We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Induction of interleukin-1beta, tumour necrosis factor-alpha and apoptosis in mouse organs by amphotericin B is neutralized by conjugation with arabinogalactan.
- Authors
Falk, Rama; Hacham, Moshe; Nyska, Abraham; Foley, Julie F; Domb, Abraham J; Polacheck, Itzhack
- Abstract
<bold>Objectives: </bold>To investigate the possibilities that: (i) organ toxicity of amphotericin B-deoxycholate (AMB-DOC) is related to induction of interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha) 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.<bold>Methods: </bold>Organ expression of IL-1beta and TNF-alpha 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.<bold>Results: </bold>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-1beta and TNF-alpha in kidney lysates. Unlike AMB-AG, AMB-DOC also induced enhanced IL-1beta and TNF-alpha 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-1beta and enhance secretion of TNF-alpha in kidneys, effects possibly involved in prevention of apoptosis.<bold>Conclusions: </bold>AMB-related toxicity is associated with induction of IL-1beta, TNF-alpha and apoptosis in organs. These effects were not observed with AMB-AG conjugate, suggesting its potential as a safer formulation for therapy.
- Subjects
AMPHOTERICIN B; ANIMAL experimentation; ANTIFUNGAL agents; APOPTOSIS; COMBINATION drug therapy; COMPARATIVE studies; CYTOKINES; INTERLEUKIN-1; KIDNEYS; RESEARCH methodology; MEDICAL cooperation; MICE; POLYSACCHARIDES; RESEARCH; TUMOR necrosis factors; EVALUATION research; PHARMACODYNAMICS
- Publication
Journal of Antimicrobial Chemotherapy (JAC), 2005, Vol 55, Issue 5, p713
- ISSN
0305-7453
- Publication type
journal article
- DOI
10.1093/jac/dki090