Decreased AMP-activated protein kinase (AMPK) function and protective effect of metformin in neonatal rat pups exposed to hyperoxia lung injury.
Decreased AMP-activated protein kinase (AMPK) function and protective effect of metformin in neonatal rat pups exposed to hyperoxia lung injury.
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DOI：
10.14814/phy2.14587
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发表时间：
2020-09
影响因子：
2.5
通讯作者：
Konduri GG
中科院分区：
文献类型：
--
作者：
Yadav A;Rana U;Michalkiewicz T;Teng RJ;Konduri GG
我们研究了一种假设，即在发育的囊状阶段将肺暴露于高氧导致持续的生长停滞和细胞中关键能量传感器5 'AMP活化蛋白激酶（AMPK）的功能障碍。我们将出生后第1 - 10天（P1-P10）的新生大鼠幼仔暴露于≥90%的氧气或对照常氧。幼仔在P4或P10处以安乐死，或在常氧条件下恢复，直至P21处以安乐死。每组中一半的幼仔从P1至P10腹腔内接受AMPK激活剂、二甲双胍或生理盐水。在P10和P21进行肺组织学、形态计量学分析、免疫荧光和免疫印迹，以观察肺结构的变化以及在P4、P10和P21进行AMPK功能的变化。在高氧暴露的幼崽中，在P10和P21时肺中AMPK磷酸化（p-AMPK）降低。在高氧幼崽中，二甲双胍在P4、P10和P21时增加了p-AMPK和PGC-1α的水平，PGC-1 α是调节线粒体生物合成的下游AMPK靶点。肺ATP水平在高氧期间降低，二甲双胍在P10和P21时升高。在P10时，高氧暴露幼仔的径向肺泡计数和肺泡间隔尖端减少，平均线性截距增加，这些变化持续到P21;二甲双胍改善了这些变化。在P10和P21时，高氧暴露幼仔的肺毛细血管数量减少，二甲双胍使其恢复。高氧导致AMPK功能、能量平衡和肺泡简化受损。在高氧诱导的肺损伤大鼠幼崽模型中，AMPK激活剂二甲双胍可改善AMPK功能以及肺泡和血管生长。高氧诱导的新生大鼠肺生长受损与AMP激酶功能降低相关。二甲双胍增加AMP激酶功能并恢复高氧暴露新生大鼠幼崽的肺生长。
We investigated the hypothesis that exposure of lungs at the saccular stage of development to hyperoxia leads to persistent growth arrest and dysfunction of 5’AMP‐activated protein kinase (AMPK), a key energy sensor in the cell. We exposed neonatal rat pups from postnatal day 1‐ day 10 (P1–P10) to ≥90% oxygen or control normoxia. Pups were euthanized at P4 or P10 or recovered in normoxia until euthanasia at P21. Half of the pups in each group received AMPK activator, metformin, or saline intraperitoneally from P1 to P10. Lung histology, morphometric analysis, immunofluorescence, and immunoblots were done for changes in lung structure at P10 and P21 and AMPK function at P4, P10, and P21. Phosphorylation of AMPK (p‐AMPK) was decreased in lungs at P10 and P21 in hyperoxia‐exposed pups. Metformin increased the levels of p‐AMPK and PGC‐1α, a downstream AMPK target which regulates mitochondrial biogenesis, at P4, P10, and P21 in hyperoxia pups. Lung ATP levels decreased during hyperoxia and were increased by metformin at P10 and P21. Radial alveolar count and alveolar septal tips were decreased and mean linear intercept increased in hyperoxia‐exposed pups at P10 and the changes persisted at P21; these were improved by metformin. Lung capillary number was decreased in hyperoxia‐exposed pups at P10 and P21 and was restored by metformin. Hyperoxia leads to impaired AMPK function, energy balance and alveolar simplification. The AMPK activator, metformin improves AMPK function and alveolar and vascular growth in this rat pup model of hyperoxia‐induced lung injury. Hyperoxia‐induced impairment of lung growth in newborn rats is associated with decreased AMP kinase function. Metformin increases AMP Kinase function and restores lung growth in hyperoxia‐exposed neonatal rat pups.
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影响因子：
29
作者：
Gowans GJ;Hawley SA;Ross FA;Hardie DG
通讯作者：
Hardie DG
DOI：
10.1152/ajplung.00176.2014
发表时间：
2015-08-15
影响因子：
4.9
作者：
Datta, Ankur;Kim, Gina A.;Berkelhamer, Sara K.
通讯作者：
Berkelhamer, Sara K.
DOI：
10.1164/rccm.201412-2142pp
发表时间：
2015-07-15
影响因子：
24.7
作者：
Islam, Jessica Y.;Keller, Roberta L.;Moore, Paul E.
通讯作者：
Moore, Paul E.
DOI：
10.1152/ajplung.00200.2012
发表时间：
2013-01-01
影响因子：
4.9
作者：
Teng, Ru-Jeng;Du, Jianhai;Konduri, Girija G.
通讯作者：
Konduri, Girija G.
影响因子：
64.8
作者：
Fulton, D;Gratton, JP;Sessa, WC
通讯作者：
Sessa, WC