Microphysiological Models for Mechanistic-Based Prediction of Idiosyncratic DILI.
Microphysiological Models for Mechanistic-Based Prediction of Idiosyncratic DILI.
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DOI：
10.3390/cells12111476
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发表时间：
2023-05-25
期刊：
影响因子：
6
通讯作者：
Sadrieh, Nakissa
中科院分区：
文献类型：
--
作者：
Stern, Sydney;Wang, Hongbing;Sadrieh, Nakissa
药物性肝损伤（DILI）是候选药物和上市药物中高损耗率的主要原因，也是一个关键的监管、行业和全球健康问题。虽然急性和剂量依赖性DILI（即内源性DILI）在临床前模型中是可预测的，并且通常是可重现的，但由于疾病发病机制复杂，特异质DILI（iDILI）的性质限制了对其机制的理解，并且使用体外和体内模型进行重现极具挑战性。然而，肝脏炎症是iDILI的关键特征，主要由先天性和适应性免疫系统协调。本文综述了利用免疫系统的作用研究iDILI的体外共培养模型。特别是，这篇评论的重点是人类为基础的3D多细胞模型的进展，试图补充体内模型，往往缺乏可预测性和显示种间变异。利用iDILI的免疫介导机制，在这些肝毒性模型中纳入非实质细胞，即枯否细胞、星状细胞、树突状细胞和肝窦内皮细胞，引入异型细胞-细胞相互作用并模拟肝脏微环境。此外，1996-2010年期间从美国市场召回的药物在这些不同模型中进行了研究，突出了进一步协调和比较模型特征的必要性。描述了有关疾病相关终点的挑战，模拟具有不同细胞-细胞接触的3D结构，细胞来源以及潜在的多细胞和多阶段机制。我们相信，深入了解iDILI的潜在发病机制将为药物安全性筛选提供机制线索和方法，以更好地预测临床试验和上市后的肝损伤。
Drug-induced liver injury (DILI) is a major contributor to high attrition rates among candidate and market drugs and a key regulatory, industry, and global health concern. While acute and dose-dependent DILI, namely, intrinsic DILI, is predictable and often reproducible in preclinical models, the nature of idiosyncratic DILI (iDILI) limits its mechanistic understanding due to the complex disease pathogenesis, and recapitulation using in vitro and in vivo models is extremely challenging. However, hepatic inflammation is a key feature of iDILI primarily orchestrated by the innate and adaptive immune system. This review summarizes the in vitro co-culture models that exploit the role of the immune system to investigate iDILI. Particularly, this review focuses on advancements in human-based 3D multicellular models attempting to supplement in vivo models that often lack predictability and display interspecies variations. Exploiting the immune-mediated mechanisms of iDILI, the inclusion of non-parenchymal cells in these hepatoxicity models, namely, Kupffer cells, stellate cells, dendritic cells, and liver sinusoidal endothelial cells, introduces heterotypic cell–cell interactions and mimics the hepatic microenvironment. Additionally, drugs recalled from the market in the US between 1996–2010 that were studies in these various models highlight the necessity for further harmonization and comparison of model characteristics. Challenges regarding disease-related endpoints, mimicking 3D architecture with different cell–cell contact, cell source, and the underlying multi-cellular and multi-stage mechanisms are described. It is our belief that progressing our understanding of the underlying pathogenesis of iDILI will provide mechanistic clues and a method for drug safety screening to better predict liver injury in clinical trials and post-marketing.
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DOI：
10.1093/toxsci/kfx289
发表时间：
2018-04-01
期刊：
Toxicological sciences : an official journal of the Society of Toxicology
影响因子：
--
作者：
Bell CC;Dankers ACA;Lauschke VM;Sison-Young R;Jenkins R;Rowe C;Goldring CE;Park K;Regan SL;Walker T;Schofield C;Baze A;Foster AJ;Williams DP;van de Ven AWM;Jacobs F;Houdt JV;Lähteenmäki T;Snoeys J;Juhila S;Richert L;Ingelman-Sundberg M
通讯作者：
Ingelman-Sundberg M
影响因子：
3
作者：
Bale, Shyam Sundhar;Golberg, Inna;Yarmush, Martin L.
通讯作者：
Yarmush, Martin L.
影响因子：
6.1
作者：
Albrecht, Wiebke;Kappenberg, Franziska;Hengstler, Jan G.
通讯作者：
Hengstler, Jan G.
影响因子：
3.8
作者：
Chan, Rosa;Benet, Leslie Z.
通讯作者：
Benet, Leslie Z.
影响因子：
3.8
作者：
Adams, David H.;Ju, Cynthia;Jaeschke, Hartmut
通讯作者：
Jaeschke, Hartmut