Targeting PI3K-p110α Suppresses Influenza Virus Infection in Chronic Obstructive Pulmonary Disease
Targeting PI3K-p110α Suppresses Influenza Virus Infection in Chronic Obstructive Pulmonary Disease
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DOI：
10.1164/rccm.201501-0188oc
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发表时间：
2015-05-01
影响因子：
24.7
通讯作者：
Hansbro, Philip M.
中科院分区：
文献类型：
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作者：
Hsu, Alan Chen-Yu;Starkey, Malcolm R.;Hansbro, Philip M.
理由：慢性阻塞性肺疾病（COPD）和流感病毒感染是主要的全球健康问题。COPD患者更容易感染，这会加重他们的病情并增加发病率和死亡率。易感性增加的机制仍然知之甚少;目前的预防和治疗有很大的局限性。目的：描述COPD患者对流感病毒感染易感性增加的机制以及治疗靶向的潜力。方法：我们使用来自COPD和健康对照受试者的原代支气管上皮细胞（pBEC）的组合，香烟烟雾诱导的实验性COPD的小鼠模型，和流感感染。磷脂酰肌醇-3-激酶（PI 3 K）通路的作用，其特征在于使用分子方法，其潜在的靶向评估使用inhibitors. Measures和主要结果：COPD pBECs容易增加病毒的进入和复制。感染实验性COPD的小鼠也有更严重的感染（病毒滴度和肺部炎症增加，肺功能受损）。这些过程与抗病毒免疫受损、维甲酸诱导基因I减少以及IFN/细胞因子和趋化因子应答相关。COPD pBECs和/或小鼠中PI 3 K-p110 α水平和活性的增加是感染增加和抗病毒反应降低的原因。全球PI 3 K，特异性治疗p110 α抑制剂，或外源性IFN-β恢复保护性抗病毒反应，抑制感染，并改善肺function.Conclusions：COPD患者对流感的易感性增加可能是由于抗病毒反应受损，这是由PI 3 K-p110 α活性增加介导的。在季节性或大流行爆发期间，可以在COPD或健康个体中治疗性靶向该途径以预防和/或治疗流感。
Rationale: 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.Objectives: To characterize the mechanisms of increased susceptibility to influenza virus infection in COPD and the potential for therapeutic targeting.Methods: 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.Measurements and Main Results: 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-p110 alpha levels and activity in COPD pBECs and/or mice were responsible for increased infection and reduced antiviral responses. Global PI3K, specific therapeutic p110 alpha inhibitors, or exogenous IFN-beta restored protective antiviral responses, suppressed infection, and improved lung function.Conclusions: The increased susceptibility of individuals with COPD to influenza likely results from impaired antiviral responses, which are mediated by increased PI3K-p110 alpha activity. This pathway may be targeted therapeutically in COPD, or in healthy individuals, during seasonal or pandemic outbreaks to prevent and/or treat influenza.