Thromboxane and histamine mediate PVR elevation during xenogeneic pig lung perfusion with human blood
Thromboxane and histamine mediate PVR elevation during xenogeneic pig lung perfusion with human blood
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DOI：
10.1111/xen.12458
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发表时间：
2019-03-01
影响因子：
3.9
通讯作者：
Pierson, Richard N., III
中科院分区：
文献类型：
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作者：
Burdorf, Lars;Harris, Donald;Pierson, Richard N., III
背景肺血管阻力（PVR）升高、血小板粘附、凝血激活和炎症反应是异种肺排斥反应的显著特征。在这里，我们评估血栓素和组胺在PVR中的作用，以及它们对其他异种肺移植损伤机制的贡献。方法用新鲜的肝素化人血离体灌注GalTKO.hCD46单个猪肺：肺用1-苄咪唑（1-BIA）联合组胺受体阻滞剂法莫替丁（n = 4）或苯海拉明（n = 6）、单独1-BIA（n = 6）处理或不处理（n = 9）。结果9个对照实验中的6个（未处理的GalTKO.hCD46）“存活”直到4小时时选择性终止。在未治疗的情况下，最初30分钟内的初始PVR升高在接下来的一小时内部分消退，并在灌注的最后2小时内逐渐升高。相比之下，1-BIA单独或与抗组胺药联合治疗与低稳定PVR相关。当与未处理的参考相比时，组合处理显著降低气道压力。尽管任何干预均未持续改变血小板和中性粒细胞隔离以及凝血级联激活，但联合治疗显著减弱了未治疗肺中终末湿/干重比的增加。结论当GalTKO.hCD46肺灌注人血时，血栓素和组胺通路联合阻断可防止PVR升高，并显著抑制血管屏障功能丧失。尽管有有效的补体调节，血小板活化和血小板和中性粒细胞隔离在所有组中持续存在，并且似乎独立于血栓素和组胺拮抗作用而发生。我们的工作确定了血栓素和组胺作为异种肺损伤的关键介质，并将这些途径定义为实现成功异种肺移植的治疗靶点。
Background Elevated pulmonary vascular resistance (PVR), platelet adhesion, coagulation activation, and inflammation are prominent features of xenolung rejection. Here, we evaluate the role of thromboxane and histamine on PVR, and their contribution to other lung xenograft injury mechanisms. Methods GalTKO.hCD46 single pig lungs were perfused ex vivo with fresh heparinized human blood: lungs were either treated with 1-Benzylimidazole (1-BIA) combined with histamine receptor blocker famotidine (n = 4) or diphenhydramine (n = 6), 1-BIA alone (n = 6) or were left untreated (n = 9). Results Six of the nine control experiments (GalTKO.hCD46 untreated), "survived" until elective termination at 4 hours. Without treatment, initial PVR elevation within the first 30 minutes resolved partially over the following hour, and increased progressively during the final 2 hours of perfusion. In contrast, 1-BIA, alone or in addition to either antihistamine treatment, was associated with low stable PVR. Combined treatments significantly lowered the airway pressure when compared to untreated reference. Although platelet and neutrophil sequestration and coagulation cascade activation were not consistently altered by any intervention, increased terminal wet/dry weight ratio in untreated lungs was significantly blunted by combined treatments. Conclusion Combined thromboxane and histamine pathway blockade prevents PVR elevation and significantly inhibits loss of vascular barrier function when GalTKO.hCD46 lungs are perfused with human blood. Platelet activation and platelet and neutrophil sequestration persist in all groups despite efficient complement regulation, and appear to occur independent of thromboxane and histamine antagonism. Our work identifies thromboxane and histamine as key mediators of xenolung injury and defines those pathways as therapeutic targets to achieve successful xenolung transplantation.