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- Title
Induction of interleukin-1, tumour necrosis factor-a and apoptosis in mouse organs by amphotericin B is neutralized by conjugation with arabinogalactan.
- Authors
Rama Falk; Moshe Hacham; Abraham Nyska; Julie F. Foley; Abraham J. Domb; Itzhack Polacheck
- Abstract
Objectives: To investigate the possibilities that: (i) organ toxicity of amphotericin B-deoxycholate (AMB-DOC) is related to induction of interleukin-1 (IL-1), tumour necrosis factor-a (TNF-a) and apoptosis in target organs; and (ii) the reduced toxicity resulting from the conjugation of AMB with water-soluble arabinogalactan (AMB-AG), is related to modulation of these parameters.Methods: Organ expression of IL-1 and TNF-a was evaluated by enzyme-linked immunosorbent assay (ELISA) in mouse organ biological fluids and in situ by immunohistochemistry. Tissue damage was evaluated histologically, and apoptosis was demonstrated by terminal dUTP nick end-labelling (TUNEL) staining. AMB-AG conjugate was compared with the micellar (AMB-DOC) and liposomal (AmBisome) AMB formulations.Results: Treatment with AMB-AG or AmBisome caused no observable histopathological damage in the kidneys. In contrast, treatment with AMB-DOC resulted in disruptive changes and apoptosis in renal tubular cells. These effects were found to correlate with induction of high levels of IL-1 and TNF-a in kidney lysates. Unlike AMB-AG, AMB-DOC also induced enhanced IL-1 and TNF-a expression in lysates of lungs, brain, liver and spleen. The marked elevation of these inflammation-apoptosis-promoting cytokines after treatment with AMB-DOC may mediate its systemic and local renal damage. Treatment with AMB-AG (but not AmBisome) appears to uniquely modulate the in situ expression of IL-1 and enhance secretion of TNF-a in kidneys, effects possibly involved in prevention of apoptosis.Conclusions: AMB-related toxicity is associated with induction of IL-1, TNF-a and apoptosis in organs. These effects were not observed with AMB-AG conjugate, suggesting its potential as a safer formulation for therapy.
- Subjects
APOPTOSIS; CELL death; CYTOKINES; NEPHROLOGY
- Publication
Journal of Antimicrobial Chemotherapy (JAC), 2005, Vol 55, Issue 5, p713
- ISSN
0305-7453
- Publication type
Article
- DOI
10.1093/jac/dki090