Precision-cut lung slices: a novel model for respiratory tract toxicology

Abstract

The lungs are a prominent target organ for numerous types of chemically-induced pathological changes. Current concepts of the pathogenesis of lung injury and repair are derived from in vitro and in vivo investigations. In light of the increasing emphasis on in vitro techniques for toxicologic research, the precision-cut lung slice model was extended to the mouse to determine the predictive value of this system for assessing interspecies differences in metabolism and toxicity. Validation of the lung slice model as a toxicological tool was accomplished by examining several biochemical parameters of functional viability and correlating them with histologic parameters in control lung slices. In addition, comparative studies utilizing rat and mouse lung slices were completed to justify statements regarding interspecies validation. Characterization of the model as a toxicological tool for studying interspecies differences was accomplished by studies with two classic pneumotoxicants, paraquat and butylated hydroxytoluene. These well-characterized lung toxins are uniquely different in their mechanisms of action and toxicity. Results indicated that 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. Thus, utilization of the lung slice model to screen the toxicity of several alkylphenols was also approached. The alkylphenols that were examined include butylated hydroxytoluene, eugenol, p-cresol, p-isopropylphenol, and two structural analogs of butylated hydroxytoluene (BMP and BDMP). Overall, adult mouse and rat lung slices cultured maintained a reasonable level of function. Generally, the species differences observed in our metabolism studies agree with previously reported in vitro and in vivo data. Furthermore, the toxicity of BHT and paraquat in lung slices closely paralleled observations in other well-established in vitro and in vivo systems. Factors which modulated the toxicity of BHT did so in a manner consistent with the proposed mechanisms of action and was consistent with results obtained in previous in vivo and in vitro studies. Thus, these results demonstrate the usefulness of precision-cut lung slices as a rapid in vitro model system for investigating species differences in xenobiotic-induced toxicity.