HIF-VEGF pathways are critical for chronic otitis media in Junbo and Jeff mouse mutants.
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 f...
Guardado en:
| Autores principales: | , , , , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Public Library of Science (PLoS)
2011
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/12d63bc415b249f7b612e2389bb1acab |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:12d63bc415b249f7b612e2389bb1acab |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:12d63bc415b249f7b612e2389bb1acab2021-11-18T06:19:16ZHIF-VEGF pathways are critical for chronic otitis media in Junbo and Jeff mouse mutants.1553-73901553-740410.1371/journal.pgen.1002336https://doaj.org/article/12d63bc415b249f7b612e2389bb1acab2011-10-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22028672/pdf/?tool=EBIhttps://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Otitis 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.Michael T CheesemanHayley E TyrerDebbie WilliamsTertius A HoughParas PathakMaria R RomeroHelen HiltonSulzhan BaliAndrew ParkerLucie VizorTom PurnellKate VowellSara WellsMahmood F BhuttaPaul K PotterSteve D M BrownPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 7, Iss 10, p e1002336 (2011) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Genetics QH426-470 |
| spellingShingle |
Genetics QH426-470 Michael T Cheeseman Hayley E Tyrer Debbie Williams Tertius A Hough Paras Pathak Maria R Romero Helen Hilton Sulzhan Bali Andrew Parker Lucie Vizor Tom Purnell Kate Vowell Sara Wells Mahmood F Bhutta Paul K Potter Steve D M Brown HIF-VEGF pathways are critical for chronic otitis media in Junbo and Jeff mouse mutants. |
| description |
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. |
| format |
article |
| author |
Michael T Cheeseman Hayley E Tyrer Debbie Williams Tertius A Hough Paras Pathak Maria R Romero Helen Hilton Sulzhan Bali Andrew Parker Lucie Vizor Tom Purnell Kate Vowell Sara Wells Mahmood F Bhutta Paul K Potter Steve D M Brown |
| author_facet |
Michael T Cheeseman Hayley E Tyrer Debbie Williams Tertius A Hough Paras Pathak Maria R Romero Helen Hilton Sulzhan Bali Andrew Parker Lucie Vizor Tom Purnell Kate Vowell Sara Wells Mahmood F Bhutta Paul K Potter Steve D M Brown |
| author_sort |
Michael T Cheeseman |
| title |
HIF-VEGF pathways are critical for chronic otitis media in Junbo and Jeff mouse mutants. |
| title_short |
HIF-VEGF pathways are critical for chronic otitis media in Junbo and Jeff mouse mutants. |
| title_full |
HIF-VEGF pathways are critical for chronic otitis media in Junbo and Jeff mouse mutants. |
| title_fullStr |
HIF-VEGF pathways are critical for chronic otitis media in Junbo and Jeff mouse mutants. |
| title_full_unstemmed |
HIF-VEGF pathways are critical for chronic otitis media in Junbo and Jeff mouse mutants. |
| title_sort |
hif-vegf pathways are critical for chronic otitis media in junbo and jeff mouse mutants. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2011 |
| url |
https://doaj.org/article/12d63bc415b249f7b612e2389bb1acab |
| work_keys_str_mv |
AT michaeltcheeseman hifvegfpathwaysarecriticalforchronicotitismediainjunboandjeffmousemutants AT hayleyetyrer hifvegfpathwaysarecriticalforchronicotitismediainjunboandjeffmousemutants AT debbiewilliams hifvegfpathwaysarecriticalforchronicotitismediainjunboandjeffmousemutants AT tertiusahough hifvegfpathwaysarecriticalforchronicotitismediainjunboandjeffmousemutants AT paraspathak hifvegfpathwaysarecriticalforchronicotitismediainjunboandjeffmousemutants AT mariarromero hifvegfpathwaysarecriticalforchronicotitismediainjunboandjeffmousemutants AT helenhilton hifvegfpathwaysarecriticalforchronicotitismediainjunboandjeffmousemutants AT sulzhanbali hifvegfpathwaysarecriticalforchronicotitismediainjunboandjeffmousemutants AT andrewparker hifvegfpathwaysarecriticalforchronicotitismediainjunboandjeffmousemutants AT lucievizor hifvegfpathwaysarecriticalforchronicotitismediainjunboandjeffmousemutants AT tompurnell hifvegfpathwaysarecriticalforchronicotitismediainjunboandjeffmousemutants AT katevowell hifvegfpathwaysarecriticalforchronicotitismediainjunboandjeffmousemutants AT sarawells hifvegfpathwaysarecriticalforchronicotitismediainjunboandjeffmousemutants AT mahmoodfbhutta hifvegfpathwaysarecriticalforchronicotitismediainjunboandjeffmousemutants AT paulkpotter hifvegfpathwaysarecriticalforchronicotitismediainjunboandjeffmousemutants AT stevedmbrown hifvegfpathwaysarecriticalforchronicotitismediainjunboandjeffmousemutants |
| _version_ |
1718424460575375360 |