Journal Article

Induction of interleukin-1β, tumour necrosis factor-α and apoptosis in mouse organs by amphotericin B is neutralized by conjugation with arabinogalactan

Rama Falk, Moshe Hacham, Abraham Nyska, Julie F. Foley, Abraham J. Domb and Itzhack Polacheck

in Journal of Antimicrobial Chemotherapy

Volume 55, issue 5, pages 713-720
Published in print May 2005 | ISSN: 0305-7453
Published online May 2005 | e-ISSN: 1460-2091 | DOI: http://dx.doi.org/10.1093/jac/dki090
Induction of interleukin-1β, tumour necrosis factor-α and apoptosis in mouse organs by amphotericin B is neutralized by conjugation with arabinogalactan

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Objectives: To investigate the possibilities that: (i) organ toxicity of amphotericin B-deoxycholate (AMB-DOC) is related to induction of interleukin-1β (IL-1β), tumour necrosis factor-α (TNF-α) 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-1β and TNF-α 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-1β and TNF-α in kidney lysates. Unlike AMB-AG, AMB-DOC also induced enhanced IL-1β and TNF-α 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-1β and enhance secretion of TNF-α in kidneys, effects possibly involved in prevention of apoptosis.

Conclusions: AMB-related toxicity is associated with induction of IL-1β, TNF-α and apoptosis in organs. These effects were not observed with AMB-AG conjugate, suggesting its potential as a safer formulation for therapy.

Keywords: AMB toxicity; cytokines; AMB formulations; antifungals

Journal Article.  6353 words.  Illustrated.

Subjects: Medical Oncology ; Critical Care

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