Development and validation of lung slices as an in vitro model for pulmonary toxicity studies

Abstract

In light of the increasing emphasis on in vitro techniques for toxicologic research, a new model system was developed for preparation and short term maintenance of mammalian lung slice in dynamic organ culture. Viability of explanted tissue, characterized by a number of biochemical and histological parameters, was maintained for 5 days in culture. Validation as a toxicologic tool was accomplished by screening a series of classical toxicants (acrolein, nitrofurantoin, paraquat, cyclophosphamide, monocrotaline, bleomycin and amiodarone). Results indicated this in vitro model system can be used to mimic the acute in vivo toxicity of direct-acting compounds, including the production of cell-specific injury. Application to mechanistic study was approached by investigating the toxicity induced by redox cycling compounds. The toxicity of nitrofurantoin and paraquat was enhanced by high O₂ and attenuated by catalase. Evidence of lipid peroxidation was provided by measuring the disappearance of polyunsaturated fatty acids, and by concomitant depletion of vitamin E. NPSH content of slices remained unchanged, suggesting that GSH is not a primary target for these agents.