Vickers Alison E M, Fisher Robyn L
Safety Evaluation, Allergan Inc., 2525 Dupont Drive, Irvine, CA 92623, USA.
Chem Biol Interact. 2004 Nov 1;150(1):87-96. doi: 10.1016/j.cbi.2004.09.005.
Human organ slices, an in vitro model representing the multicellular and functional features of in vivo tissue, is a promising model for characterizing mechanisms of drug-induced organ injury and for identifying biomarkers of organ injury. Target organ injury is a significant clinical issue. In vitro models, which compare human and animal tissue to improve the extrapolation of animal in vivo studies for predicting human outcome, will contribute to improving drug candidate selection and to defining species susceptibilities in drug discovery and development programs. A critical aspect to the performance and outcome of human organ slice studies is the use of high quality tissue, and the use of culture conditions that support optimum organ slice survivability, in order to accurately reproduce mechanisms of organ injury in vitro. The attribute of organ slices possessing various cell types and interactions contributes to the overall biotransformation, inflammatory response and assessment of injury. Regional differences and changes in morphology can be readily evaluated by histology and special stains, similar to tissue obtained from in vivo studies. The liver is the major organ of which slice studies have been performed, however the utility of extra-hepatic derived slices, as well as co-cultures is increasing. Recent application of integrating gene expression, with human organ slice function and morphology demonstrate the increased potential of this model for defining the molecular and biochemical pathways leading to drug-induced tissue changes. By gaining a more detailed understanding of the mechanisms of drug-induced organ injury, and by correlating clinical measurements with drug-induced effects in the in vitro models, the vision of human in vitro models to identify more sensitive and discriminating markers of organ damage is attainable.
人体器官切片是一种体外模型，可呈现体内组织的多细胞和功能特征，是用于表征药物性器官损伤机制和识别器官损伤生物标志物的一种很有前景的模型。靶器官损伤是一个重大的临床问题。体外模型通过比较人体和动物组织，以改进动物体内研究的外推法来预测人体结果，将有助于改进候选药物的选择，并确定药物发现和开发项目中的物种易感性。人体器官切片研究的性能和结果的一个关键方面是使用高质量的组织，以及使用支持最佳器官切片存活能力的培养条件，以便在体外准确再现器官损伤的机制。器官切片具有多种细胞类型和相互作用的特性有助于整体生物转化、炎症反应和损伤评估。与体内研究获得的组织类似，通过组织学和特殊染色可以很容易地评估区域差异和形态变化。肝脏是进行切片研究的主要器官，然而，肝外来源的切片以及共培养的应用正在增加。最近将基因表达与人体器官切片功能和形态相结合的应用表明，该模型在定义导致药物诱导组织变化的分子和生化途径方面具有更大的潜力。通过更详细地了解药物性器官损伤的机制，并将临床测量与体外模型中的药物诱导效应相关联，利用人体体外模型识别更敏感和有区分性的器官损伤标志物的愿景是可以实现的。
