Cell Adhesion Molecules of Experimental Otitis Media in the Rat

Kamimura, Masami; Himi, Tetsuo; Kataura, Akikatsu

doi:10.3109/00016489609137941

Cited by 10 publications

(9 citation statements)

References 15 publications

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“…Il-1β and Tnf-α serum titers are comparable in mutant and +/+ mice suggesting that OM is not a cause of systemic inflammation, nor is it part of an ongoing systemic inflammatory condition in Junbo and Jeff models. A number of inflammatory genes associated with OM have been published; for a review, see [38] and [39]–[63] and our array data adds another 20 genes to this list (Table S2). However, middle ear inflammation appeared less pronounced in Jf/+ mice.…”

Section: Discussionmentioning

confidence: 99%

HIF–VEGF Pathways Are Critical for Chronic Otitis Media in Junbo and Jeff Mouse Mutants

et al. 2011

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Otitis media with effusion (OME) is the commonest cause of hearing loss in children, yet the underlying genetic pathways and mechanisms involved are incompletely understood. Ventilation of the middle ear with tympanostomy tubes is the commonest surgical procedure in children and the best treatment for chronic OME, but the mechanism by which they work remains uncertain. As hypoxia is a common feature of inflamed microenvironments, moderation of hypoxia may be a significant contributory mechanism. We have investigated the occurrence of hypoxia and hypoxia-inducible factor (HIF) mediated responses in Junbo and Jeff mouse mutant models, which develop spontaneous chronic otitis media. We found that Jeff and Junbo mice labeled in vivo with pimonidazole showed cellular hypoxia in inflammatory cells in the bulla lumen, and in Junbo the middle ear mucosa was also hypoxic. The bulla fluid inflammatory cell numbers were greater and the upregulation of inflammatory gene networks were more pronounced in Junbo than Jeff. Hif-1α gene expression was elevated in bulla fluid inflammatory cells, and there was upregulation of its target genes including Vegfa in Junbo and Jeff. We therefore investigated the effects in Junbo of small-molecule inhibitors of VEGFR signaling (PTK787, SU-11248, and BAY 43-9006) and destabilizing HIF by inhibiting its chaperone HSP90 with 17-DMAG. We found that both classes of inhibitor significantly reduced hearing loss and the occurrence of bulla fluid and that VEGFR inhibitors moderated angiogenesis and lymphangiogenesis in the inflamed middle ear mucosa. The effectiveness of HSP90 and VEGFR signaling inhibitors in suppressing OM in the Junbo model implicates HIF–mediated VEGF as playing a pivotal role in OM pathogenesis. Our analysis of the Junbo and Jeff mutants highlights the role of hypoxia and HIF–mediated pathways, and we conclude that targeting molecules in HIF–VEGF signaling pathways has therapeutic potential in the treatment of chronic OM.

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Section: Discussionmentioning

confidence: 99%

HIF–VEGF Pathways Are Critical for Chronic Otitis Media in Junbo and Jeff Mouse Mutants

et al. 2011

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“…The main cell subtypes involved are neutrophils, lymphocytes, macrophages and monocytes. The appearance of these cell subtypes in the middle ear cavity have shown different kinetics in previous studies [11]. Neutrophils initially appear and subsequently are followed by infiltrations of monocytes/macrophages and lymphocytes into the middle ear cavity.…”

Section: Discussionmentioning

confidence: 95%

“…We previously found significant levels of soluble ICAM-1 in the middle ear effusions of pediatric otitis media [10]. The expression of ICAM-1 in the middle ear mucosa has also been observed in the inflammatory stage of experimentally induced otitis media in rats [11], as well as in other human middle ear effusions [16]. In contrast, the in vivo expression of VCAM-1 in inflammatory response of the middle ear has not been well investigated to date.…”

Section: Introductionmentioning

confidence: 89%

Expression profile of vascular cell adhesion molecule-1 (CD106) in the middle ear using radiolabeled monoclonal antibody

Himi

Kairemo

Ramsay

1998

European Archives of Oto-Rhino-Laryngology

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Adhesive interactions between leukocytes and endothelium are required for subsequent leukocyte extravasation toward inflammatory sites. Understanding the possible kinetic expression of vascular cell adhesion molecule-1 (VCAM-1) in the middle ear cavity during an inflammatory cascade in vivo may be important for clarifying local immunological responses in otitis media. Two inflammatory models were produced in the rat and involved acute middle ear mucosal and cutaneous inflammation induced after inoculation or intradermal injection of lipopolysaccharide (LPS). After intravenous injection of both 125I-labeled anti-VCAM-1 and 131I-labeled control monoclonal antibody (mAb), the kinetic expression of VCAM-1 in the middle ear and skin was assessed by local radionuclide uptake. The biodistribution of an 125I-labeled anti-VCAM-1 mAb as a potential detector of focal inflammation was examined in normal rats. Both inflammatory lesions were characterized by early and sustained (up to 24 h) expression of VCAM-1, with maximal expression at 4 h after LPS stimulation. The kinetics of VCAM-1 expression was similar among the middle ear mucosa or skin specimens studied and different stimulation methods. A similar biodistribution and clearance of radioactivity between 125I-labeled anti-VCAM-1 mAb and 131I- or 99mTc-labeled control mAb were observed. The present result suggest that functional VCAM-1 induced by LPS is expressed in both middle ear tissue and skin lesions and may play a role in the initial stage of inflammatory response produced. Although VCAM-1 upregulation is a very early event in the inflammatory cascade, 125I-labeled anti-VCAM-1 mAb may be useful for the early detection of focal inflammation in the middle ear.

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“…It was suspected that this discrepancy in protein synthesis between chemokine and TNF-alpha may have been due to the short observation period in this study. The numbers of infiltrated macrophages in rat middle ear effusion were few until day 3 and elevated 7 days after antigen exposure to the middle ear (18). Initial interaction between pathogen and host was considered to start when the bacteria attached to epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

Cytokine and Chemokine Induction Using Cell Wall Component and Toxin Derived from Gram-Positive Bacteria in the Rat Middle Ear

Kita

Himi²

1999

Acta Oto-Laryngologica

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Lipoteichoic acid (LTA) is one of the components present within the cell wall layer of most gram-positive bacteria. It plays an important role in the initiation and progression of bacterial infection. In this study, we performed a rat middle ear and nasal perfusion with LTA purified from two different gram-positive bacterial species. Using ELISA and RT-PCR, the production and mRNA expression of rat chemokine, GRO/CINC-1, proinflammatory cytokine, TNF-alpha, in rat middle ear lavage and mucosa were investigated. GRO/CINC-1 in middle ear lavage was produced by stimulation of LTA in a time-dependent fashion; however, TNF-alpha production into the lavage was not detectable using ELISA assay. The mRNA expressions of GRO/CINC-1 and TNF-alpha in the middle ear mucosa were both induced after LTA and exotoxin exposures. The expression of IL-10 mRNA was also induced after 6 h of LTA and exotoxin exposures. The profile of the production of GRO/CINC-1 and TNF-alpha in rat nasal lavage was similar to that in the middle ear; however, the mRNA expressions of GRO/CINC-1, TNF-alpha and IL-10 in the nasal mucosa were different from those in the middle ear mucosa. These results suggest that the cell wall component and exotoxin of gram-positive bacteria can induce several cytokines in vivo and play an important role in the initiation of the inflammatory cascade in the middle ear.

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Cell Adhesion Molecules of Experimental Otitis Media in the Rat

Cited by 10 publications

References 15 publications

HIF–VEGF Pathways Are Critical for Chronic Otitis Media in Junbo and Jeff Mouse Mutants

HIF–VEGF Pathways Are Critical for Chronic Otitis Media in Junbo and Jeff Mouse Mutants

Expression profile of vascular cell adhesion molecule-1 (CD106) in the middle ear using radiolabeled monoclonal antibody

Cytokine and Chemokine Induction Using Cell Wall Component and Toxin Derived from Gram-Positive Bacteria in the Rat Middle Ear

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