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Pentoxifylline modulates activation of human neutrophils by amphotericin B in vitro
G W Sullivan1, H T Carper, G L Mandell
1Department of Medicine, University of Virginia, Charlottesville 22908, USA.
Abstract:
The antifungal agent amphotericin B (AmB) alters neutrophil (polymorphonuclear leukocyte [PMN]) function, and this may be the mechanism for some of the adverse effects caused by AmB. AmB is a potent inhibitor of PMN migration, increases PMN adherence and aggregation, and primes PMN for increased oxidative activity in response to a second stimulus. AmB also stimulates mononuclear leukocytes (MNLs) to release inflammatory mediators which augment the effects of AmB on PMN function. In the present study, we observed that the methylxanthine derivative pentoxifylline decreased the effects of AmB on PMN function. AmB (2 micrograms/ml) priming doubled PMN chemiluminescence stimulated by fMet-Leu-Phe. In the presence of MNLs, AmB priming increased fMet-Leu-Phe-stimulated PMN chemiluminescence to 622% of unprimed PMN activity. Pentoxifylline (100 microM) blunted the rise in AmB-augmented PMN chemiluminescence in the presence of MNLs to 282% of unprimed PMN activity, and pentoxifylline metabolites were active at 10 microM. Pentoxifylline (100 microM) also blocked AmB-augmented PMN oxidative activity in whole blood, as measured by nitroblue tetrazolium reduction. In the presence of MNL, AmB (2 micrograms/ml) doubled the expression of the important PMN adherence factor Mac-1. Pentoxifylline (1 mM) decreased AmB-stimulated PMN Mac-1 expression back to unstimulated amounts. In the presence of MNLs, AmB (2 micrograms/ml) decreased PMN nondirected and directed migration to fMet-Leu-Phe to 40 and 38% of control PMN migration, respectively. Pentoxifylline (300 microM) counteracted AmB inhibition of nondirected and directed migration to fMet-Leu-Phe, resulting in migration that was 71 and 87% of control PMN migration, respectively. In contrast, the methylxanthine caffeine (100 muM) increased AmB-enhanced chemiluminescence but did not affect AmB-inhibited PMN migration. Pentoxifylline should be evaluated as adjunctive therapy to lessen the inflammatory damage caused by AmB.
Insights
Pentoxifylline reduces the inflammatory effects of amphotericin B (AmB) on neutrophils (PMNs). This methylxanthine derivative counteracts AmB-induced increases in PMN oxidative activity and Mac-1 expression, while restoring PMN migration.
Area of Science:
- Immunology
- Pharmacology
Background:
- Amphotericin B (AmB) is an antifungal agent known to alter neutrophil (polymorphonuclear leukocyte [PMN]) function, potentially causing adverse effects.
- AmB impairs PMN migration, enhances adherence and aggregation, and primes PMNs for increased oxidative activity. It also stimulates mononuclear leukocytes (MNLs) to release mediators that augment these effects on PMNs.
Purpose of the Study:
- To investigate the effects of the methylxanthine derivative pentoxifylline on AmB-induced alterations in PMN function.
- To determine if pentoxifylline can mitigate the inflammatory responses mediated by AmB in the presence of MNLs.
Main Methods:
- Assessed PMN chemiluminescence, oxidative activity (nitroblue tetrazolium reduction), Mac-1 expression, and directed/nondirected migration in response to AmB and pentoxifylline.
- Experiments were conducted with and without the presence of mononuclear leukocytes (MNLs) to evaluate synergistic effects.
Main Results:
- Pentoxifylline significantly blunted AmB-augmented PMN chemiluminescence and oxidative activity, particularly in the presence of MNLs.
- Pentoxifylline counteracted AmB-induced increases in PMN Mac-1 expression and restored AmB-inhibited PMN migration.
- Caffeine, another methylxanthine, enhanced AmB-induced chemiluminescence but did not affect AmB-inhibited PMN migration.
Conclusions:
- Pentoxifylline effectively mitigates key inflammatory effects of amphotericin B on neutrophils.
- Pentoxifylline demonstrates potential as an adjunctive therapy to reduce AmB-associated inflammatory damage.
- The findings suggest a therapeutic role for pentoxifylline in managing AmB toxicity.