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  • Title: Characteristics of amphotericin B-induced endothelial cell injury.
    Author: Cutaia M, Bullard SR, Rudio K, Rounds S.
    Journal: J Lab Clin Med; 1993 Feb; 121(2):244-56. PubMed ID: 8381844.
    Abstract:
    The polyene antibiotic amphotericin B has been implicated in vascular injury in human subjects and lung injury in an animal model. Our objective was to determine whether amphotericin B directly injures endothelial cells and to investigate several possible mechanisms of injury. Confluent cultures of bovine endothelial cells were incubated with different concentrations of amphotericin B for varying time periods. Injury was assessed by using a chromium 51 release assay, adherent cell counts, and morphologic changes in the endothelial cell monolayers by phase microscopy. Amphotericin B increased 51Cr release in a dose- and time-dependent fashion. Corresponding to changes in 51Cr release, amphotericin B decreased adherent cell counts and disrupted the monolayers. Incubation with vehicle alone (sodium desoxycholate, 8.2 micrograms/ml) did not alter any of these parameters. Incubation of cells with a dose of antibiotic (1 micrograms/ml), which did not produce overt cell injury, significantly increased membrane permeability to K+ ions and activated the sodium/potassium adenosine triphosphatase (Na/K ATPase). Inhibition of the ATPase at this same antibiotic concentration (1 micrograms/ml) produced endothelial cell injury equivalent to the magnitude of injury observed with high doses of the antibiotic (10 micrograms/ml). In the presence of 10% fetal calf serum, the injury at 24 hours was significantly attenuated. This protective effect could not be attributed to binding of the drug by albumin because varying concentrations of bovine serum albumin in minimal essential medium without other serum constitutents had no effect on the magnitude of injury. Incubation of cells with several exogenous oxygen radical scavengers (dimethylthiourea, catalase, and mannitol) or a decrease in ambient oxygen tension during antibiotic exposure did not alter the magnitude of injury. The results demonstrate that amphotericin B directly injures endothelial cells in a dose- and time-dependent manner and demonstrate the importance of the Na/K ATPase for the maintenance of normal endothelial cell function and viability in response to this form of injury.
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