A lung transplant is the last resort treatment for many patients with advanced lung disease. The majority of donated lungs come from donors following brain death (BD). The endothelin axis is upregulated in the blood and lung of the donor after BD resulting in systemic inflammation, lung damage and poor lung graft outcomes in the recipient. Tezosentan (endothelin receptor blocker) improves the pulmonary haemodynamic profile; however, it induces adverse effects on other organs at high doses. Application of ex vivo lung perfusion (EVLP) allows the development of organ-specific hormone resuscitation, to maximise and optimise the donor pool. Therefore, we investigate whether the combination of EVLP and tezosentan administration could improve the quality of donor lungs in a clinically relevant 6-h ovine model of brain stem death (BSD). After 6 h of BSD, lungs obtained from 12 sheep were divided into two groups, control and tezosentan-treated group, and cannulated for EVLP. The lungs were monitored for 6 h and lung perfusate and tissue samples were processed and analysed. Blood gas variables were measured in perfusate samples as well as total proteins and pro-inflammatory biomarkers, IL-6 and IL-8. Lung tissues were collected at the end of EVLP experiments for histology analysis and wet-dry weight ratio (a measure of oedema). Our results showed a significant improvement in gas exchange [elevated partial pressure of oxygen (P = 0.02) and reduced partial pressure of carbon dioxide (P = 0.03)] in tezosentan-treated lungs compared to controls. However, the lungs hematoxylin–eosin staining histology results showed minimum lung injuries and there was no difference between both control and tezosentan-treated lungs. Similarly, IL-6 and IL-8 levels in lung perfusate showed no difference between control and tezosentan-treated lungs throughout the EVLP. Histological and tissue analysis showed a non-significant reduction in wet/dry weight ratio in tezosentan-treated lung tissues (P = 0.09) when compared to control. These data indicate that administration of tezosentan could improve pulmonary gas exchange during EVLP.

中文翻译：

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内皮素受体拮抗剂在离体灌注系统中改善供体肺功能

肺移植是许多晚期肺疾病患者的不得已的治疗方法。捐赠的肺大部分来自脑死亡（BD）后的捐赠者。BD后供血者的血液和肺中的内皮素轴上调，导致全身性炎症，肺损伤和受体的肺移植结果差。Tezosentan（内皮素受体阻滞剂）可改善肺血流动力学。但是，高剂量会引起对其他器官的不良影响。离体肺灌注（EVLP）的应用允许器官特异性激素复苏的发展，以最大化和优化供体库。因此，我们研究了在临床相关的6小时绵羊脑干死亡（BSD）临床相关模型中，EVLP和Tezosentan联合给药是否可以改善供体肺的质量。BSD 6小时后，从12只绵羊获得的肺分为两组，对照组和替佐生坦治疗组，并插管EVLP。监测肺6小时，并处理和分析肺灌注液和组织样品。测量灌注液样品中的血气变量以及总蛋白和促炎生物标记物IL-6和IL-8。在EVLP实验结束时收集肺组织，以进行组织学分析和干湿比（水肿的度量）。我们的研究结果显示，与对照组相比，用地佐生坦治疗的肺部的气体交换[氧分压升高（P = 0.02）和二氧化碳分压降低（P = 0.03）]有了显着改善。然而，肺苏木精-伊红染色的组织学结果表明，肺部损伤最小，对照和经替佐生坦治疗的肺部之间无差异。同样，在整个EVLP中，肺灌注液中的IL-6和IL-8水平在对照组和经替佐生坦治疗的肺之间均无差异。组织学和组织分析表明，与对照组相比，经地佐森坦处理的肺组织的干重比无明显下降（P = 0.09）。这些数据表明替佐生坦的施用可以改善EVLP期间的肺气体交换。09）与对照相比。这些数据表明替佐生坦的施用可以改善EVLP期间的肺气体交换。09）与对照相比。这些数据表明替佐生坦的施用可以改善EVLP期间的肺气体交换。