Division of Lung Transplant and Lung Failure, Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
Division of Lung Transplant and Lung Failure, Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
J Heart Lung Transplant. 2023 Jun;42(6):697-706. doi: 10.1016/j.healun.2023.03.010. Epub 2023 Mar 21.
We hypothesized that enhancing glycocalyx preservation would reduce endothelial damage in lung grafts during ex-vivo lung perfusion (EVLP) leading to better transplant outcomes. In this study, we characterized the effects of inhibiting heparanase (HPSE), an enzyme responsible for glycocalyx shedding, on lung quality during EVLP.
Human clinical EVLP perfusate from lung graft patients was utilized to identify a potential association between glycocalyx integrity in grafted lung tissue and clinical data. In addition, we performed pre-clinical studies in which rat lungs underwent normothermic EVLP for 4 hours with/without HPSE inhibitors, heparin (1,000-U/h) or heparastatin (SF4; 1-μM), added to the perfusate. After 4-hours EVLP, left lungs were transplanted into syngeneic rats then evaluated for graft quality 2-hours after reperfusion.
Clinically, increased degradation of syndecan-1 was identified in dysfunctional grafts during EVLP. Levels of heparan sulfate in perfusate after EVLP were associated with incidence of graft dysfunction after transplantation. In the pre-clinical rat study, SF4 effectively inhibited HPSE activity, and significantly attenuated dissociated glycocalyx levels, endothelial dysfunction, edema, and inflammation in lungs during EVLP compared to both controls and heparin groups. High-doses of heparin demonstrated markedly increased perfusate syndecan-1 concentrations and deteriorated lung quality during EVLP compared with controls. Post-transplant graft function and inflammation were significantly improved in SF4-treated group compared to those in both control and heparin-treated groups.
This study demonstrated that HPSE activity inhibition by SF4 can improve graft preservation during EVLP by protecting the glycocalyx and endothelial function, leading to better lung function following transplantation.
我们假设在体外肺灌注 (EVLP) 过程中增强糖萼的保护作用会减少肺移植物中的内皮损伤，从而改善移植结果。在这项研究中，我们研究了抑制负责糖萼脱落的肝素酶 (HPSE) 对 EVLP 过程中肺质量的影响。
我们利用从肺移植患者的 EVLP 灌流液中鉴定出糖萼完整性与移植肺组织临床数据之间的潜在关联。此外，我们进行了临床前研究，在该研究中，大鼠的肺在常温 EVLP 下进行 4 小时，同时添加 HPSE 抑制剂肝素（1000-U/h）或硫酸乙酰肝素酶抑制剂 SF4（1-μM）。经过 4 小时的 EVLP 后，左肺被移植到同基因大鼠体内，然后在再灌注后 2 小时评估移植物质量。
临床上，在 EVLP 期间，功能障碍的移植物中发现 syndecan-1 的降解增加。EVLP 后灌流液中肝素硫酸盐的水平与移植后移植物功能障碍的发生率有关。在临床前大鼠研究中，SF4 有效抑制了 HPSE 的活性，并显著降低了 EVLP 期间分离的糖萼水平、内皮功能障碍、水肿和炎症。与对照组和肝素组相比，高剂量肝素在 EVLP 期间显示出明显增加的灌流液 syndecan-1 浓度和恶化的肺质量。与对照组和肝素组相比，SF4 处理组的移植后移植物功能和炎症明显改善。
这项研究表明，SF4 通过保护糖萼和内皮功能抑制 HPSE 活性可改善 EVLP 期间的移植物保存，从而改善移植后的肺功能。
