miRNA-200c-3p is crucial in acute respiratory distress syndrome.
miRNA-200c-3p is crucial in acute respiratory distress syndrome.
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miRNA-200c-3p 在急性呼吸窘迫综合征中至关重要
DOI：
10.1038/celldisc.2017.21
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发表时间：
2017
期刊：
影响因子：
33.5
通讯作者：
Jiang C
中科院分区：
文献类型：
--
作者：
Liu Q;Du J;Yu X;Xu J;Huang F;Li X;Zhang C;Li X;Chang J;Shang D;Zhao Y;Tian M;Lu H;Xu J;Li C;Zhu H;Jin N;Jiang C
已知流感感染和肺炎通过诱导急性呼吸窘迫综合征（ARDS）而导致其大部分死亡，所述急性呼吸窘迫综合征是急性肺损伤（ALI）的最严重形式。血管紧张素转换酶2（ACE2）是肾素-血管紧张素系统中血管紧张素II的负调节因子，在ALI中起着重要作用。ACE 2表达下调与禽流感病毒、SARS冠状病毒、呼吸道合胞病毒和脓毒症等引起的ALI或ARDS有关。然而，ACE2在ALI中表达降低的分子机制尚不清楚。在此，我们发现禽流感病毒H5N1诱导miR-200c-3p的上调，然后证明其靶向ACE2的3 ′-非翻译区。随后，我们发现H5N1病毒感染过程中非结构蛋白1和病毒RNA参与了miR-200c-3p的诱导。此外，病毒双链RNA的合成类似物（poly（I：C））、细菌脂多糖和脂磷壁酸都可以以核因子-κ B依赖的方式显著增加miR-200 c-3p的表达。此外，在重症肺炎患者中观察到miR-200c-3p的血浆水平显著升高。抑制miR-200c-3p可改善H5N1病毒感染诱导的急性肺损伤，提示miR-200c-3p是一个潜在的治疗靶点。因此，我们确定了病毒和细菌肺部感染诱导的ALI/ARDS的共同机制，即通过核因子-κ B依赖性上调miR-200 c-3p以降低ACE2水平，从而导致血管紧张素II水平升高并随后导致肺损伤。
Influenza infection and pneumonia are known to cause much of their mortality by inducing acute respiratory distress syndrome (ARDS), which is the most severe form of acute lung injury (ALI). Angiotensin-converting enzyme 2 (ACE2), which is a negative regulator of angiotensin II in the renin–angiotensin system, has been reported to have a crucial role in ALI. Downregulation of ACE2 is always associated with the ALI or ARDS induced by avian influenza virus, severe acute respiratory syndrome-coronavirus, respiratory syncytial virus and sepsis. However, the molecular mechanism of the decreased expression of ACE2 in ALI is unclear. Here we show that avian influenza virus H5N1 induced the upregulation of miR-200c-3p, which was then demonstrated to target the 3′-untranslated region of ACE2. Then, we found that nonstructural protein 1 and viral RNA of H5N1 contributed to the induction of miR-200c-3p during viral infection. Additionally, the synthetic analog of viral double-stranded RNA (poly (I: C)), bacterial lipopolysaccharide and lipoteichoic acid can all markedly increase the expression of miR-200c-3p in a nuclear factor-κB-dependent manner. Furthermore, markedly elevated plasma levels of miR-200c-3p were observed in severe pneumonia patients. The inhibition of miR-200c-3p ameliorated the ALI induced by H5N1 virus infection in vivo, indicating a potential therapeutic target. Therefore, we identify a shared mechanism of viral and bacterial lung infection-induced ALI/ARDS via nuclear factor-κB-dependent upregulation of miR-200c-3p to reduce ACE2 levels, which leads increased angiotensin II levels and subsequently causes lung injury.