ATP depletion and loss of cell integrity in anoxic hepatocytes and silica-treated P388D1 macrophages.
The relationship between ATP depletion and the loss of cell integrity was examined in the killing of hepatocytes by anoxia and P388D1 macrophages by silica. ATP depletion is a feature of the reaction to either hazard. Treatment of hepatocytes, however, with antimycin, oligomycin, sodium azide, or N,N'-dicyclohexylcarbodiimide produced a rate and extent of ATP depletion comparable with anoxia without significant loss of viability. Treatment of P388D1 cells with 2-deoxyglucose plus antimycin, oligomycin, or sodium azide reproduced the loss of ATP accompanying silica particle intoxication. Again, there was no loss of viability. These data dissociate the loss of cellular ATP from the genesis of lethal injury in both cell types. ATP depletion was, however, associated with a loss of lysosomal integrity. With the metabolic inhibitors, loss of lysosomal integrity occurred in the absence of irreversible cell injury over the time course that anoxia and silica intoxication significantly damaged the cells. This implies that neither hazard produces lethal damage through mechanisms dependent on intracellular lysosomal enzyme release. While ATP depletion can cause lysosomal rupture in P388D1 macrophages, phagocytosis of silica particles in the absence of extracellular Ca2+ ions is associated with release of lysosomal contents without depletion of ATP or loss of cell integrity. Silica particles are concluded to interact directly with both the plasma and lysosomal membranes. The former leads to Ca2+ influx with resultant cell death and ATP depletion. The latter leads to release of lysosomal contents that is not followed by irreversible cell injury.
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002470:Cell Survival; D005260:Female; D000860:Hypoxia / Q000378:metabolism*; D007700:Kinetics; D007941:Leukemia P388 / Q000378:metabolism* / Q000473:pathology; D007942:Leukemia, Experimental / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008247:Lysosomes / Q000648:ultrastructure; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D012822:Silicon Dioxide / Q000494:pharmacology*
D012822:Silicon Dioxide; D000255:Adenosine Triphosphate