Bleomycin-induced pulmonary endothelial cell injury: evidence for the role of iron-catalyzed toxic oxygen-derived species.
Bleomycin, an effective cancer chemotherapeutic agent, is associated with serious pulmonary toxicity. As an in vitro model of bleomycin pulmonary toxicity, this study examined the ability of bleomycin to injure chromium 51-labeled bovine pulmonary artery endothelial (BPAE) cells in an 18-hour cytotoxicity assay. The data indicate that bleomycin-mediated injury to cultured BPAE cells can be quantified by 51Cr release, expressed as cytotoxic index (CI). Bleomycin-mediated injury to 51Cr-labeled BPAE cells (CI 19.4 +/- 1.6) could be significantly reduced by the iron chelator deferoxamine, 10(-3) mol/L (CI 7.5 +/- 1.1, P less than 0.001), but not by ethylenediaminetetraacetic acid, 10(-5) mol/L (CI 19.8 +/- 2.2). Similarly, bleomycin-mediated injury to BPAE cells (monitored by lactate dehydrogenase release) with a CI 27.1 +/- 4.8 could be reduced by 10(-3) mol/L deferoxamine to CI 10.5 +/- 2.6 (P less than 0.01). In contrast, hyperoxia (95% O2) accelerated bleomycin (1 to 100 mU/ml) toxicity to BPAE cells (P less than 0.01, all comparisons). This study suggests that bleomycin-induced injury of pulmonary endothelial cells may be dependent in part on two critical factors in the cellular environment: the availability of iron to the cell and the ambient O2 concentration.
D000818:Animals; D001761:Bleomycin / Q000633:toxicity*; D002417:Cattle; D002478:Cells, Cultured; D002860:Chromium Radioisotopes; D003676:Deferoxamine / Q000494:pharmacology; D004492:Edetic Acid / Q000494:pharmacology; D004727:Endothelium / Q000187:drug effects; D007501:Iron / Q000502:physiology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D010100:Oxygen / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects*; D013482:Superoxide Dismutase / Q000494:pharmacology
D002860:Chromium Radioisotopes; D001761:Bleomycin; D004492:Edetic Acid; D007501:Iron; D007770:L-Lactate Dehydrogenase; D013482:Superoxide Dismutase; D003676:Deferoxamine; D010100:Oxygen