Chapter 11: Pathways of Organ Injury to Define Human Response in Organotypic Cultures

Organ slices possess the three-dimensional architecture, multi-cellular complexity to mimic the dynamic cell–cell and cell–matrix interactions of in vivo tissues, enabling mechanistic investigations of drug-induced organ injury that represent in vivo outcomes. The application of human tissue to organ slice, organotypic, models enhances our ability to focus on the clinical relevance of the potential side-effects and to identify biomarkers of the side-effects, thereby expanding the scope of translational research for drug-safety assessment. Understanding molecular mechanisms of drug action on the activation of cell death and survival pathways which includes oxidative stress, inflammation, apoptosis, and repair, will provide greater insight and characterization of key pathways that are causal to organ dysfunction and injury, as well as define the threshold of functional change. Dose–response relationships in the organotypic models will discern drug concentrations that have no effect from those which alter organ function or affect morphology, providing insight into drug concentrations and the extent of injury which could pose a risk for humans. Organ injury pathways have been evaluated in organotypic cultures, incorporating gene expression profiling, with functional measurements and morphology. The integration of these technologies with the organotypic cultures was initially applied to liver and kidney slices using known hepatotoxicants and nephrotoxicants to verify the model. The organotypic models have now been extended to other organs including thyroid, lung and to co-cultures of liver and blood, as well as to generating a stressed liver model by modulating liver glutathione levels. In these examples mechanisms of drug-induced organ injury is elucidated, species susceptibility to organ injury is defined, and the characterization of human response is advanced.