Neutralizing antibody against granulocyte/macrophage colony–stimulating factor inhibits inflammatory response in experimental otitis media

Kariya, Shin; Okano, Mitsuhiro; Higaki, Toru; Makihara, Seiichiro; Tamano, Haruna; Eguchi, Mika; Nishizaki, Kazunori

doi:10.1002/lary.23795

Cited by 11 publications

(11 citation statements)

References 22 publications

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“…GM-CSF has been reported to promote neutrophil recruitment during acute pulmonary inflammation 18–21 and is also required for full recruitment of neutrophils and production of CXCL1 (KC) in an experimental model of otitis media. 48 Within the gut, GM-CSF has also been shown to promote neutrophil recruitment during 2,4,6-trinitrobenzenesulfonic acid (TNBS)-colitis. 49 Additionally, one study suggests that GM-CSF can function directly as a chemoattractant for neutrophils.…”

Section: Discussionmentioning

confidence: 99%

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Role of GM-CSF in the inflammatory cytokine network that regulates neutrophil influx into the colonic mucosa duringClostridium difficileinfection in mice

et al. 2014

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Clostridium difficile infection in antibiotic-treated mice results in acute colitis characterized by severe intestinal histopathology, robust neutrophil influx, and increased expression of numerous inflammatory cytokines, including GM-CS F. We utilized a neutralizing monoclonal antibody (mAb) against GM-CS F in a murine model to study the role of GM-CS F during acute C. difficile colitis. Cefoperazone-treated mice were challenged with C. difficile (strain 630) spores. Expression of GM-CS F was significantly increased in animals challenged with C. difficile. Treatment with an anti-GM-CS F mAb did not alter C. difficile colonization levels, weight loss, or expression of IL-22 and RegIIIγ. However, expression of the inflammatory cytokines TNFα and IL-1β, as well as iNOS, was significantly reduced following anti-GM-CS F treatment. Expression of the neutrophil chemokines CXCL1 and CXCL2, but not the chemokines CC L2, CC L4, CXCL9, and CXCL10, was significantly reduced by anti-GM-CS F treatment. Consistent with a decrease in neutrophil-attractant chemokine expression, there were fewer neutrophils in histology sections and a reduction in the expression of secretory leukocyte protease inhibitor (SLPI), a tissue anti-protease that protects against damage by secreted neutrophil elastase. These data indicate that GM-CS F plays a role in the inflammatory signaling network that drives neutrophil recruitment in response to C. difficile infection but does not appear to play a role in clearance of the infection.

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Section: Discussionmentioning

confidence: 99%

“…GM-CSF also promotes TNFα production during middle-ear inflammation. 48 Inflammatory cytokine expression during chemically-induced colitis is also dependent upon GM-CSF. 22 Consistent with other reports, our data strongly suggest that GM-CSF promotes inflammatory cytokine expression during C. difficile colitis.…”

Section: Discussionmentioning

confidence: 99%

Role of GM-CSF in the inflammatory cytokine network that regulates neutrophil influx into the colonic mucosa duringClostridium difficileinfection in mice

et al. 2014

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“…The pathogenesis and pathophysiology of OM are affected by multiple factors, including inflammatory mediators, Eustachian tube dysfunction, and pathogenicity of pathogens [1]. Copious studies have also indicated that a broad array of cytokines and chemokines are involved in the pathogenesis of OM.…”

Section: Introductionmentioning

confidence: 99%

Blocking macrophage migration inhibitory factor activity alleviates mouse acute otitis media in vivo

Zhang

Zheng

et al. 2014

Immunology Letters

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This study was to investigate the role of macrophage migration inhibitory factor (MIF) in mouse acute otitis media (AOM), we hypothesize that blocking MIF activity will relieve mouse AOM. A mouse AOM model was constructed by injecting lipopolysaccharide (LPS) into the middle ear of C57BL/6 mice through the tympanic membrane (TM). MIF levels were measured by real-time PCR (RT-PCR) and ELISA after LPS application. Normal or AOM mice were given PBS or ISO-1 (MIF antagonist) every day for 10 days and the hearing levels were determined by measuring auditory brainstem response (ABR) threshold. After the ABR test finished, H&E staining was conducted and the inflammation was also measured by detecting interleukin (IL)-1β, tumor necrosis factor (TNF)-α and vascular endothelial growth factor (VEGF) levels with RT-PCR and ELISA. TLR-4 expression was determined by western blotting and NF-κB activation was determined by electrophoretic mobility shift assays. Compared with the normal control, MIF levels in the middle ear of LPS-induced AOM mice were significant increased. The ABR results showed that mean ABR thresholds in ISO-1 treated AOM mice were significantly reduced compared with PBS treated AOM mice since day 7, indicating that ISO-1 treatment potentially improved the hearing levels of AOM mice. H&Estaining showed that ISO-1 treatment could reduce the mucosal thickness of AOM mice. In ISO-1 treated mice, TLR-4 expression and levels of IL-1β, TNF-α and VEGF were significantly lower compared with PBS treated AOM mice. ISO-1 treatment also significantly inhibited NF-κB activation in AOM mice compared with PBS treated AOM mice. These results suggested that blocking the activity of MIF by ISO-1 could reduce the inflammation in AOM mice in which process TLR-4 and NF-κB were involved. The reduction in MIF activity is conducive to alleviate mouse AOM, which may serve as a potential therapeutic target for the treatment of AOM.

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“…Stol et al [74] underlined the early effect on cytokine production in middle ear homogenates as IL-1β and TNF-α were induced at 48 and 96 h after nasopharyngeal infection by SP but not at 144 h. Endotoxins from Salmonella Typhimurium or LPS were used to induce OM in three studies by transtympanic inoculation [101][102][103]. All the cytokines cited before were also upregulated in these experiments, assaying the protein concentration in MEEs or middle ear washes.…”

Section: Infection Of the Middle Ear By Bacteria Results In Pro-inflamentioning

confidence: 95%

“…Some studies report good correlation ranging from 86 to 91 % [98,99], suggesting continued presence of bacteria in the middle ear in a high proportion of cases with persistent symptoms. Others report that MEF from children with AOM in whom symptoms are persistent is sterile in 42-49 % of cases [100,101]. A change in antibiotic may not be required in some children with mild persistent symptoms.…”

Section: Initial Antibiotic Treatment Failurementioning

confidence: 99%

Otitis Media: State of the art concepts and treatment

Preciado¹

2015

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Neutralizing antibody against granulocyte/macrophage colony–stimulating factor inhibits inflammatory response in experimental otitis media

Cited by 11 publications

References 22 publications

Role of GM-CSF in the inflammatory cytokine network that regulates neutrophil influx into the colonic mucosa duringClostridium difficileinfection in mice

Role of GM-CSF in the inflammatory cytokine network that regulates neutrophil influx into the colonic mucosa duringClostridium difficileinfection in mice

Blocking macrophage migration inhibitory factor activity alleviates mouse acute otitis media in vivo

Otitis Media: State of the art concepts and treatment

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