选择性非甾体（GRT7）和甾体（GRT10）糖皮质激素受体（GR）激动剂可显著抑制促炎（IL-6 和 IL-8）和抗病毒（IFN-λ1）细胞因子的产生和 RV 感染的支气管上皮细胞中的干扰素刺激基因（ISGs）OAS 和 viperin 的表达，从而导致病毒复制增加。我们还表明，FP、GRT7 和 GRT10 抑制重组 IFN-β 刺激细胞后 STAT1 Y701 和/或 STAT2 Y690 磷酸化和 ISG mRNA 的诱导。此外，我们研究了 ICS 布地奈德（BD）和长效β2 激动剂（LABA）福莫特罗单独或作为 ICS/LABA 联合治疗对 RV 诱导的 ISG 表达和病毒复制的影响。BD/formoterol 的联合使用增加了与 BD 和 formoterol 单独使用相比观察到的 OAS 和 viperin mRNA 的抑制，但仅在用 BD 治疗时观察到病毒 RNA 的增加，而在用 formoterol 治疗时则没有。总的来说，我们提供了 GC 治疗会损害先天抗病毒免疫反应以及 GCs 可能增强病毒复制的证据。这些发现可能具有重要的临床意义。
