Immunomodulatory and Protective Effects of Moxifloxacin againstCandida albicans-Induced Bronchopneumonia in Mice Injected with Cyclophosphamide

Abstract

In a previous study, moxifloxacin was shown to ameliorate immunosuppression and enhance cytokine production in several tissues, including the lungs of cyclophosphamide-injected mice. We examined here the effects of moxifloxacin on Candida albicans lung infection in cyclophosphamide-injected mice. Mice were injected on day 0 with 250 mg of cyclophosphamide/kg, and on days 1 to 4 they were given moxifloxacin at 22.5 mg/kg/day compared to controls given ceftazidime at 75 mg/kg/day or saline. On day 6, C. albicans (10 7 CFU/ mouse) was inoculated intratracheally, and animals were observed for the development of bronchopneumonia, weight loss, mortality, the presence of C. albicans, and lung cytokine production. Histopathology on day 10 postinoculation revealed bronchopneumonia in 50, 67, and 0% of saline-, ceftazidime-, and moxifloxacintreated mice, respectively (P < 0.05). The mortality rates were 28, 17, and 5%, respectively (P < 0.05), and weight loss occurred at 20, 32, and 0%, respectively (P < 0.05). By day 15, C. albicans was eliminated from all moxifloxacin-treated mice but was still isolated from lung homogenates of 50 to 60% of the saline-and ceftazidime-treated groups. Among the cytokines tested on days 0 to 15, we found an increased production of tumor necrosis factor alpha, KC (functional interleukin-8), and gamma interferon in the lungs of ceftazidimeand saline-treated controls compared to the moxifloxacin pretreatment that abolished their secretion. In conclusion, moxifloxacin protected cyclophosphamide-injected mice from C. albicans-induced lung infection and significantly reduced pneumonia, weight loss, and mortality despite the lack of direct antifungal activity. This is most likely due to an immunomodulating activity conferred by moxifloxacin, as shown in this model and in our previous studies. Its potential protective role should be studied in patients undergoing chemotherapy and immune suppression.

Anti-Inflammatory Effects of Moxifloxacin on Activated Human Monocytic Cells: Inhibition of NF-κB and Mitogen-Activated Protein Kinase Activation and of Synthesis of Proinflammatory Cytokines

“…The inhibitory effects described above confirm the results of previous in vivo studies showing that pretreatment with MXF of mice injected with cyclophosphamide and inoculated with C. albicans significantly inhibited neutrophilic infiltration and TNF-␣ and IL-8 production in the lungs (35).…”

“…It is of note that additional anti-inflammatory agents, such as sodium salicylate, acetylsalicylic acid, and sanguinarine, were also found to inhibit I-B degradation (8,22). The findings from previous in vivo studies (35) and the present in vitro data, which demonstrate and expand our understanding of the anti-inflammatory effects of MXF, provide further support for other observations relating to modulation of the inflammatory response by other quinolone compounds. In vitro studies with LPS-stimulated human monocytes have shown that ciprofloxacin, trovafloxacin, moxifloxacin, grepafloxacin, and levofloxacin have inhibitory effects on various proinflammatory cytokines, mainly IL-1␣, IL-1␤, ⌻⌵F-␣, IL-6, and IL-8 (3,5,9,21,30,45,47).…”

“…Exposure of monocytes to 10 ng of LPS per ml for a short period (4 h) induced a marked increase in the levels of IL-8 production by the cells. MXF at concentrations of 5, 10, and 20 g/ml inhibited the induction of IL-8 secretion by 26,35, and 40%, respectively (P Ͻ 0.05) (Fig. 1).…”

Moxifloxacin enhances antiproliferative and apoptotic effects of etoposide but inhibits its proinflammatory effects in THP-1 and Jurkat cells

“…Using a murine model of Candida pneumonia in immune-suppressed animals, we found that MXF exerted a protective anti-inflammatory effect, resulting in a marked decrease in bronchopneumonia and enhanced survival. This protective efficacy was associated with a significant reduction in IL-8 and TNF-a in lung homogenates and an inhibition of NF-kB nuclear mobilisation in alveolar macrophages and lung epithelial cells (Shalit et al, 2002).…”

“…It also had a protective anti-inflammatory effect in vivo in a model of Candida albicans pneumonia in immune suppressed animals, resulting in enhanced survival and reduction in IL-8 and TNF-a in lung homogenates (Shalit et al, 2002). In the present study, we investigated the effect of MXF alone and in combination with VP-16 on isolated human topo IIa activity and further studied the effect of the combination on cell proliferation, cytotoxicity and apoptosis in two tumourderived cell lines, THP-1 and Jurkat.…”