Atkinson Samantha K, Morice Alyn H, Sadofsky Laura R
Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, University of Hull, Hull, UK.
Respiratory Research Group, Hull York Medical School, Castle Hill Hospital, Cottingham, UK.
ERJ Open Res. 2020 Oct 19;6(4). doi: 10.1183/23120541.00159-2020. eCollection 2020 Oct.
Human rhinovirus (RV) is the most common cause of upper respiratory tract infection (URTI) and chronic airway disease exacerbation. Cough is present in 50-80% of URTI cases, accompanied by heightened airway hypersensitivity, yet no effective treatment currently exists for this infectious cough. The mechanism by which RV causes cough and airway hypersensitivity in URTI is still unknown despite recent advances in potential therapies for chronic cough. The effect of RV-16 infection (MOI 1) on intracellular ATP stores and ATP release in A549 alveolar epithelial cells was measured. RV-16 infection was found to significantly increase (by 50% from basal at 24 h) followed by decrease (by 50% from basal at 48 and 72 h) intracellular ATP concentrations, while increasing ATP release (from 72 h) independently of secondary stimulation. This effect was mimicked by intercellular adhesion molecule 1 receptor binding alone through ultraviolet-inactivated sham control. In addition, RV-16-infected cells became more sensitive to secondary stimulation with both hypotonic and isotonic solutions, suggestive of a hypersensitive response. These responses were not mediated increased TRPV4 or pannexin-1 whole-cell expression as determined by Western blotting. Interestingly, the increased ATP release seen was not a result of increased mitochondrial ATP production. Thus, this is the first report demonstrating that RV-16 infection of airway epithelial cells causes hypersensitivity by increasing ATP release. These finding provide a novel insight into the process by which viruses may cause cough and identify a potential target for treatment of viral and post-viral cough.
人鼻病毒（RV）是上呼吸道感染（URTI）和慢性气道疾病加重的最常见原因。50%-80%的URTI病例伴有咳嗽，并伴有气道高敏反应增强，但目前尚无针对这种感染性咳嗽的有效治疗方法。尽管慢性咳嗽的潜在治疗方法最近取得了进展，但RV在URTI中引起咳嗽和气道高敏反应的机制仍然未知。测量了RV-16感染（感染复数为1）对A549肺泡上皮细胞内ATP储存和ATP释放的影响。发现RV-16感染显著增加（在24小时时比基础水平增加50%），随后降低（在48小时和72小时时比基础水平降低50%）细胞内ATP浓度，同时增加ATP释放（从72小时开始），且与二次刺激无关。单独通过紫外线灭活的假对照，细胞间黏附分子1受体结合可模拟这种效应。此外，RV-16感染的细胞对低渗和等渗溶液的二次刺激变得更加敏感，提示存在高敏反应。通过蛋白质印迹法测定，这些反应并非由TRPV4或泛连接蛋白-1全细胞表达增加介导。有趣的是，观察到的ATP释放增加并非线粒体ATP产生增加的结果。因此，这是第一份证明气道上皮细胞的RV-16感染通过增加ATP释放导致高敏反应的报告。这些发现为病毒可能引起咳嗽的过程提供了新的见解，并确定了治疗病毒感染性咳嗽和病毒感染后咳嗽的潜在靶点。
