Yan S F, Ogawa S, Stern D M, Pinsky D J
Department of Physiology, Columbia University, College of Physicians and Surgeons, New York, New York, USA.
Kidney Int. 1997 Feb;51(2):419-25. doi: 10.1038/ki.1997.56.
The endothelial cell response to hypoxia involves a range of adaptive mechanisms that reflect an active response of the cell's biosynthetic and metabolic apparatus. Hypoxia-mediated suppression of endothelial barrier function, resulting in increased vascular leakage, is likely to contribute to pulmonary and cerebral edema associated with high altitude and is closely associated with a fall in intracellular cyclic AMP levels. Buttressing of this second messenger pathway in the endothelium using membrane permeant cyclic AMP analogs prevents increased vascular leakage due to hypoxia. Application of this principle to organ preservation has shown that supplementation with cyclic AMP analogs or inhibition of endogenous cAMP metabolism enables extension of the time a harvested organ can remain extracorporeally, after which transplantation is successful. The underlying mechanism through which cyclic AMP exerts its effects appears to be maintenance of vascular homeostasis in the graft. A distinct adaptive mechanism triggered in the endothelium by hypoxia is expression of the cytokine interleukin-6 (IL-6) by a novel mechanism involving transcription driven by the nuclear factor IL-6 (NF-IL-6) DNA binding site in the promoter. IL-6 may exert protective effects on vascular function, thereby limiting vascular injury by a different mechanism than those recruited by elevated cAMP levels. These studies provide insights into tow independent mechanisms through which endothelium responds to oxygen deprivation, and suggest possible new approaches to attentuate vascular injury associated with ischemia.
内皮细胞对缺氧的反应涉及一系列适应性机制，这些机制反映了细胞生物合成和代谢装置的积极反应。缺氧介导的内皮屏障功能抑制，导致血管通透性增加，可能导致与高原相关的肺水肿和脑水肿，并且与细胞内环状AMP水平下降密切相关。使用膜通透性环状AMP类似物在内皮中支持这一第二信使途径可防止因缺氧导致的血管通透性增加。将这一原理应用于器官保存已表明，补充环状AMP类似物或抑制内源性cAMP代谢能够延长收获的器官在体外可保存的时间，之后移植会成功。环状AMP发挥其作用的潜在机制似乎是维持移植物中的血管稳态。缺氧在内皮中触发的一种独特的适应性机制是通过一种新机制表达细胞因子白细胞介素-6（IL-6），该机制涉及由启动子中的核因子IL-6（NF-IL-6）DNA结合位点驱动的转录。IL-6可能对血管功能发挥保护作用，从而通过一种不同于cAMP水平升高所引发的机制来限制血管损伤。这些研究深入了解了内皮细胞对缺氧作出反应的两种独立机制，并提出了减轻与缺血相关的血管损伤的可能新方法。
