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JAC Advance Access originally published online on August 13, 2003
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Journal of Antimicrobial Chemotherapy (2003) 52, 428-434
© 2003 The British Society for Antimicrobial Chemotherapy

Effect of amphotericin B treatment on kinetics of cytokines and parameters of fungal load in neutropenic rats with invasive pulmonary aspergillosis

Martin J. Becker*, Siem de Marie, Marcel H. A. M. Fens, Henri A. Verbrugh and Irma A. J. M. Bakker-Woudenberg

Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Center Rotterdam, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

Received 20 March 2003; returned 4 May 2003; revised 12 June 2003; accepted 12 June 2003

Objective: The kinetics of various parameters of fungal load and cytokines were investigated, in order to acquire insight into the pathogenesis of invasive pulmonary aspergillosis (IPA) during antifungal treatment with amphotericin B.

Methods: Neutropenic rats with left-sided IPA received either treatment with amphotericin B or remained untreated. At 0, 4, 8, 16, 24, 48, 72 and 120 h after fungal inoculation, the rats were dissected. The size of the macroscopic pulmonary lesions, the number of cfu and amounts of chitin were determined in the infected left lung. Galactomannan concentrations were measured both in the left lung and serum. The cytokines tumour necrosis factor (TNF)-{alpha}, interleukin (IL)-1ß, IL-6, interferon (IFN)-{gamma}, IL-4, IL-10, and the chemokines macrophage inflammatory protein (MIP)-2 and monocyte chemoattractant protein (MCP)-1 were determined quantitatively by ELISA in the infected left lung, uninfected right lung and serum.

Results: Amphotericin B treatment of IPA resulted in changed aspect of pulmonary lesions and significantly reduced levels of left lung chitin (72 and 120 h), left lung galactomannan (72 and 120 h) and serum galactomannan (120 h), but not left lung cfu, compared with untreated infected rats. In addition, amphotericin B treatment resulted in a significant decrease in levels of left lung IL-6 (at 72 and 120 h), MIP-2 (at 120 h) and MCP-1 (at 120 h). No local or systemic increases in TNF-{alpha}, IL-1ß or IFN-{gamma} were observed during infection.

Conclusion: It is concluded that treatment with amphotericin B results in decreased fungal load in the infected lung. This reduction in fungal load probably results in a decreased local inflammatory response, as measured by decreased levels of IL-6, MIP-2 and MCP-1 in the infected lung.

Keywords: chemokines, interleukins, chitin, galactomannan, Aspergillus

* Corresponding author. Tel: +31-10-4087827; Fax: +31-10-4089454; E-mail: m.becker@erasmusmc.nl


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