Hsia Connie C W, Ravikumar Priya, Ye Jianfeng
Department of Internal Medicine, Pulmonary and Critical Care Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9034, United States of America.
Department of Internal Medicine, Pulmonary and Critical Care Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9034, United States of America; Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX 75390-9034, United States of America.
Bone. 2017 Jul;100:100-109. doi: 10.1016/j.bone.2017.03.047. Epub 2017 Mar 24.
The lung interfaces with atmospheric oxygen via a large surface area and is perfused by the entire venous return bearing waste products collected from the whole body. It is logical that the lung is endowed with generous anti-oxidative capacity derived both locally and from the circulation. The single-pass pleiotropic alpha-Klotho (αKlotho) protein was discovered when its genetic disruption led to premature multi-organ degeneration and early death. The extracellular domain of αKlotho is cleaved by secretases and released into circulation as endocrine soluble αKlotho protein, exerting wide-ranging cytoprotective effects including anti-oxidation on distant organs including the lung, which exhibits high sensitivity to circulating αKlotho insufficiency. Because circulating αKlotho is derived mainly from the kidney, acute kidney injury (AKI) leads to systemic αKlotho deficiency that in turn increases the risks of pulmonary complications, i.e., edema and inflammation, culminating in the acute respiratory distress syndrome. Exogenous αKlotho increases endogenous anti-oxidative capacity partly via activation of the Nrf2 pathway to protect lungs against injury caused by direct hyperoxia exposure or AKI. This article reviews the current knowledge of αKlotho antioxidation in the lung in the setting of AKI as a model of circulating αKlotho deficiency, an under-recognized condition that weakens innate cytoprotective defenses and contributes to the dysfunction in distant organs.
肺通过大面积与大气中的氧气进行气体交换，并接受来自全身的静脉回流血液灌注，这些血液携带着从全身收集的代谢废物。因此，肺具有强大的抗氧化能力，这种能力既源于局部，也来自循环系统，这是合乎逻辑的。单通道多效性α-klotho（αKlotho）蛋白是在其基因破坏导致过早的多器官退化和早期死亡时被发现的。αKlotho的细胞外结构域被分泌酶切割，作为内分泌可溶性αKlotho蛋白释放到循环系统中，对包括肺在内的远处器官发挥广泛的细胞保护作用，肺对循环中αKlotho不足表现出高度敏感性。由于循环中的αKlotho主要来源于肾脏，急性肾损伤（AKI）会导致全身αKlotho缺乏，进而增加肺部并发症（如水肿和炎症）的风险，最终导致急性呼吸窘迫综合征。外源性αKlotho部分通过激活Nrf2途径增加内源性抗氧化能力，以保护肺部免受直接高氧暴露或AKI所致的损伤。本文综述了以AKI作为循环αKlotho缺乏模型时，αKlotho在肺抗氧化方面的现有知识，这是一种未被充分认识的情况，它削弱了先天性细胞保护防御，并导致远处器官功能障碍。
