Endothelial Stanniocalcin 1 Maintains Mitochondrial Bioenergetics and Prevents Oxidant-Induced Lung Injury via Toll-Like Receptor 4.
Endothelial Stanniocalcin 1 Maintains Mitochondrial Bioenergetics and Prevents Oxidant-Induced Lung Injury via Toll-Like Receptor 4.
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DOI：
10.1089/ars.2018.7514
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发表时间：
2019-04
影响因子：
6.6
通讯作者：
Yi Zhang;P. Shan;A. Srivastava;Zhenyu Li;Patty J. Lee
中科院分区：
文献类型：
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作者：
Yi Zhang;P. Shan;A. Srivastava;Zhenyu Li;Patty J. Lee
目的氧化剂诱导的内皮损伤在急性肺损伤(ALI)及其继发性呼吸衰竭的发病机制中起重要作用。我们以前的研究揭示了热休克蛋白70(Hsp70)-Toll样受体4(TLR4)信号通路介导的肺内皮细胞内源性抗氧化和保护途径。然而，下游的效应器机制仍然不清楚。史丹尼卡素1(STC1)被报道在肺等组织中介导抗氧化反应。然而，STC1表达的调节以及它在肺中的生理功能尚不清楚。我们试图在体内外阐明TLR4和STC1在高氧性肺损伤中的关系，并明确STC1在肺内皮细胞中的功能作用。结果TLR4基因敲除小鼠肺组织和TLR4基因敲除小鼠原代肺内皮细胞中STC1表达显著降低。STC1的过度表达与内皮细胞保护有关，而表达降低或表达不足与氧化剂诱导的损伤和死亡增加有关。热休克蛋白70-TLR4-核因子-活化B细胞轻链增强子(NF-κB)信号介导肺和血管内皮细胞STC1s的诱导。我们还通过TLR4证明了线粒体相关的STC1在维持正常糖酵解、线粒体生物能量学和线粒体钙水平方面的先前未知的作用。到目前为止，STC1在氧化剂诱导的ALI中的生理作用尚未确定。此外，我们的研究表明，STC1受TLR4调节，在无菌氧化剂诱导的肺损伤中发挥肺和内皮保护作用。结论我们的研究揭示了一种新的TLR4-STC1介导的线粒体途径，它在肺内皮细胞中具有动态平衡和氧化诱导的细胞保护功能。
AIMS Oxidant-induced endothelial injury plays a critical role in the pathogenesis of acute lung injury (ALI) and subsequent respiratory failure. Our previous studies revealed an endogenous antioxidant and protective pathway in lung endothelium mediated by heat shock protein 70 (Hsp70)-toll-like receptor 4 (TLR4) signaling. However, the downstream effector mechanisms remained unclear. Stanniocalcin 1 (STC1) has been reported to mediate antioxidant responses in tissues such as the lungs. However, regulators of STC1 expression as well as its physiological function in the lungs were unknown. We sought to elucidate the relationship between TLR4 and STC1 in hyperoxia-induced lung injury in vitro and in vivo and to define the functional role of STC1 expression in lung endothelium. RESULTS We identified significantly decreased STC1 expression in TLR4 knockout mouse lungs and primary lung endothelium isolated from TLR4 knockout mice. Overexpression of STC1 was associated with endothelial cytoprotection, whereas decreased or insufficient expression was associated with increased oxidant-induced injury and death. An Hsp70-TLR4-nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) signal mediates STC1 induction in the lungs and endothelial cells. We also demonstrated a previously unrecognized role for mitochondrial-associated STC1, via TLR4, in maintaining normal glycolysis, mitochondrial bioenergetics, and mitochondrial calcium levels. INNOVATION To date, a physiological role for STC1 in oxidant-induced ALI has not been identified. In addition, our studies show that STC1 is regulated by TLR4 and exerts lung and endothelial protection in response to sterile oxidant-induced lung injury. CONCLUSIONS Our studies reveal a novel TLR4-STC1-mediated mitochondrial pathway that has homeostatic as well as oxidant-induced cytoprotective functions in lung endothelium.