Use of ex vivo organotypic lung tissue in translational research of respiratory injury and inflammation diseases

Translational science has remarkably changed the general perception of 3D organotypic tissue models such as precision-cut lung slices (PCLS), parenchymal strips, isolated vessels and airways. These models are considered to be of importance since the cellular anatomy of the respiratory tract comprises many extensively varying cell types with different functions. Moreover, according to the 3R concept, more and more 3D models are used in tiered approaches - testing first in vitro and ex vivo before first in vivo - which provides supporting data early in drug development. Precision-cut lung slices for example are now widely used for basic research and pre-clinical efficacy and toxicity testing of (biological) compounds. Such tissue sections of the lung contain for example epithelial cells, fibroblast, smooth muscle cells, nerve fibres, and immune cells such as antigenpresenting cells and T-Cells. Cells are still viable and interact with each other, by this reflecting the highly specialized function of the lung. In the context of our mechanistic understanding of airway biology and pathology it is important to use appropriate in vitro models with highest impact on the real life situation. By exploring these mechanisms in advanced tissue and cell culture models with chemical and biological agents such as pharmaceuticals, immune active proteins, antibodies, cytokines, and drugs we take into account that individual cell types may respond differently to the same mediator, drug or substance. Therefore, lung tissue is exposed ex vivo to these substances and examined for phenotyping of cellular changes, respiratory toxicity, broncho- and vasoconstriction and -dilation, immune responses, and tumor invasion. By this, different features of respiratory diseases such as acute lung injury, asthma, COPD, fibrosis, infection and tumor can be investigated - by using tissue of different species, including human. We found that the tissue response is highly comparable with the in vivo response and can be used for the prediction of toxicological endpoints and adverse health outcomes such as organ injury, respiratory sensitization and inflammation. The presentation will give an overview about the current use of lung tissue in inhalation toxicology but also state their use for drug research.