Kalsi Ranjeet S, Ostrowska Alina, Olson Adam, Quader Mubina, Deutsch Melvin, Arbujas-Silva Norma J, Symmonds Jen, Soto-Gutierrez Alejandro, Crowley John J, Reyes-Mugica Miguel, Sanchez-Guerrero Giselle, Jaeschke Hartmut, Amiot Bruce P, Cascalho Marilia, Nyberg Scott L, Platt Jeffrey L, Tafaleng Edgar N, Fox Ira J
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
Front Med (Lausanne). 2022 Sep 30;9:964448. doi: 10.3389/fmed.2022.964448. eCollection 2022.
Acute hepatic failure is associated with high morbidity and mortality for which the only definitive therapy is liver transplantation. Some fraction of those who undergo emergency transplantation have been shown to recover native liver function when transplanted with an auxiliary hepatic graft that leaves part of the native liver intact. Thus, transplantation could have been averted with the development and use of some form of hepatic support. The costs of developing and testing liver support systems could be dramatically reduced by the availability of a reliable large animal model of hepatic failure with a large therapeutic window that allows the assessment of efficacy and timing of intervention. Non-lethal forms of hepatic injury were examined in combination with liver-directed radiation in non-human primates (NHPs) to develop a model of acute hepatic failure that mimics the human condition. Porcine hepatocyte transplantation was then tested as a potential therapy for acute hepatic failure. After liver-directed radiation therapy, delivery of a non-lethal hepatic ischemia-reperfusion injury reliably and rapidly generated liver failure providing conditions that can enable pre-clinical testing of liver support or replacement therapies. Unfortunately, in preliminary studies, low hepatocyte engraftment and over-immune suppression interfered with the ability to assess the efficacy of transplanted porcine hepatocytes in the model. A model of acute liver failure in NHPs was created that recapitulates the pathophysiology and pathology of the clinical condition, does so with reasonably predictable kinetics, and results in 100% mortality. The model allowed preliminary testing of xenogeneic hepatocyte transplantation as a potential therapy.
急性肝衰竭与高发病率和高死亡率相关，对此唯一确切的治疗方法是肝移植。一些接受紧急移植的患者在移植辅助性肝移植物（保留部分自身肝脏完整）后已被证明可恢复自身肝功能。因此，若能开发并使用某种形式的肝脏支持手段，或许可避免进行移植。若能获得一种可靠的大型动物肝衰竭模型，其具有较大的治疗窗口，可用于评估疗效和干预时机，那么开发和测试肝脏支持系统的成本可大幅降低。在非人灵长类动物（NHP）中，将非致死性肝损伤形式与肝脏定向放疗相结合进行研究，以建立一种模拟人类情况的急性肝衰竭模型。随后对猪肝细胞移植作为急性肝衰竭的潜在治疗方法进行了测试。在肝脏定向放疗后，给予非致死性肝缺血再灌注损伤可可靠且迅速地引发肝衰竭，从而为肝脏支持或替代疗法的临床前测试提供条件。不幸地是，在初步研究中，低肝细胞植入率和过度免疫抑制干扰了在该模型中评估移植猪肝细胞疗效的能力。建立了一种NHP急性肝衰竭模型，该模型概括了临床病症的病理生理学和病理学，具有合理可预测的动力学，且导致100%的死亡率。该模型允许对异种肝细胞移植作为一种潜在治疗方法进行初步测试。
