Oxygen-mediated impairment of human pulmonary endothelial cell growth: evidence for a specific threshold of toxicity.
Oxygen toxicity to the lung is characterized by injury of the pulmonary capillary endothelium with progressive loss of functioning alveolar-capillary units. Current concepts suggest that the risk of O2 toxicity in human subjects is greatly increased with O2 concentrations exceeding 50% to 60%, although there are no data to support a cellular basis for this apparent threshold of toxicity. Our study suggests that a cellular threshold may exist in human pulmonary endothelial cells for O2 toxicity. Hyperoxia was directly toxic to cultured human pulmonary artery endothelial (HPAE) cells, with impairment of replicative function, expressed as growth impairment (GI) index, monitored by two independent parameters: cell number determination and tritiated thymidine incorporation. Impaired cell growth occurred as early as 8 hours after beginning exposure to 95% O2 and with concentrations as low as 60% during a 48-hour incubation. For example, 60% O2 resulted in an impairment of HPAE cell growth at 48 hours with a GI index (cell number) of 37.5 +/- 2.1 (p less than 0.001, comparison with control cells in normoxia). Furthermore, 95% O2 impaired cell growth, as monitored by tritiated thymidine incorporation, as early as 8 hours after exposure (GI index of 43.6 +/- 4.9) however, the injury was completely reversible when cells were reincubated in normoxia for 6 hours (GI index of 4.2 +/- 4.7), p less than 0.001. O2 toxicity was associated with an increase in cellular glutathione levels but was not associated with a detectable loss of antioxidant enzyme activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Martin
W J
WJ
Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.
Kachel
D L
DL
D002374:Catalase / Q000378:metabolism; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D010100:Oxygen / Q000008:administration & dosage* / Q000494:pharmacology / Q000633:toxicity; D014176:Protein Biosynthesis; D011651:Pulmonary Artery / Q000166:cytology* / Q000187:drug effects; D012313:RNA / Q000096:biosynthesis; D013482:Superoxide Dismutase / Q000378:metabolism
D012313:RNA; D004247:DNA; D007770:L-Lactate Dehydrogenase; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D005978:Glutathione; D010100:Oxygen