1 Priority Research Centre for Asthma and Respiratory Diseases, Hunter Medical Research Institute and The University of Newcastle, Newcastle, New South Wales, Australia.
Am J Respir Crit Care Med. 2015 May 1;191(9):1012-23. doi: 10.1164/rccm.201501-0188OC.
Chronic obstructive pulmonary disease (COPD) and influenza virus infections are major global health issues. Patients with COPD are more susceptible to infection, which exacerbates their condition and increases morbidity and mortality. The mechanisms of increased susceptibility remain poorly understood, and current preventions and treatments have substantial limitations.
To characterize the mechanisms of increased susceptibility to influenza virus infection in COPD and the potential for therapeutic targeting.
We used a combination of primary bronchial epithelial cells (pBECs) from COPD and healthy control subjects, a mouse model of cigarette smoke-induced experimental COPD, and influenza infection. The role of the phosphoinositide-3-kinase (PI3K) pathway was characterized using molecular methods, and its potential for targeting assessed using inhibitors.
COPD pBECs were susceptible to increased viral entry and replication. Infected mice with experimental COPD also had more severe infection (increased viral titer and pulmonary inflammation, and compromised lung function). These processes were associated with impaired antiviral immunity, reduced retinoic acid-inducible gene-I, and IFN/cytokine and chemokine responses. Increased PI3K-p110α levels and activity in COPD pBECs and/or mice were responsible for increased infection and reduced antiviral responses. Global PI3K, specific therapeutic p110α inhibitors, or exogenous IFN-β restored protective antiviral responses, suppressed infection, and improved lung function.
The increased susceptibility of individuals with COPD to influenza likely results from impaired antiviral responses, which are mediated by increased PI3K-p110α activity. This pathway may be targeted therapeutically in COPD, or in healthy individuals, during seasonal or pandemic outbreaks to prevent and/or treat influenza.
慢性阻塞性肺疾病（COPD）和流感病毒感染是全球性的重大健康问题。COPD 患者更容易感染，这会使病情恶化，增加发病率和死亡率。其易感性增加的机制仍知之甚少，目前的预防和治疗方法存在很大的局限性。
阐明 COPD 患者对流感病毒感染易感性增加的机制，以及潜在的治疗靶点。
我们使用了 COPD 和健康对照受试者的原代支气管上皮细胞（pBEC）、香烟烟雾诱导的实验性 COPD 小鼠模型和流感感染模型。使用分子方法对磷酸肌醇 3-激酶（PI3K）途径的作用进行了表征，并使用抑制剂评估了其靶向治疗的潜力。
COPD pBEC 易受病毒进入和复制增加的影响。患有实验性 COPD 的感染小鼠也出现了更严重的感染（病毒滴度增加、肺部炎症和肺功能受损）。这些过程与抗病毒免疫受损、视黄酸诱导基因-I 减少以及 IFN/细胞因子和趋化因子反应受损有关。COPD pBEC 和/或小鼠中增加的 PI3K-p110α 水平和活性是导致感染增加和抗病毒反应减弱的原因。全身性 PI3K、特定的 p110α 治疗抑制剂或外源性 IFN-β 恢复了保护性抗病毒反应，抑制了感染并改善了肺功能。
COPD 患者对流感的易感性增加可能是由于抗病毒反应受损所致，而这是由 PI3K-p110α 活性增加介导的。该途径可在 COPD 患者或健康个体中进行靶向治疗，以预防和/或治疗季节性或大流行流感期间的流感。
