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首页> 外文期刊>RSC Advances >Extracellular histones are clinically associated with primary graft dysfunction in human liver transplantation
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Extracellular histones are clinically associated with primary graft dysfunction in human liver transplantation

机译：细胞外组蛋白在临床上与人肝移植中原发性移植物功能障碍有关

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Extracellular histones have been involved in numerous inflammatory conditions such as ischemia/reperfusion (I/R) injury, trauma, and infection. There is growing evidence of I/R injury associated with primary graft dysfunction (PGD) following organ transplantation. Here we investigated whether extracellular histones are clinically involved with PGD in human liver transplantation. In total 58 patients undergoing liver transplantation were studied. We collected blood samples from the recipients before and serially after transplantation (24?h, 72 h). We measured extracellular histones, myeloperoxidase (MPO), S100A8/A9, and multiple inflammatory cytokines. Additionally, we exposed human L02 hepatocytes or U937 monocytic cells to the recipient's sera overnight, and assessed cellular viability and cytokine production respectively. Lastly, we assessed the effect of histone-targeted interventions by administration of heparin or an anti-histone antibody. It showed that extracellular histones increased immediately after transplantation, peaked within 24 hours and remained at high levels up to 72 hours (all p < 0.01). Notably, extracellular histone levels were significantly higher in recipients with PGD ( n = 9) than recipients without PGD ( n = 49, p = 0.004). Extracellular histones correlated positively with MPO, S100A8/A9 and most detected cytokines. Ex vivo analysis demonstrated that the patients' sera after graft markedly induced L02 cell death and caused profound cytokine production in cultured U937 cells, which could be abrogated by heparin or an anti-histone antibody. Collectively, extracellular histones were increased significantly after liver transplantation, which may contribute to the occurrence of PGD through direct cytotoxicity and enhancement of systemic inflammation. Targeting extracellular histones may provide a promising approach for preventing PGD or other complications in clinical practice.
机译：细胞外组蛋白已参与多种炎性疾病，例如缺血/再灌注（I / R）损伤，创伤和感染。越来越多的证据表明，器官移植后与原发性移植物功能障碍（PGD）相关的I / R损伤。在这里，我们调查了细胞外组蛋白在人类肝移植中是否与PGD临床相关。共研究了58位接受肝移植的患者。我们在移植前后（24小时，72小时）从接受者那里采集了血液样本。我们测量了细胞外组蛋白，髓过氧化物酶（MPO），S100A8 / A9和多种炎症细胞因子。此外，我们将人类L02肝细胞或U937单核细胞暴露于受体的血清中过夜，并分别评估了细胞活力和细胞因子的产生。最后，我们通过给予肝素或抗组蛋白抗体评估了针对组蛋白的干预措施的效果。结果表明，细胞外组蛋白在移植后立即增加，在24小时内达到峰值，并在72小时内保持高水平（所有p <0.01）。值得注意的是，有PGD的接受者（n = 9）的细胞外组蛋白水平显着高于无PGD的接受者（n = 49，p = 0.004）。细胞外组蛋白与MPO，S100A8 / A9和大多数检测到的细胞因子呈正相关。离体分析表明，移植后患者的血清显着诱导了L02细胞死亡，并在培养的U937细胞中引起大量的细胞因子生成，而肝素或抗组蛋白抗体可废除该细胞因子。总的来说，肝移植后细胞外组蛋白显着增加，这可能通过直接的细胞毒性和增强全身性炎症而促进了PGD的发生。靶向细胞外组蛋白可能为临床上预防PGD或其他并发症提供有前途的方法。

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