Pulmonary complications are no longer rare clinical phenomena interfering with cancer treatment. Although pulmonary injury generally reverses upon termination of the drug treatment, the outcome is unpredictable when fibrosis is a complicating factor. Recognition of the potential for this early discovery or preclinical development is therefore important for clinical studies and for developing less toxic analogues. In vitro approaches offer an attractive option for studying the effects of drugs and chemicals on target cell systems from different species including man to refine and improve predictions of safe clinical dose levels. So far, use of in vitro models for most organs including lung have been limited to studying or testing for acute target organ toxicity effects only, often with single cell types more easy to isolate and maintain in culture. The study and assessment of chronic effects in lung such as fibrosis and their reversibility require relatively long-term cultures and multicellular systems representative of the organ from which they are derived. The objective of this project is to develop, optimize, and validate an in vitro lung cell assay that can assess the potential for both acute and chronic effects by effectively addressing these technical limitations. Research in the R21 phase focused on precision-cut lung slices as one system that might meet that objective. Using an adaptation of newer techniques that extend survival time for liver slices in dynamic organ culture and a combination of histological and biochemical techniques have made it possible to replicate in vivo lesions and effects produced by pulmonary toxicants in vivo. The R33 phase will focus on developing the full capabilities of the assay as an important and critical part of the in vitro toxicity test battery needed by the NCI to screen for target organ toxicities and to aid in predicting safe dose levels and regimens for clinical trials. Success in this effort will demonstrate the value of the system for mechanistic studies and encourage adaptation for a wider range of chronic lesions and conditions.
