Rationale: Acute liver failure (ALF) causes severe liver injury and a systemic inflammatory response, leading to multiorgan failure with a high short-term mortality. Bioartificial liver (BAL) therapy is a promising approach that is hampered by the lack of appropriate bioreactors and carriers to retain hepatic cell function and poor understanding of BAL treatment mechanisms in ALF and extrahepatic organ injury. Recently, we used a fiber scaffold bioreactor (FSB) for the high-density, three-dimensional (3D) culture of primary porcine hepatocytes (PPHs) combined with an absorption component to construct a BAL and verified its function in a D-galactosamine (D-gal)-induced ALF porcine model to evaluate its protective effects on the liver and extrahepatic organs./nMethods: Male pigs were randomized into standard/supportive therapy (ST), ST+no-cell BAL (ST+Sham BAL) and ST+BAL groups and received treatment 48 h after receiving a D-gal injection. Changes in blood chemistry and clinical symptoms were monitored for 120 h. Tissues and plasma were collected for analysis by pathological examination, immunoblotting, quantitative PCR and immunoassays./nResults: PPHs cultured in the FSB obtained sufficient aeration and nutrition for high-density, 3D culture and maintained superior viability and functionality (biosynthesis and detoxification) compared with those cultured in flasks. All the animals developed ALF, acute kidney injury (AKI) and hepatic encephalopathy (HE) 48 h after D-gal infusion and received corresponding therapies. Animals in the BAL group showed markedly improved survival (4/5; 80%) compared with those in the ST+Sham BAL (0/5; p < 0.001) and ST (0/5; p < 0.001) groups. The levels of blood ammonia and biochemical and inflammatory indices were alleviated after BAL treatment. Increased liver regeneration and attenuations in the occurrence and severity of ALF, AKI and HE were observed in the ST+BAL group compared with the ST (p = 0.0009; p = 0.038) and ST+Sham BAL (p = 0.011; p = 0.031) groups. Gut leakage, the plasma endotoxin level, bacterial translocation, and peripheral and neuroinflammation were alleviated in the ST+BAL group compared with those in the other groups./nConclusions: BAL treatment enhanced liver regeneration and alleviated the systemic inflammatory response and extrahepatic organ injury to prolong survival in the ALF model and has potential as a therapeutic approach for ALF patients.

中文翻译：

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纤维支架生物人工肝治疗缓解猪急性肝衰竭和肝外器官损伤


理由：急性肝衰竭（ALF）会导致严重的肝损伤和全身炎症反应，导致多器官衰竭，短期死亡率很高。生物人工肝 (BAL) 疗法是一种很有前途的方法，但由于缺乏适当的生物反应器和载体来保留肝细胞功能，以及对 ALF 和肝外器官损伤的 BAL 治疗机制了解甚少，因此受到阻碍。最近，我们使用纤维支架生物反应器（FSB）对原代猪肝细胞（PPH）进行高密度、三维（3D）培养，并结合吸收成分构建BAL，并验证其在D-半乳糖胺中的功能。 D-gal)诱导的ALF猪模型，评价其对肝脏和肝外器官的保护作用。/n方法：雄性猪随机分为标准/支持治疗（ST）、ST+无细胞BAL（ST+Sham BAL） ST+BAL组在注射D-gal后48小时接受治疗。监测血液化学和临床症状的变化120小时。收集组织和血浆，通过病理检查、免疫印迹、定量 PCR 和免疫测定进行分析。/n结果：在 FSB 中培养的 PPH 获得了高密度 3D 培养所需的充足通气和营养，并保持了卓越的活力和功能（生物合成和解毒）与烧瓶中培养的相比。所有动物在输注D-gal后48 h均出现ALF、急性肾损伤（AKI）和肝性脑病（HE）并接受相应治疗。与 ST+Sham BAL (0/5; p < 0.001) 和 ST (0/5; p < 0.001) 组相比，BAL 组动物的存活率显着提高 (4/5; 80%)。 BAL治疗后血氨、生化及炎症指标水平得到缓解。与 ST（p = 0.0009；p = 0.038）和 ST+Sham BAL（p = 0.011；p = 0.031）相比，ST+BAL 组观察到肝再生增加，ALF、AKI 和 HE 的发生率和严重程度减弱。 ）组。与其他组相比，ST+BAL 组的肠漏、血浆内毒素水平、细菌移位、外周和神经炎症均减轻。/n结论： BAL 治疗增强肝再生，减轻全身炎症反应和肝外器官损伤延长 ALF 模型的生存期，并有可能作为 ALF 患者的治疗方法。