1 Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut.
2 Division of Endocrinology, Department of Medicine, College of Medicine, University of Arizona, Tucson, Arizona.
Antioxid Redox Signal. 2019 May 20;30(15):1775-1796. doi: 10.1089/ars.2018.7514. Epub 2018 Oct 25.
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.
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.
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.
Our studies reveal a novel TLR4-STC1-mediated mitochondrial pathway that has homeostatic as well as oxidant-induced cytoprotective functions in lung endothelium.
氧化应激诱导的内皮损伤在急性肺损伤（ALI）发病机制及随后的呼吸衰竭中起着关键作用。我们之前的研究揭示了肺内皮中由热休克蛋白 70（Hsp70）- toll 样受体 4（TLR4）信号介导的内源性抗氧化和保护途径。然而，下游效应机制尚不清楚。研究表明，钙调蛋白 1（STC1）可介导肺等组织的抗氧化反应。然而，STC1 表达的调节因子及其在肺部的生理功能尚不清楚。我们旨在阐明 TLR4 与体外和体内高氧诱导肺损伤中 STC1 之间的关系，并确定 STC1 表达在肺内皮中的功能作用。
我们发现 TLR4 敲除小鼠肺组织和 TLR4 敲除小鼠原代肺内皮中 STC1 表达明显降低。STC1 的过表达与内皮细胞保护作用有关，而表达减少或不足与氧化应激诱导的损伤和死亡增加有关。Hsp70-TLR4-核因子 kappa-轻链增强子的活化 B 细胞（NFκB）信号介导 STC1 在肺和内皮细胞中的诱导。我们还证明了 TLR4 通过线粒体相关 STC1 在维持正常糖酵解、线粒体生物能学和线粒体钙水平方面的以前未被认识的作用。
迄今为止，STC1 在氧化应激诱导的 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，在应对非特异性氧化应激诱导的肺损伤时发挥肺和内皮保护作用。
我们的研究揭示了一种新的 TLR4-STC1 介导的线粒体途径，该途径在肺内皮中具有稳态和氧化应激诱导的细胞保护功能。
