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Hypercapnia Suppresses Macrophage Antiviral Activity and Increases Mortality of Influenza A Infection via Akt1
The Journal of Immunology ( IF 4.4 ) Pub Date : 2020-06-15 , DOI: 10.4049/jimmunol.2000085
S Marina Casalino-Matsuda 1 , Fei Chen 2 , Francisco J Gonzalez-Gonzalez 2 , Aisha Nair 2 , Sandra Dib 2 , Alex Yemelyanov 2 , Khalilah L Gates 2 , G R Scott Budinger 2, 3 , Greg J Beitel 4 , Peter H S Sporn 2, 3
Affiliation  

Key Points Hypercapnia increases lung injury and mortality in mice infected with influenza A. Hypercapnia inhibits antiviral responses and increases influenza replication in MØs. Hypercapnic suppression of the MØ antiviral response is mediated by Akt1. Visual Abstract Hypercapnia (HC), elevation of the partial pressure of CO2 in blood and tissues, is a risk factor for mortality in patients with severe acute and chronic lung diseases. We previously showed that HC inhibits multiple macrophage and neutrophil antimicrobial functions and increases the mortality of bacterial pneumonia in mice. In this study, we show that normoxic HC increases viral replication, lung injury, and mortality in mice infected with influenza A virus (IAV). Elevated CO2 increased IAV replication and inhibited antiviral gene and protein expression in macrophages in vivo and in vitro. HC potentiated IAV-induced activation of Akt, whereas specific pharmacologic inhibition or short hairpin RNA knockdown of Akt1 in alveolar macrophages blocked HC’s effects on IAV growth and the macrophage antiviral response. Our findings suggest that targeting Akt1 or the downstream pathways through which elevated CO2 signals could enhance macrophage antiviral host defense and improve clinical outcomes in hypercapnic patients with advanced lung disease.

中文翻译:

高碳酸血症通过 Akt1 抑制巨噬细胞抗病毒活性并增加甲型流感感染的死亡率

要点 高碳酸血症会增加感染甲型流感的小鼠的肺损伤和死亡率。高碳酸血症会抑制抗病毒反应并增加 MØ 中的流感病毒复制。MØ 抗病毒反应的高碳酸血症抑制由 Akt1 介导。视觉摘要 高碳酸血症 (HC) 是血液和组织中 CO2 分压升高,是严重急性和慢性肺病患者死亡的危险因素。我们之前表明,HC 可抑制多种巨噬细胞和嗜中性粒细胞的抗菌功能,并增加小鼠细菌性肺炎的死亡率。在这项研究中,我们表明含氧量正常的 HC 会增加感染甲型流感病毒 (IAV) 的小鼠的病毒复制、肺损伤和死亡率。升高的 CO2 增加了 IAV 复制并抑制了巨噬细胞体内和体外的抗病毒基因和蛋白质表达。HC 增强了 IAV 诱导的 Akt 激活,而肺泡巨噬细胞中 Akt1 的特异性药理学抑制或短发夹 RNA 敲低阻断了 HC 对 IAV 生长和巨噬细胞抗病毒反应的影响。我们的研究结果表明,靶向 Akt1 或升高的 CO2 信号所通过的下游通路可以增强巨噬细胞抗病毒宿主防御并改善患有晚期肺病的高碳酸血症患者的临床结果。
更新日期:2020-06-15
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