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      Immunomodulatory Effect of Gatifloxacin on Mouse Peritoneal Macrophages in vitro and in Models of Endotoxin-Induced Rat Conjunctivitis and Rabbit Bacterial Keratitis

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          Abstract

          Aim: To determine the anti-inflammatory activity of gatifloxacin in ophthalmic use. Methods: The following 3 experiments were carried out. (1) Rabbits were inoculated intracorneally with methicillin-resistant Staphylococcus aureus and topically treated with gatifloxacin or levofloxacin. The severity of infection and viable bacterial count were assessed. (2) Thioglycollate-elicited mouse peritoneal macrophages were stimulated by Pseudomonas lipopolysaccharides (LPS) in the presence of graded concentrations of fluoroquinolones, and macrophage-derived tumor necrosis factor α (TNF-α) was assessed. (3) The effects of fluoroquinolones on TNF-α production were compared in an LPS-induced rat conjunctivitis model. Results: In the rabbit keratitis model, the ocular inflammation was significantly reduced by gatifloxacin as compared to levofloxacin but there was no significant difference between the groups in the number of viable bacteria. Gatifloxacin and levofloxacin suppressed TNF-α production in mouse macrophages in a concentration-dependent manner, and the effect of gatifloxacin was more potent than that of levofloxacin. Moxifloxacin exhibited no effect in this condition. In the rat conjunctivitis model, the tissue TNF-α level was significantly reduced only in the group instilled with gatifloxacin ophthalmic solution. Conclusion: These results indicate that gatifloxacin has not only antibacterial activity but an anti-inflammatory action caused by at least inhibiting TNF-α production at the doses used in topical ophthalmic therapy.

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          Immunomodulatory effects of quinolones.

          We review data on the in-vitro, ex-vivo, in-vivo, and clinical effects of fluoroquinolones on the synthesis of cytokines and their mechanisms of immunomodulation. In general, most fluoroquinolone derivatives superinduce in-vitro interleukin 2 synthesis but inhibit synthesis of interleukin 1 and tumour necrosis factor (TNF)alpha; furthermore, they enhance significantly the synthesis of colony-stimulating factors (CSF). Fluoroquinolones affect in-vivo cellular and humoral immunity by attenuating cytokine responses. Interleukins 10 and 12 have an important role in the functional differentiation of immunocompetent cells and trigger the initiation of the acquired immune response. In addition, certain fluoroquinolones were seen to enhance haematopoiesis by increasing the concentrations of CSF in the lung as well as in the bone marrow and shaft. Those fluoroquinolones exerting significant effects on haematopoiesis were those with a cyclopropyl moiety at position N1 of their quinolone core structure. Mechanisms that could explain the various immunomodulatory effects of fluoroquinolones include: (1) an effect on intracellular cyclic adenosine-3',5'-monophosphate and phosphodiesterases; (2) an effect on transcription factors such as nuclear factor (NF)kappaB, activator protein 1, NF-interleukin-6 and nuclear factor of activated T cells; and (3) a triggering effect on the eukaryotic equivalent of bacterial SOS response with its ensuing intracellular events. Further studies are required, especially in the clinical setting to exploit fully the potential of the immunomodulatory effect of fluoroquinolones during, for example, immunosuppression, chronic airway inflammatory diseases, and sinusitis.
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            Anti-inflammatory effects of moxifloxacin on activated human monocytic cells: inhibition of NF-kappaB and mitogen-activated protein kinase activation and of synthesis of proinflammatory cytokines.

            We previously showed that moxifloxacin (MXF) exerts protective anti-inflammatory effects in immunosuppressed mice infected with Candida albicans by inhibiting interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-alpha) production in the lung. Immunohistochemistry demonstrated inhibition of nuclear factor (NF)-kappaB translocation in lung epithelium and macrophages in MXF-treated mice. In the present study we investigated the effects of MXF on the production of proinflammatory cytokines (i.e., IL-8, TNF-alpha, and IL-1beta) by activated human peripheral blood monocytes and THP-1 cells and analyzed the effects of the drug on the major signal transduction pathways associated with inflammation: NF-kappaB and the mitogen-activated protein kinases ERK and c-Jun N-terminal kinase (JNK). The levels of IL-8, TNF-alpha, and IL-1beta secretion rose 20- and 6.7-fold in lipopolysaccharide (LPS)-activated monocytes and THP-1 cells, respectively. MXF (5 to 20 microg/ml) significantly inhibited cytokine production by 14 to 80% and 15 to 73% in monocytes and THP-1 cells, respectively. In THP-1 cells, the level of NF-kappaB nuclear translocation increased fourfold following stimulation with LPS-phorbol myristate acetate (PMA), and this was inhibited (38%) by 10 microg of MXF per ml. We then assayed the degradation of inhibitor (I)-kappaB by Western blotting. LPS-PMA induced degradation of I-kappaB by 73%, while addition of MXF (5 microg/ml) inhibited I-kappaB degradation by 49%. Activation of ERK1/2 and the 46-kDa p-JNK protein was enhanced by LPS and LPS-PMA and was significantly inhibited by MXF (54 and 42%, respectively, with MXF at 10 microg/ml). We conclude that MXF suppresses the secretion of proinflammatory cytokines in human monocytes and THP-1 cells and that it exerts its anti-inflammatory effects in THP-1 cells by inhibiting NF-kappaB, ERK, and JNK activation. Its anti-inflammatory properties should be further assessed in clinical settings.
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              Mode of action of long-term low-dose macrolide therapy for chronic sinusitis in the light of neutrophil recruitment.

              Chronic sinusitis is a common inflammatory upper respiratory tract disease. One of the prominent features of this disease is persistent purulent effusion containing numerous emigrated neutrophils in the paranasal sinuses. Recent advances in sinusitis research have revealed two positive feedback mechanisms that explain the chronic neutrophil accumulation in the sinus. First, interleukin (IL)-1beta secreted by monocytes, macrophages and fibroblasts upregulates the expression of E-selectin and intercellular adhesion molecule-1 (ICAM-1) in vascular endothelial cells, and thereby induces the extravascular transmigration of neutrophils. The emigrated neutrophils then secrete IL-1beta, which amplifies the expression of E-selectin and ICAM-1, resulting in further neutrophil infiltration. Second, chemoattractants including IL-8 in the sinus effusion initiate neutrophil exudation. Emigrated neutrophils then secrete IL-8, which elicits further neutrophil accumulation in the sinus effusion. Long-term low-dose macrolide therapy was first introduced for the treatment of diffuse panbronchiolitis in the 1980's. In the 1990's it was also shown to be an effective treatment for chronic sinusitis. The inhibitory effect of macrolides on neutrophil infiltration in inflammatory sites has been well documented in these diseases. Several lines of evidence indicate that macrolides do not function simply as a bactericide. In vitro studies have demonstrated various effects of macrolides on immunocompetent cells, inflammatory cells and airway epithelial cells. It has been shown that macrolides inhibit the production of IL-8 and IL-1beta and the expression of ICAM-1, suggesting that macrolides block the aforementioned dual positive feedback system of neutrophil recruitment and thereby exert their clinical efficacy in the treatment of chronic sinusitis. The inhibitory effects of macrolides on multiple steps in the process of neutrophil recruitment are presumably mediated by the inhibition of transcription factors such as nuclear factor-kB and activator protein-1. Further investigation of the mode of action of macrolides at the molecular level would lead to the development of safer and more effective drugs for the treatment of chronic sinusitis. In addition, the possible risk of this therapy such as the occurrence of resistant strains have to be carefully surveyed hereafter.
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                Author and article information

                Journal
                ORE
                Ophthalmic Res
                10.1159/issn.0030-3747
                Ophthalmic Research
                S. Karger AG
                0030-3747
                1423-0259
                2008
                February 2008
                25 January 2008
                : 40
                : 2
                : 54-60
                Affiliations
                Research Laboratories, Senju Pharmaceutical Co., Ltd., Kobe, Japan
                Article
                113883 Ophthalmic Res 2008;40:54–60
                10.1159/000113883
                18223298
                3cba3235-2431-4a71-99fe-d5ee60775e4f
                © 2008 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 03 May 2007
                : 30 May 2007
                Page count
                Figures: 5, References: 14, Pages: 7
                Categories
                Original Paper

                Vision sciences,Ophthalmology & Optometry,Pathology
                Levofloxacin,Macrophage,Gatifloxacin,Lipopolysaccharides,Immunomodulatory activity,Moxifloxacin,Tumor necrosis factor,Anti-inflammation,Bacterial infection

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