Division of Cardiac Surgery, Department of Surgery, University of Maryland School of Medicine, and VA Maryland Health Care System, Baltimore, Maryland.
Center for Transplantation Sciences and Division of Cardiac Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts.
Xenotransplantation. 2019 Mar;26(2):e12458. doi: 10.1111/xen.12458. Epub 2018 Sep 3.
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.
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).
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.
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.
升高的肺血管阻力（PVR）、血小板黏附、凝血激活和炎症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对 PVR 的作用，以及它们对其他肺异种移植物损伤机制的贡献。
GalTKO.hCD46 单猪肺在新鲜肝素化人血中进行离体灌注：肺要么用 1-苯并咪唑（1-BIA）与组胺受体阻滞剂法莫替丁（n=4）或苯海拉明（n=6）联合治疗，要么用 1-BIA 单独治疗（n=6），要么不治疗（n=9）。
在 4 小时的选择性终止之前，9 个对照实验中的 6 个（GalTKO.hCD46 未治疗）“存活”下来。未经治疗，最初 30 分钟内的 PVR 升高在接下来的 1 小时内部分缓解，并在灌注的最后 2 小时内逐渐升高。相比之下，1-BIA 单独或与任何抗组胺治疗联合使用时，与低稳定 PVR 相关。联合治疗与未治疗的参考相比，显著降低气道压力。尽管血小板和中性粒细胞的滞留和凝血级联激活没有因任何干预而持续改变，但未治疗肺的终末湿/干重比的增加明显被联合治疗所抑制。
当 GalTKO.hCD46 肺用人血灌注时，联合血栓素和组胺途径阻断可防止 PVR 升高，并显著抑制血管屏障功能的丧失。尽管有效的补体调节，血小板激活以及血小板和中性粒细胞的滞留仍然存在，并且似乎独立于血栓素和组胺拮抗作用发生。我们的工作确定了血栓素和组胺是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。
