Abstract
Primary cultures of human lung cells can serve as a model system to study the mechanisms underlying the effects of irritants in air and to get a deeper insight into the (patho)physiological roles of the xenobiotic detoxification systems. For 99 human lung cancer cases the culture duration for bronchial epithelium and peripheral lung cells (PLC) are given in term of generations and weeks. Using this system, we investigated whether and how prostaglandins (PG) modify multidrug resistance related protein (MRP) function in normal human lung cells. PGF2α had no effect on MRP function, whereas PGE2 induced MRP activity in cultured NHBECs. The transport activity study of MRP in NHBEC, PLC, and A549 under the effect of exogenously supplied PGF2α (10 μM, 1 day) using single cell fluorimetry revealed no alteration in transport activity of MRP. PG concentrations were within the physiological range. COX I and II inhibitors indomethacin (5, 10 μM) and celecoxib (5, 10 μM) could substantially decrease the transport activity of MRP in NHBEC, PLC, and A549 in 1- and 4-day trials. Prostaglandin E2 did not change cadmium-induced caspase 3/7 activation in NHBECs and had no own effect on caspase 3/7 activity. Cadmium chloride (5, 10 μM) was an effective inducer of caspase 3/7 activation in NHBECs with a fivefold and ninefold rise of activity. In primary human lung cells arachidonic acid activates MRP transport function only in primary epithelial lung cells by prostaglandin E2 but not by F2α mediated pathways and this effect needs some time to develop.
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Acknowledgments
The material from lung resections were obtained from cooperation with Dr. Stephan Hofmann, Clinic for lung and chest surgery, Martin Luther University and we thank him for his continuous support. We thank Hedwig Grygier, Thea Hensel Dagmar Funk, and Tina Roeder for excellent technical assistance. Research described in this article was supported by the External Research program of Philip Morris Incorporated and Deutsche Forschungsgesellschaft (DFG) Graduiertenkolleg (A. Torky).
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Abdelrahman Torky and Anja Raemisch have contributed equally to this study.
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Torky, A., Raemisch, A., Glahn, F. et al. Arachidonic acid pathway activates multidrug resistance related protein in cultured human lung cells. Arch Toxicol 82, 323–332 (2008). https://doi.org/10.1007/s00204-007-0251-0
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DOI: https://doi.org/10.1007/s00204-007-0251-0