Tumor necrosis factor enhances endothelial cell susceptibility to oxygen toxicity: role of glutathione.
The effect of tumor necrosis factor-alpha (TNF) on hyperoxia-induced endothelial injury in vitro was investigated. TNF caused a time- and dose-dependent reduction in the number of viable pulmonary artery endothelial cells. The TNF-mediated endothelial cytotoxicity was more pronounced under hyperoxia (95% O2 and 5% CO2) than under normoxia (95% air and 5% CO2). Pretreatment of endothelial cells with TNF (0.01 micrograms/ml or 240 U/ml) for 18 h at normoxia reduced the intracellular concentration of total glutathione (GSH), whereas the concentration of oxidized GSH was increased. These TNF-treated endothelial cells were more susceptible to hyperoxia- or hydrogen peroxide-mediated cytotoxicity. TNF also induced changes in endothelial morphology and in the distribution and density of actin filaments. Exogenous GSH or L-2-oxothiazolidine-4-carboxylate, which enhanced endothelial GSH concentrations, partially protected endothelial cells against TNF-mediated cytotoxicity, morphologic changes, and actin filament redistribution, especially under the hyperoxic condition. These results suggest an important role of GSH in modulating endothelial response to TNF.
Marcho
Z
Z
Research Service, Department of Veterans Affairs Medical Center, Albany, NY 12208.
White
J E
JE
Higgins
P J
PJ
Tsan
M F
MF
D000199:Actins / Q000187:drug effects; D000818:Animals; D002417:Cattle; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D005978:Glutathione / Q000032:analysis / Q000502:physiology*; D006861:Hydrogen Peroxide / Q000633:toxicity; D010100:Oxygen / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000199:Actins; D014409:Tumor Necrosis Factor-alpha; D006861:Hydrogen Peroxide; D005978:Glutathione; D010100:Oxygen