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

Abstract

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.

A Genome-Wide Association Study of Chronic Otitis Media with Effusion and Recurrent Otitis Media Identifies a Novel Susceptibility Locus on Chromosome 2

“…Additionally, IQGAP1 was found to be needed to organize ROS-dependent VEGF signaling via VEGFR2 in endothelial cells which may contribute to the repair and maintenance of blood vessels and angiogenesis (Yamaoka-Tojo et al 2004). VEGF signaling is known to induce angiogenesis, increase vascular permeability, and influence inflammation in several ways, all which could increase risk of chronic otitis media by effusion build-up and in- Cheeseman et al 2011). These roles of IQGAP1 indicate that IQGAP1 may be involved in COME/ ROM pathogenesis though further investigation is necessary.…”

TFAP2A Regulates Nasopharyngeal Carcinoma Growth and Survival by Targeting HIF-1α Signaling Pathway

“…Hypoxia-inducible factor-1a (HIF-1a) is a transcription factor that activates the expression of a number of genes involved in diverse aspects of cellular and physiologic processes (33,34). Under hypoxic conditions, HIF-1a forms a heterodimer with HIF-1b, and binds to the hypoxia-responsive elements of the promoters to activate downstream hypoxia-responsive genes, including VEGF, to increase angiogenesis and tumor metastasis or to promote cancer cell proliferation and migration (35)(36)(37).…”

Adaptive Immunity in the Middle Ear Mucosa with Chronic Otitis Media

“…There are multiple factors involved in this process. It has been reported that anatomic abnormality, genetic predisposition, and middle ear immunity play important roles in the pathogenesis of COM [3][4][5][6][7]. To make middle ear infection chronic, there must be some compromised innate or adaptive immunity in the middle ear mucosa.…”