PDF(Pubmed)
Abstract：
UNASSIGNED: The adverse effects of ischemia-reperfusion injury (IRI) remain a principal barrier to a successful outcome after lifesaving orthotopic liver transplantation (OLT). Gene expression during different phases of IRI is dynamic and modified by individual exposures, making it attractive for identifying potential therapeutic targets for improving the number of suitable organs for transplantation and patient outcomes. However, data remain limited on the functional landscape of gene expression during liver graft IRI, spanning procurement to reperfusion and recovery. Therefore, we sought to characterize transcriptomic profiles of IRI during multiple phases in human OLT.
UNASSIGNED: We conducted clinical data analyses, histologic evaluation, and RNA sequencing of 17 consecutive human primary OLT. We performed liver allograft biopsies at 4 time points: baseline (B, before donor cross-clamp), at the end of cold ischemia (CI), during early reperfusion (ER, after revascularization), and during late reperfusion (LR). Data were generated and then recipients grouped by post-OLT outcomes categories: immediate allograft function (IAF; n = 11) versus early allograft dysfunction (EAD; n = 6) groups.
UNASSIGNED: We observed that CI (vs B) modified a transcriptomic landscape enriched for a metabolic and immune process. Expression levels of hallmark inflammatory response genes were higher transitioning from CI to ER and decreased from ER to LR. IAF group predominantly showed higher bile and fatty acid metabolism activity during LR compared with EAD group, while EAD group maintained more immunomodulatory activities. Throughout all time points, EAD specimens exhibited decreased metabolic activity in both bile and fatty acid pathways.
UNASSIGNED: We report transcriptomic profiles of human liver allograft IRI from prepreservation in the donor to posttransplantation in the recipient. Immunomodulatory and metabolic landscapes across ER and LR phases were different between IAF and EAD allografts. Our study also highlights marker genes for these biological processes that we plan to explore as novel therapeutic targets or surrogate markers for severe allograft injury in clinical OLT.
UNASSIGNED: We conducted clinical data analyses, histologic evaluation, and RNA sequencing of 17 consecutive human primary OLT. We performed liver allograft biopsies at 4 time points: baseline (B, before donor cross-clamp), at the end of cold ischemia (CI), during early reperfusion (ER, after revascularization), and during late reperfusion (LR). Data were generated and then recipients grouped by post-OLT outcomes categories: immediate allograft function (IAF; n = 11) versus early allograft dysfunction (EAD; n = 6) groups.
UNASSIGNED: We observed that CI (vs B) modified a transcriptomic landscape enriched for a metabolic and immune process. Expression levels of hallmark inflammatory response genes were higher transitioning from CI to ER and decreased from ER to LR. IAF group predominantly showed higher bile and fatty acid metabolism activity during LR compared with EAD group, while EAD group maintained more immunomodulatory activities. Throughout all time points, EAD specimens exhibited decreased metabolic activity in both bile and fatty acid pathways.
UNASSIGNED: We report transcriptomic profiles of human liver allograft IRI from prepreservation in the donor to posttransplantation in the recipient. Immunomodulatory and metabolic landscapes across ER and LR phases were different between IAF and EAD allografts. Our study also highlights marker genes for these biological processes that we plan to explore as novel therapeutic targets or surrogate markers for severe allograft injury in clinical OLT.
摘要：
■缺血再灌注损伤（IRI）的不良反应仍然是挽救生命的原位肝移植（OLT）后成功结局的主要障碍。在IRI的不同阶段的基因表达是动态的，并通过个体暴露而改变，这对于确定潜在的治疗目标以改善移植合适器官的数量和患者的预后具有吸引力。然而,肝移植IRI期间基因表达的功能景观数据仍然有限，从采购到再灌注和恢复。因此,我们试图表征人OLT中多个阶段IRI的转录组学特征。
■我们进行了临床数据分析，组织学评估，和17个连续人原代OLT的RNA测序。我们在4个时间点进行了肝脏移植活检：基线（B，在供体交叉夹之前)，在冷缺血（CI）结束时，在早期再灌注期间（ER，血运重建后)，和晚期再灌注（LR）。生成数据，然后按OLT后结局类别对接受者进行分组：立即同种异体移植功能（IAF；n=11）与早期同种异体移植功能障碍（EAD；n=6）组。
■我们观察到CI（vsB）改变了代谢和免疫过程的转录组景观。标志性炎症反应基因的表达水平从CI过渡到ER较高，从ER过渡到LR降低。与EAD组相比，IAF组主要表现出较高的胆汁和脂肪酸代谢活性。而EAD组保持较多的免疫调节活性。在所有时间点，EAD标本在胆汁和脂肪酸途径中均表现出降低的代谢活性。
■我们报告了从供体的预保存到受体的移植后的人肝脏同种异体移植IRI的转录组学特征。在IAF和EAD同种异体移植物之间，ER和LR阶段的免疫调节和代谢景观不同。我们的研究还强调了这些生物过程的标记基因，我们计划探索作为临床OLT中严重同种异体移植损伤的新型治疗靶标或替代标记。
■我们进行了临床数据分析，组织学评估，和17个连续人原代OLT的RNA测序。我们在4个时间点进行了肝脏移植活检：基线（B，在供体交叉夹之前)，在冷缺血（CI）结束时，在早期再灌注期间（ER，血运重建后)，和晚期再灌注（LR）。生成数据，然后按OLT后结局类别对接受者进行分组：立即同种异体移植功能（IAF；n=11）与早期同种异体移植功能障碍（EAD；n=6）组。
■我们观察到CI（vsB）改变了代谢和免疫过程的转录组景观。标志性炎症反应基因的表达水平从CI过渡到ER较高，从ER过渡到LR降低。与EAD组相比，IAF组主要表现出较高的胆汁和脂肪酸代谢活性。而EAD组保持较多的免疫调节活性。在所有时间点，EAD标本在胆汁和脂肪酸途径中均表现出降低的代谢活性。
■我们报告了从供体的预保存到受体的移植后的人肝脏同种异体移植IRI的转录组学特征。在IAF和EAD同种异体移植物之间，ER和LR阶段的免疫调节和代谢景观不同。我们的研究还强调了这些生物过程的标记基因，我们计划探索作为临床OLT中严重同种异体移植损伤的新型治疗靶标或替代标记。
