Novel spheroid reservoir bioartificial liver improves survival of nonhuman primates in a toxin-induced model of acute liver failure
Novel spheroid reservoir bioartificial liver improves survival of nonhuman primates in a toxin-induced model of acute liver failure
复制标题
新型球体储库生物人工肝可提高毒素诱导的急性肝衰竭模型中非人灵长类动物的存活率
DOI：
10.7150/thno.26540
复制
发表时间：
2018-01-01
期刊：
影响因子：
12.4
通讯作者：
Bu, Hong
中科院分区：
文献类型：
--
作者：
Li, Yi;Wu, Qiong;Bu, Hong
本研究旨在评估具有猪肝细胞类器官的球体储库生物人工肝（SRBAL）在急性肝衰竭（ALF）临床前非人灵长类动物模型中的有效性和安全性。方法：将 30 只健康恒河猴注射 α-鹅膏蕈碱和脂多糖，随机分为 5 组（单独 ALF 对照组；假无细胞 SRBAL 治疗组；A、B 和 C 组分别在 ALF 诱导后 12 h、24 h 和 36 h 开始 SRBAL 治疗）。动物连续使用 SRBAL 装置治疗 6 小时，并随访长达 336 小时。结果：与对照组相比，肝细胞 SRBAL 治疗后 ALF 猴的存活率有所提高。所有肝细胞 SRBAL 治疗组的血氨和总胆红素均较低，白蛋白水平较高。 SRBAL 治疗后，在猴肝脏或血液中没有发现猪内源性逆转录病毒的证据。 SRBAL治疗后猴抗体（IgG、IgM）滴度没有升高。在存活病例中，SRBAL 治疗组的坏死和凋亡肝细胞比例较低，肝脏再生较早导致恢复。 SRBAL 治疗改善了细胞因子 TNF-α、IL-6、IL-12、IL-1β、IL-8、IFN-γ 和 IL-2，同时 M-CSF 水平得到改善。 HGF、EGF 和 VEGF； IL-1RA 和 MIF 在肝再生的启动、增殖和后期阶段上升。结论：SRBAL治疗的益处包括预防作用和治疗作用。 SRBAL 在药物诱导的 ALF 的非人灵长类动物模型中提高了生存率并延长了中位生存时间，但这些益处随着治疗开始的延迟而下降。 ALF猴的存活率和恢复率的提高与血氨水平的降低、ALF促炎反应的抑制有关，并提供了更适合受损肝脏再生的微环境。
This study aims to evaluate the effectiveness and safety of the spheroid reservoir bioartificial liver (SRBAL) with porcine hepatocyte organoids in a preclinical nonhuman primate model of acute liver failure (ALF). Methods: Thirty healthy rhesus monkeys were infused with α-amanitin and lipopolysaccharide and randomized into five groups (ALF alone control group; sham no-cell SRBAL treatment group; groups A, B and C with SRBAL treatment started at 12 h, 24 h and 36 h after induction of ALF, respectively). Animals were continuously treated with the SRBAL device for 6 h and followed for up to 336 h. Results: Survival of ALF monkeys improved with hepatocyte SRBAL treatment compared to control groups. Blood ammonia and total bilirubin were lower, and albumin levels were higher in all hepatocyte SRBAL treatment groups. No evidence of porcine endogenous retrovirus was identified in monkey liver or blood after SRBAL treatment. Titers of monkey antibody (IgG, IgM) did not rise after SRBAL treatment. In survival cases, the proportion of necrotic and apoptotic hepatocytes was lower in SRBAL-treated groups, with earlier liver regeneration leading to recovery. Cytokines TNF-α, IL-6, IL-12, IL-1β, IL-8, IFN-γ and IL-2 were ameliorated by the SRBAL treatment, while levels of M-CSF; HGF, EGF and VEGF; IL-1RA and MIF rose on priming, proliferation and the late phase of liver regeneration. Conclusions: The benefit of SRBAL therapy included preventive effects and therapeutic effects. SRBAL improved survival rate and prolonged median survival time in a nonhuman primate model of drug-induced ALF, and these benefits declined with a delay in the initiation of therapy. Improved survival and recovery of ALF monkeys was associated with a reduction in blood ammonia levels, inhibition of the pro-inflammatory response of ALF, and provided a microenvironment more suitable for regeneration of the injured liver.