Zhao Hailin, Huang Han, Ologunde Rele, Lloyd Dafydd G, Watts Helena, Vizcaychipi Marcela P, Lian Qingquan, George Andrew J T, Ma Daqing
From the Anaesthetics, Pain Medicine, and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom (H.Z., H.H., R.O., D.G.L., H.W., M.P.V., D.M.); Department of Anesthesiology, West China Second Hospital, Sichuan University, Chengdu, China (H.H.); The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China (Q.L.); and Section of Molecular Immunology, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom (A.J.T.G.). Current address: Brunel University London, Uxbridge, Middlesex, United Kingdom (A.J.T.G.).
Anesthesiology. 2015 Jun;122(6):1312-26. doi: 10.1097/ALN.0000000000000664.
Ischemia-reperfusion injury (IRI) of renal grafts may cause remote organ injury including lungs. The authors aimed to evaluate the protective effect of xenon exposure against remote lung injury due to renal graft IRI in a rat renal transplantation model.
For in vitro studies, human lung epithelial cell A549 was challenged with H2O2, tumor necrosis factor-α, or conditioned medium from human kidney proximal tubular cells (HK-2) after hypothermia-hypoxia insults. For in vivo studies, the Lewis renal graft was stored in 4°C Soltran preserving solution for 24 h and transplanted into the Lewis recipient, and the lungs were harvested 24 h after grafting. Cultured lung cells or the recipient after engraftment was exposed to 70% Xe or N2. Phospho (p)-mammalian target of rapamycin (mTOR), hypoxia-inducible factor-1α (HIF-1α), Bcl-2, high-mobility group protein-1 (HMGB-1), TLR-4, and nuclear factor κB (NF-κB) expression, lung inflammation, and cell injuries were assessed.
Recipients receiving ischemic renal grafts developed pulmonary injury. Xenon treatment enhanced HIF-1α, which attenuated HMGB-1 translocation and NF-κB activation in A549 cells with oxidative and inflammatory stress. Xenon treatment enhanced p-mTOR, HIF-1α, and Bcl-2 expression and, in turn, promoted cell proliferation in the lung. Upon grafting, HMGB-1 translocation from lung epithelial nuclei was reduced; the TLR-4/NF-κB pathway was suppressed by xenon treatment; and subsequent tissue injury score (nitrogen vs. xenon: 26 ± 1.8 vs. 10.7 ± 2.6; n = 6) was significantly reduced.
Xenon treatment confers protection against distant lung injury triggered by renal graft IRI, which is likely through the activation of mTOR-HIF-1α pathway and suppression of the HMGB-1 translocation from nuclei to cytoplasm.
肾移植的缺血再灌注损伤（IRI）可能导致包括肺在内的远隔器官损伤。作者旨在评估在大鼠肾移植模型中，氙气暴露对肾移植IRI所致远隔肺损伤的保护作用。
体外研究中，人肺上皮细胞A549在经历低温缺氧损伤后，分别用过氧化氢、肿瘤坏死因子-α或人肾近端小管细胞（HK-2）的条件培养基进行刺激。体内研究中，将Lewis肾移植肾在4°C的Soltran保存液中保存24小时，然后移植到Lewis受体中，移植后24小时收获肺组织。将培养的肺细胞或移植后的受体暴露于70%的氙气或氮气中。评估磷酸化（p）-哺乳动物雷帕霉素靶蛋白（mTOR）、缺氧诱导因子-1α（HIF-1α）、Bcl-2、高迁移率族蛋白-1（HMGB-1）、Toll样受体4（TLR-4）和核因子κB（NF-κB）的表达、肺炎症和细胞损伤情况。
接受缺血性肾移植的受体发生了肺损伤。氙气处理增强了HIF-1α的表达，这减弱了氧化和炎症应激状态下A549细胞中HMGB-1的易位和NF-κB的激活。氙气处理增强了p-mTOR、HIF-1α和Bcl-2的表达，进而促进了肺细胞的增殖。移植后，肺上皮细胞核中HMGB-1的易位减少；氙气处理抑制了TLR-4/NF-κB途径；随后的组织损伤评分（氮气组与氙气组：26±1.8 vs. 10.7±2.6；n = 6）显著降低。
氙气处理可对肾移植IRI引发的远隔肺损伤起到保护作用，这可能是通过激活mTOR-HIF-1α途径以及抑制HMGB-1从细胞核向细胞质的易位来实现的。
