@entity2172 with effusion (OME) is the commonest cause of @entity393 in @entity1 , 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 @entity1 and the best treatment for chronic OME, but the mechanism by which they work remains uncertain. As @entity519 is a common feature of inflamed microenvironments, moderation of @entity519 may be a significant contributory mechanism. We have investigated the occurrence of @entity519 and @entity519 -inducible factor (HIF) mediated responses in Junbo and Jeff @entity19 mutant models, which develop spontaneous @entity102 media. We found that Jeff and Junbo @entity19 labeled in vivo with @entity12184 showed cellular @entity519 in inflammatory cells in the bulla lumen, and in Junbo the @entity2172 was also @entity519 . The bulla fluid inflammatory cell numbers were greater and the upregulation of inflammatory gene networks were more pronounced in Junbo than Jeff. @entity1965 gene expression was elevated in bulla fluid inflammatory cells, and there was upregulation of its target genes including @entity1611 in Junbo and Jeff. We therefore investigated the effects in Junbo of small-molecule inhibitors of VEGFR signaling ( @entity17482 , @entity2240 , and @entity2857 ) and destabilizing HIF by inhibiting its chaperone @entity23118 with @entity27212 . We found that both classes of inhibitor significantly reduced @entity393 and the occurrence of bulla fluid and that VEGFR inhibitors moderated angiogenesis and lymphangiogenesis in the inflamed @entity2172 . The effectiveness of @entity23118 and VEGFR signaling inhibitors in suppressing OM in the Junbo model implicates HIF-mediated @entity1611 as playing a pivotal role in OM pathogenesis. Our analysis of the Junbo and Jeff mutants highlights the role of @entity519 and HIF-mediated pathways, and we conclude that targeting molecules in HIF- @entity1611 signaling pathways has therapeutic potential in the treatment of chronic OM.

HIF- XXXX pathways are critical for @entity102 media in Junbo and Jeff @entity19 mutants.

@entity1 :: ('9606', 'Species') :: ['children'] @entity23118 :: ('111058(Tax:10090)', 'Gene') :: ['HSP90'] @entity2172 :: ('MESH:D010033', 'Disease') :: ['Otitis media', 'middle ear mucosa'] @entity2240 :: ('MESH:C473478', 'Chemical') :: ['SU-11248'] @entity19 :: ('10090', 'Species') :: ['mice', 'mouse'] @entity17482 :: ('MESH:C404768', 'Chemical') :: ['PTK787'] @entity2857 :: ('MESH:C471405', 'Chemical') :: ['BAY 43-9006'] @entity27212 :: ('MESH:C448659', 'Chemical') :: ['17-DMAG'] @entity102 :: ('MESH:D002908', 'Disease') :: ['chronic otitis'] @entity519 :: ('MESH:D000860', 'Disease') :: ['hypoxic', 'hypoxia'] @entity1965 :: ('15251(Tax:10090)', 'Gene') :: ['Hif-1a'] @entity1611 :: ('22339(Tax:10090)', 'Gene') :: ['Vegfa', 'VEGF'] @entity393 :: ('MESH:D034381', 'Disease') :: ['hearing loss'] @entity12184 :: ('MESH:C033815', 'Chemical') :: ['pimonidazole']
@entity1611 :: (22339(Tax:10090),Gene) :: ['VEGF']
