title: Bleomycin-induced pulmonary endothelial cell injury: evidence for the role of iron-catalyzed toxic oxygen-derived species.
abstract: 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.
mesh_terms: 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
chemical_list: D002860:Chromium Radioisotopes; D001761:Bleomycin; D004492:Edetic Acid; D007501:Iron; D007770:L-Lactate Dehydrogenase; D013482:Superoxide Dismutase; D003676:Deferoxamine; D010100:Oxygen