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Effects of antifungal agents on the function of human neutrophils in vitro
E Roilides1, T J Walsh, M Rubin
1Infectious Diseases Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland 20892.
Abstract:
Polymorphonuclear leukocytes (PMNs) are an important component of the host defense against fungi. We investigated the influence of five antifungal agents on PMN function and compared them with amphotericin B (AmB). The in vitro effects of AmB, flucytosine, ketoconazole, fluconazole, Sch-39304, and cilofungin (LY121019) on chemotaxis, phagocytosis, oxidative metabolism of PMN as reflected by superoxide anion (O2-) generation, and intracellular killing of Candida albicans blastoconidia were examined. With regard to chemotaxis in response to N-formylmethionyl-leucyl-phenylalanine, as measured by the multiwell chamber method, AmB induced a marked decrease (greater than or equal to 5 micrograms/ml), whereas ketoconazole at 5 micrograms/ml enhance it. Phagocytosis was significantly decreased after pretreatment of PMNs with AmB and Sch-39304 (greater than 5 and 1 to 10 micrograms/ml, respectively). O2- production after stimulation of PMNs with N-formylmethionyl-leucyl-phenyl-alanine was significantly decreased by AmB (greater than 5 micrograms/ml) and enhanced by Sch-39304 (1 to 5 micrograms/ml). In contrast, intracellular killing, as tested by methylene blue staining, was enhanced by ketoconazole (5 micrograms/ml) and Sch-39304 (1 to 5 micrograms/ml). Flucytosine, fluconazole, and cilofungin did not affect PMN function at therapeutic concentrations. The results of this comprehensive study indicate that AmB, flucytosine, cilofungin, and the newer azoles, at safely achievable concentrations, generally do not suppress PMN function at therapeutic enhance selective functions.
Insights
This study examined how five antifungal drugs affect polymorphonuclear leukocyte (PMN) functions. Most antifungals, at therapeutic doses, do not suppress PMN immune responses, with some even enhancing them.
Area of Science:
- Immunology
- Pharmacology
- Mycology
Background:
- Polymorphonuclear leukocytes (PMNs) are crucial for fungal host defense.
- Understanding antifungal agent effects on PMN function is vital for effective treatment strategies.
Purpose of the Study:
- To investigate the in vitro effects of amphotericin B (AmB), flucytosine, ketoconazole, fluconazole, Sch-39304, and cilofungin on key PMN functions.
- To compare these effects with amphotericin B and assess their impact on host defense.
Main Methods:
- Evaluated PMN chemotaxis, phagocytosis, oxidative metabolism (superoxide anion generation), and intracellular killing of Candida albicans.
- Utilized multiwell chamber method for chemotaxis and methylene blue staining for intracellular killing assays.
Main Results:
- Amphotericin B decreased PMN chemotaxis, phagocytosis, and superoxide anion generation at higher concentrations.
- Ketoconazole and Sch-39304 demonstrated varied effects, enhancing some functions like intracellular killing.
- Flucytosine, fluconazole, and cilofungin showed no significant impact on PMN function at therapeutic concentrations.
Conclusions:
- Most tested antifungal agents, including newer azoles, do not suppress PMN function at therapeutic concentrations.
- Some agents may even selectively enhance specific PMN functions, supporting their role in host defense against fungal infections.