Circulating mitochondria in deceased organ donors are associated with immune activation and early allograft dysfunction.
Circulating mitochondria in deceased organ donors are associated with immune activation and early allograft dysfunction.
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DOI：
10.1172/jci.insight.121622
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发表时间：
2018-08
期刊：
影响因子：
8
通讯作者：
J. Pollara;R. Edwards;Liwen Lin;V. Bendersky;T. Brennan
中科院分区：
文献类型：
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作者：
J. Pollara;R. Edwards;Liwen Lin;V. Bendersky;T. Brennan
在死者器官捐献用于移植的情况下发生的脑死亡与不明原因的全身炎症有关。最近已经认识到，在创伤和组织损伤的情况下，释放到循环中的脊髓源性损伤相关分子模式（mtDAMP）与全身炎症反应相关。我们检查了已故器官捐献者的血液，发现炎症细胞因子和趋化因子水平升高，与mtDAMP水平相关。我们还发现，供体中性粒细胞被激活，供体血浆中含有一种嗜中性粒细胞激活因子，该因子可被环孢菌素H（一种甲酰肽受体-1拮抗剂）阻断。通过电子显微镜和流式细胞术检查供体血浆，发现游离和膜结合的线粒体在供体血浆中升高。有趣的是，我们证明了供体血浆线粒体DNA水平与肝移植受者早期同种异体移植物功能障碍之间的相关性，表明循环mtDAMP在同种异体移植物结局中的作用。目前延长同种异体移植物存活的方法主要集中在移植受者的免疫抑制上;我们的数据表明，在器官获取之前针对已故供体的炎症因子是改善移植结果的另一种潜在策略。
Brain death that occurs in the setting of deceased organ donation for transplantation is associated with systemic inflammation of unknown origin. It has recently been recognized that mitochondria-derived damage-associated molecular patterns (mtDAMPs) released into the circulation in the setting of trauma and tissue injury are associated with a systemic inflammatory response. We examined the blood of deceased organ donors and found elevated levels of inflammatory cytokines and chemokines that correlated with levels of mtDAMPs. We also found that donor neutrophils are activated and that donor plasma contains a neutrophil-activating factor that is blocked by cyclosporin H, a formyl peptide receptor-1 antagonist. Examination of donor plasma by electron microscopy and flow cytometry revealed that free- and membrane-bound mitochondria are elevated in donor plasma. Interestingly, we demonstrated a correlation between donor plasma mitochondrial DNA levels and early allograft dysfunction in liver transplant recipients, suggesting a role for circulating mtDAMPs in allograft outcomes. Current approaches to prolong allograft survival focus on immune suppression in the transplant recipient; our data indicate that targeting inflammatory factors in deceased donors prior to organ procurement is another potential strategy for improving transplant outcomes.