In vivo and in vitro effects of fluoroquinolones on lipopolysaccharide-induced pro-inflammatory cytokine production

Ogino, Hiromi; Fujii, Masashi; Ono, Mariko; Maezawa, Kayoko; Hori, Seiji; Kizu, Junko

doi:10.1007/s10156-009-0680-1

Cited by 57 publications

(41 citation statements)

References 14 publications

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“…Moreover, between 10 and 100 mg/ml ciprofloxacin was required to inhibit the in vitro TNF-a production by murine peritoneal macrophages. In the current study, based on the chronic administration of antibiotics in the drinking water (86 mg/kg/day) and the 60-min t 1/2 for ciprofloxacin in mice (43,44), an estimated plasma antibiotic concentration of 1.6 mg/ ml, which is substantially lower than the reported levels for antiinflammatory effects in vitro (42), would be achieved in the SGVHD animals. Thus, the observed effects of antibiotic therapy on the SGVHD model are most likely not to be due to the inhibitory effects of ciprofloxacin on the immune responses associated with the development of SGVHD.…”

Section: Discussionmentioning

confidence: 80%

“…A single high dose (167-214 mg/kg) injection of ciprofloxacin has been shown to inhibit LPS-induced mortality and proinflammatory cytokine production in vivo (41). Similarly, Ogino et al (42) demonstrated that a single injection of ciprofloxacin prior to LPS challenge inhibited production of TNF-a, but not of other inflammatory cytokines. Moreover, between 10 and 100 mg/ml ciprofloxacin was required to inhibit the in vitro TNF-a production by murine peritoneal macrophages.…”

Section: Discussionmentioning

confidence: 95%

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Murine Syngeneic Graft-Versus-Host Disease Is Responsive to Broad-Spectrum Antibiotic Therapy

Brandon

Jennings

Kaplan

et al. 2011

The Journal of Immunology

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Murine syngeneic graft-versus-host disease (SGVHD) initiates colon and liver inflammation following lethal irradiation, reconstitution with syngeneic bone marrow transplantation, and therapy with the immunosuppressive agent cyclosporine A. Previous studies have demonstrated that the inducible disease is mediated by CD4+ T cells with increased reactivity of peripheral and liver-associated lymphocytes against intestinal microbial Ags. In the current report, studies were performed to analyze the specificity of the CD4+ T cell response of T cells isolated from diseased animals and to determine the in vivo role of the microbiota to the development of SGVHD. Increased major histocompatibility Ag (MHC) class II-restricted responsiveness of SGVHD CD4+ T cells against microbial Ags isolated from the ceca of normal animals was observed. The enhanced proliferative response was observed in the CD62L− memory population of CD4+ T cells. To determine the role of the bacterial microbiota in the development of murine SGVHD, control and CsA-treated bone marrow transplantation animals were treated with broad-spectrum antibiotics (metronidazole, ciprofloxacin) after transplantation. Cyclosporine A-treated animals that were given antibiotic therapy failed to develop clinical symptoms and pathological lesions in the target tissues characteristic of SGVHD. Furthermore, the reduction in intestinal bacteria resulted in the elimination of the enhanced antimicrobial CD4+ T cell response and significantly reduced levels of the inflammatory cytokines, IFN-γ, IL-17, and TNF-α. The elimination of the disease-associated inflammatory immune responses and pathology by treatment with broad-spectrum antibiotics definitively links the role of the microbiota and microbial-specific immunity to the development of murine SGVHD.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 95%

Murine Syngeneic Graft-Versus-Host Disease Is Responsive to Broad-Spectrum Antibiotic Therapy

Brandon

Jennings

Kaplan

et al. 2011

The Journal of Immunology

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“…Significant evidence of in vivo and in vitro antiinflammatory activities of fluoroquinolones has been reported previously [38][39][40][41][42]. In particular, with regard to the effects of fluoroquinolones on pro-inflammatory signaling intermediates, it has been reported that norfloxacin and gemifloxacin reduce NFkB expression and activation [43][44][45], and that garenoxacin inhibits Erk1/2 phosphorylation [46].…”

Section: Discussionmentioning

confidence: 97%

A signalome screening approach in the autoinflammatory disease TNF receptor associated periodic syndrome (TRAPS) highlights the anti-inflammatory properties of drugs for repurposing

Todd

Negm

Reps

et al. 2017

Pharmacological Research

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2Abbreviations: BCA, bicinchoninic acid; CV, coefficient of variation; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PBMCs, peripheral blood mononuclear cells; RPPA, reverse phase protein array; SSMD, strictly standardised mean difference; TNFR1, tumour necrosis factor receptor-1; TRAPS, TNF receptor associated periodic syndrome; WT, wild type. 3ABSTRACT: TNF Receptor Associated Periodic Syndrome (TRAPS) is an autoinflammatory disease caused by mutations in TNF Receptor 1 (TNFR1). Current therapies for TRAPS are limited and do not target the pro-inflammatory signalling pathways that are central to the disease mechanism. Our aim was to identify drugs for repurposing as anti-inflammatories based on their ability to down-regulate molecules associated with inflammatory signalling pathways that are activated in TRAPS. This was achieved using rigorously optimised, high through-put cell culture and reverse phase protein microarray systems to screen compounds for their effects on the TRAPS-associated inflammatory signalome. 1360 approved, publically available, pharmacologically active substances were investigated for their effects on 40 signalling molecules associated with pro-inflammatory signalling pathways that are constitutively upregulated in TRAPS. The drugs were screened at four ten-fold concentrations on cell lines expressing both wild-type (WT) TNFR1 and TRAPS-associated C33Y mutant TNFR1, or WT TNFR1 alone; signalling molecule levels were then determined in cell lysates by the reversephase protein microarray. A novel mathematical methodology was developed to rank the compounds for their ability to reduce the expression of signalling molecules in the C33Y-TNFR1 transfectants towards the level seen in the WT-TNFR1 transfectants. Seven high-ranking drugs were selected and tested by RPPA for effects on the same 40 signalling molecules in lysates of peripheral blood mononuclear cells (PBMCs) from C33Y-TRAPS patients compared to PBMCs from normal controls. The fluoroquinolone antibiotic lomefloxacin, as well as others from this class of compounds, showed the most significant effects on multiple pro-inflammatory signalling pathways that are constitutively activated in TRAPS; lomefloxacin dose-dependently significantly reduced expression of 7/40 signalling molecules across the Jak/Stat, MAPK, NF-kB and PI3K/AKT pathways. This study demonstrates the power of signalome screening for identifying candidates for drug repurposing.

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“…In vivo, these differences could explain different grade of morbidity for different antibiotics. Quinolones and aminoglycosides cause a milder inflammatory response than beta-lactams, especially those beta-lactams whose site of action is PBP-3, such as ceftazidime and aztreonam [54]. Imipenem binds to PBP-2 and so, it also causes a milder response than the former agents.…”

Section: Pro-inflammatory Effect Of Bacterial Destructionmentioning

confidence: 98%

Antibiotics in Endophthalmitis: Microbiological and Pharmacokinetic Considerations

López‐Cabezas¹,

Muner²,

Massa³

et al. 2010

CCP

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Ocular infections must be treated with active antibiotics which could be administered by different routes: topical, systemic or intravitreal. In the case of endophthalmitis, the most important factor to avoid permanent damage of retina is an early antibiotic onset. Topical application of these drugs would be ineffective in the treatment of endophthalmitis, because of their poor penetration into the ocular globe. Systemic and intravitreal route of administration are the preferred in this setting, although for hydrophilic antibiotics, such as aminoglycosides, beta-lactams and glycopeptides, diffusion from plasma to vitreous cavity is not high enough to assure clinical efficacy. Intravitreal injection should be the favourite route of administration in this case. Ocular penetration of linezolid and fluorquinolones after systemic administration is excellent; hence intravitreal injections for these agents are not needed to achieve therapeutic concentrations at the vitreous cavity.

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In vivo and in vitro effects of fluoroquinolones on lipopolysaccharide-induced pro-inflammatory cytokine production

Cited by 57 publications

References 14 publications

Murine Syngeneic Graft-Versus-Host Disease Is Responsive to Broad-Spectrum Antibiotic Therapy

Murine Syngeneic Graft-Versus-Host Disease Is Responsive to Broad-Spectrum Antibiotic Therapy

A signalome screening approach in the autoinflammatory disease TNF receptor associated periodic syndrome (TRAPS) highlights the anti-inflammatory properties of drugs for repurposing

Antibiotics in Endophthalmitis: Microbiological and Pharmacokinetic Considerations

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