Metformin-stimulated AMPK-α1 promotes microvascular repair in acute lung injury
Metformin-stimulated AMPK-α1 promotes microvascular repair in acute lung injury
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DOI：
10.1152/ajplung.00173.2013
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发表时间：
2013-12-01
影响因子：
4.9
通讯作者：
Creighton, Judy R.
中科院分区：
文献类型：
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作者：
Jian, Ming-Yuan;Alexeyev, Mikhail F.;Creighton, Judy R.
Jian M-Y，Alexeyev MF，Wolkowicz PE，Zmiploski JW，Creighton JR.二甲双胍刺激AMPK-α 1促进急性肺损伤微血管修复Am J Physiol Lung Cell Mol Physiol 305：L844-L855，2013.首次发表于2013年10月4日; doi：10.1152/ajplung.00173.2013.-继发于脓毒症的急性肺损伤是脓毒症相关死亡的主要原因。目前的疗法在逆转内皮细胞功能障碍方面无效，内皮细胞功能障碍在血管通透性增加和肺功能受损中起关键作用。AMP激活蛋白激酶（AMPK）是一种重要的分子传感器，用于检测和介导细胞对血管破坏性刺激的适应。在这项研究中，我们试图确定AMPK在解决脓毒症损伤肺中内皮通透性增加的作用。使用内毒素诱导的肺损伤的大鼠模型在体内、使用分离的肺离体和使用培养的大鼠肺微血管内皮细胞（PMVEC）在体外测定AMPK功能。使用N1-（α-D-呋喃核糖基）-5-氨基咪唑-4-甲酰胺或二甲双胍的AMPK刺激降低了LPS诱导的渗透性增加，如通过过滤系数（K-f）测量所确定的，并解决了水肿，如湿干比降低所示。AMPK在内皮细胞对LPS的反应中的作用通过设计用于降低AMPK-α 1亚型在毛细血管内皮细胞中的表达的shRNA来确定。使用PMVEC的渗透性、创伤性和屏障抗性测定将AMPK-α 1鉴定为负责AMPK在肺中的有益作用的分子。我们的研究结果为AMPK-α 1作为脓毒症肺反应中重要的血管修复机制提供了新的证据，并确定了二甲双胍治疗在毛细血管损伤管理中的作用。
Jian M-Y, Alexeyev MF, Wolkowicz PE, Zmijewski JW, Creighton JR. Metformin-stimulated AMPK-alpha 1 promotes microvascular repair in acute lung injury. Am J Physiol Lung Cell Mol Physiol 305: L844-L855, 2013. First published October 4, 2013; doi:10.1152/ajplung.00173.2013.-Acute lung injury secondary to sepsis is a leading cause of mortality in sepsis-related death. Present therapies are not effective in reversing endothelial cell dysfunction, which plays a key role in increased vascular permeability and compromised lung function. AMP-activated protein kinase (AMPK) is a molecular sensor important for detection and mediation of cellular adaptations to vascular disruptive stimuli. In this study, we sought to determine the role of AMPK in resolving increased endothelial permeability in the sepsis-injured lung. AMPK function was determined in vivo using a rat model of endotoxin-induced lung injury, ex vivo using the isolated lung, and in vitro using cultured rat pulmonary microvascular endothelial cells (PMVECs). AMPK stimulation using N1-(alpha-D-ribofuranosyl)-5-aminoimidizole-4-carboxamide or metformin decreased the LPS-induced increase in permeability, as determined by filtration coefficient (K-f) measurements, and resolved edema as indicated by decreased wet-to-dry ratios. The role of AMPK in the endothelial response to LPS was determined by shRNA designed to decrease expression of the AMPK-alpha 1 isoform in capillary endothelial cells. Permeability, wounding, and barrier resistance assays using PMVECs identified AMPK-alpha 1 as the molecule responsible for the beneficial effects of AMPK in the lung. Our findings provide novel evidence for AMPK-alpha 1 as a vascular repair mechanism important in the pulmonary response to sepsis and identify a role for metformin treatment in the management of capillary injury.