Cultured Human Bronchial Cells as a Model System in Lung Toxicology and Carcinogenesis: Implications from Studies with Acrolein

Tissues and cells from both humans and laboratory animals can now be successfully cultured and used to examine in vitro the interspecial extrapolation of toxicity data. In particular, epithelial cells or fibroblasts from the human bronchus are systematically being used to study pathobiological effects of inhalation toxicants, e.g. acrolein, present in tobacco smoke and automobile emissions. Micromolar concentrations of acrolein are highly toxic to both bronchial epithelial cells and fibroblasts, and decrease their colony-forming efficiency, ability to exclude trypan blue dye, and content of low-molecular-weight thiols in a dose-dependent manner. Cytosolic free-calcium levels are increased at concentrations of acrolein lower than those required to decrease plasma membrane integrity (measured by exclusion of ethidium bromide dye). Acrolein also decreases growth rate and increases formation of cross-linked envelopes in bronchial epithelial cells, which are indicative of squamous differentiation. Moreover, acrolein causes several types of DNA damage, including single strand breaks, DNA-protein cross-links, interstrand cross-links and alkali-labile sites. The dose-response relationships in this study indicate that disturbance of the cellular thiol and calcium homeostasis and/or formation of DNA damage may be involved in acrolein-related toxicity and accelerated epithelial differentiation. These results also demonstrate that acrolein causes pathobiological effects associated with various phases of multi-stage carcinogenesis in human airway epithelium.