Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, and.
NIHR Southampton Biomedical Research Centre, Southampton Centre for Biomedical Research, Southampton General Hospital, Southampton, UK.
Am J Respir Crit Care Med. 2020 Jan 1;201(1):83-94. doi: 10.1164/rccm.201901-0214OC.
Viral infections are major drivers of exacerbations and clinical burden in patients with asthma and chronic obstructive pulmonary disease (COPD). IFN-β is a key component of the innate immune response to viral infection. To date, studies of inhaled IFN-β treatment have not demonstrated a significant effect on asthma exacerbations. The dynamics of exogenous IFN-β activity were investigated to inform on future clinical indications for this potential antiviral therapy. Monocyte-derived macrophages (MDMs), alveolar macrophages, and primary bronchial epithelial cells (PBECs) were isolated from healthy control subjects and patients with COPD and infected with influenza virus either prior to or after IFN-β stimulation. Infection levels were measured by the percentage of nucleoprotein 1-positive cells using flow cytometry. Viral RNA shedding and IFN-stimulated gene expression were measured by quantitative PCR. Production of inflammatory cytokines was measured using MSD. Adding IFN-β to MDMs, alveolar macrophages, and PBECs prior to, but not after, infection reduced the percentage of nucleoprotein 1-positive cells by 85, 56, and 66%, respectively ( < 0.05). Inhibition of infection lasted for 24 hours after removal of IFN-β and was maintained albeit reduced up to 1 week in MDMs and 72 hours in PBECs; this was similar between healthy control subjects and patients with COPD. IFN-β did not induce inflammatory cytokine production by MDMs or PBECs but reduced influenza-induced IL-1β production by PBECs. modeling of IFN-β dynamics highlights the potential for intermittent prophylactic doses of exogenous IFN-β to modulate viral infection. This provides important insights to aid the future design of clinical trials of IFN-β in asthma and COPD.
病毒感染是哮喘和慢性阻塞性肺疾病（COPD）患者加重和临床负担的主要驱动因素。IFN-β 是机体对病毒感染固有免疫反应的关键组成部分。迄今为止，吸入 IFN-β 治疗的研究并未显示对哮喘加重有显著影响。本研究旨在通过研究外源性 IFN-β 活性的动力学，为这种潜在抗病毒治疗的未来临床适应证提供信息。从健康对照者和 COPD 患者中分离出单核细胞衍生的巨噬细胞（MDM）、肺泡巨噬细胞和原代支气管上皮细胞（PBEC），并在 IFN-β 刺激之前或之后用流感病毒感染。通过流式细胞术检测核蛋白 1 阳性细胞的百分比来测量感染水平。通过定量 PCR 测量病毒 RNA 脱落和 IFN 刺激基因表达。使用 MSD 测量炎症细胞因子的产生。在感染之前而非之后向 MDM、肺泡巨噬细胞和 PBEC 添加 IFN-β 分别使核蛋白 1 阳性细胞的百分比降低 85%、56%和 66%（<0.05）。在去除 IFN-β后，感染抑制作用持续 24 小时，并且在 MDM 中维持但减少至 1 周，在 PBEC 中维持长达 72 小时；在健康对照者和 COPD 患者之间相似。IFN-β 不会诱导 MDM 或 PBEC 产生炎症细胞因子，但可降低 PBEC 中流感诱导的 IL-1β 产生。IFN-β 动力学的建模突出了间歇性给予外源性 IFN-β 预防剂量来调节病毒感染的潜力。这为未来设计 IFN-β 在哮喘和 COPD 中的临床试验提供了重要的见解。
