Cytidine 5'-Diphosphocholine Corrects Alveolar Type II Cell Mitochondrial Dysfunction in Influenza-infected Mice.
Cytidine 5'-Diphosphocholine Corrects Alveolar Type II Cell Mitochondrial Dysfunction in Influenza-infected Mice.
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胞苷 5-二磷酸胆碱可纠正流感感染小鼠的肺泡 II 型细胞线粒体功能障碍。
DOI：
10.1165/rcmb.2021-0512oc
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发表时间：
2022
影响因子：
6.4
通讯作者：
Davis,IanC
中科院分区：
文献类型：
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作者：
Doolittle,LaurenM;Binzel,Katherine;Nolan,KatherineE;Craig,Kelsey;Rosas,LuciaE;Bernier,MatthewC;Joseph,LisaM;Woods,ParkerS;Knopp,MichaelV;Davis,IanC
甲型流感病毒（IAV）感染小鼠急性呼吸窘迫综合征（ARDS）的发生与肺泡II型上皮细胞新磷脂酰胆碱合成的抑制有关，而磷脂酰胆碱前体胞苷5′-二磷酸胆碱（dp -胆碱）可减轻IAV诱导的小鼠急性呼吸窘迫综合征。我们假设抑制磷脂酰胆碱合成也会影响ATII细胞线粒体的功能。为了验证这一假设，对成年C57BL/6小鼠进行了1万pfu/小鼠流感A/WSN/33 （H1N1）的鼻内接种。用病毒稀释液模拟感染对照小鼠。小鼠接种后（dpi） 1 ~ 5 d，每天1次，分别给予生理盐水溶液或cp -胆碱（100 μg/小鼠）。采用标准肺消化方案在6 dpi时分离ATII细胞，分析线粒体功能。IAV感染增加了肺部对葡萄糖类似物氟脱氧葡萄糖f18的摄取，并导致从氧化磷酸化到有氧糖酵解的转变，这是ATII细胞合成ATP的主要手段。感染还导致ATII细胞线粒体去极化和收缩，PGC-1α上调，心磷脂含量降低，mitofusin 1、OPA1、DRP1、电子传递链复合物I和IV以及心磷脂合成相关酶的表达降低。每日使用cdp -胆碱治疗可防止IAV感染引起的氧化磷酸化、线粒体膜电位和心磷脂合成的下降，但不能完全逆转糖酵解转变。cdp -胆碱也不能阻止感染引起的线粒体蛋白表达改变。综上所述，我们的数据显示IAV感染后ATII细胞线粒体功能障碍是由新磷脂合成受损引起的，但糖酵解转移不是。
Development of acute respiratory distress syndrome (ARDS) in influenza A virus (IAV)-infected mice is associated with inhibition of ATII (alveolar type II) epithelial cellde novophosphatidylcholine synthesis, and administration of the phosphatidylcholine precursor cytidine 5′-diphosphocholine (CDP-choline) attenuates IAV-induced acute respiratory distress syndrome in mice. We hypothesized inhibition of phosphatidylcholine synthesis would also impact the function of ATII cell mitochondria. To test this hypothesis, adult C57BL/6 mice of both sexes were inoculated intranasally with 10,000 pfu/mouse influenza A/WSN/33 (H1N1). Control mice were mock-infected with virus diluent. Mice were treated with saline vehicle or CDP-choline (100 μg/mouse i.p.) once daily from 1 to 5 days postinoculation (dpi). ATII cells were isolated by a standard lung digestion protocol at 6 dpi for analysis of mitochondrial function. IAV infection increased uptake of the glucose analog fludeoxyglucose F 18 by the lungs and caused a switch from oxidative phosphorylation to aerobic glycolysis as a primary means of ATII cell ATP synthesis by 6 dpi. Infection also induced ATII cell mitochondrial depolarization and shrinkage, upregulation of PGC-1α, decreased cardiolipin content, and reduced expression of mitofusin 1, OPA1, DRP1, complexes I and IV of the electron transport chain, and enzymes involved in cardiolipin synthesis. Daily CDP-choline treatment prevented the declines in oxidative phosphorylation, mitochondrial membrane potential, and cardiolipin synthesis resulting from IAV infection but did not fully reverse the glycolytic shift. CDP-choline also did not prevent the alterations in mitochondrial protein expression resulting from infection. Taken together, our data show ATII cell mitochondrial dysfunction after IAV infection results from impairedde novophospholipid synthesis, but the glycolytic shift does not.