JAC Advance Access originally published online on April 6, 2005
Journal of Antimicrobial Chemotherapy 2005 55(5):713-720; doi:10.1093/jac/dki090
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Induction of interleukin-1ß, tumour necrosis factor-
and apoptosis in mouse organs by amphotericin B is neutralized by conjugation with arabinogalactan
1 Department of Clinical Microbiology and Infectious Diseases, The Hebrew University—Hadassah Medical Center, PO Box 12000, Jerusalem 91120, Israel; 2 Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC 27709, USA; 3 Department of Medicinal Chemistry and Natural Products, The Hebrew University of Jerusalem—School of Pharmacy, PO Box 12065, Jerusalem, Israel
* Corresponding author. Tel: +972-2-677-6592; Fax: +972-2-641-9545; Email: itzhack.polacheck{at}huji.ac.il
Objectives: To investigate the possibilities that: (i) organ toxicity of amphotericin B-deoxycholate (AMB-DOC) is related to induction of interleukin-1ß (IL-1ß), tumour necrosis factor-
(TNF-) 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-1ß and TNF- 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-1ß and TNF- in kidney lysates. Unlike AMB-AG, AMB-DOC also induced enhanced IL-1ß and TNF- 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-1ß and enhance secretion of TNF- in kidneys, effects possibly involved in prevention of apoptosis.
Conclusions: AMB-related toxicity is associated with induction of IL-1ß, TNF- 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
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