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Cadmium (Cd2+) is a widespread environmental pollutant, which is associated with a wide variety of cytotoxic and metabolic effects. Recent studies showed that intoxication with the heavy metal most importantly targets the integrity of the epithelial barrier.In our study, the lung epithelial cell line, NCI H441, was cultured with the endothelial cell line, ISO-HAS-1, as a bilayer on a 24-well HTS-Transwell® filter plate. This coculture model was exposed to various concentrations of CdCl2.The transepithelial electrical resistance decreased on the apical side only after treatment with high Cd2+ concentrations after 48 h. By contrast, a breakdown of TER to less than 5% of baseline could be observed much earlier (after 24 h) when Cd2+ was administered from the basal side. Observations of cell layer fragmentation and widening of intercellular spaces confirmed the barrier breakdown only for the basolaterally treated samples. Furthermore, the cytotoxicity and release of proinflammatory markers was enhanced if samples were exposed to Cd2+ from the basal side compared to treatment from the apical side. Moreover, we could demonstrate that a high concentration of Ca2+ could prevent the barrier-disrupting effect of Cd2+.In conclusion, the exposure of Cd2+ to cocultures of lung cells caused a decrease in TER, major morphological changes, a reduction of cell viability and an increase of cytokine release, but the effects markedly differed between the two modes of exposure. Therefore, our results suggest that intact epithelial TJs may play a major role in protecting the air–blood barrier from inhaled Cd2+.