MRC Mammalian Genetics Unit, MRC Harwell, Harwell, United Kingdom.
PLoS Genet. 2011 Oct;7(10):e1002336. doi: 10.1371/journal.pgen.1002336. Epub 2011 Oct 20.
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.
中耳积液（OME）是儿童听力损失最常见的原因，但涉及的潜在遗传途径和机制尚不完全清楚。鼓室置管术是儿童最常见的手术，也是慢性 OME 的最佳治疗方法，但其中的作用机制仍不确定。由于缺氧是炎症微环境的共同特征，因此适度缺氧可能是一个重要的促成机制。我们研究了 Junbo 和 Jeff 小鼠突变模型中缺氧和缺氧诱导因子（HIF）介导反应的发生，这两种模型会自发发展为慢性中耳炎。我们发现，用 pimonidazole 体内标记的 Jeff 和 Junbo 小鼠，在鼓室腔内的炎症细胞中显示出细胞缺氧，而 Junbo 的中耳黏膜也缺氧。Jeff 和 Junbo 相比，鼓室积液中炎症细胞数量更多，炎症基因网络的上调更为明显。Hif-1α 基因在鼓室积液中的炎症细胞中表达上调，其靶基因如 Junbo 和 Jeff 中的 Vegfa 也上调。因此，我们研究了 Junbo 中小血管内皮生长因子受体（VEGFR）信号通路的小分子抑制剂（PTK787、SU-11248 和 BAY 43-9006）和通过抑制其伴侣 HSP90 来破坏 HIF 的 17-DMAG 的作用。我们发现，这两类抑制剂都能显著降低听力损失和鼓室积液的发生，并且 VEGFR 抑制剂可调节炎症中耳黏膜中的血管生成和淋巴管生成。HSP90 和 VEGFR 信号通路抑制剂在抑制 Junbo 模型中的 OM 的有效性表明，HIF 介导的 VEGF 在 OM 发病机制中起着关键作用。我们对 Junbo 和 Jeff 突变体的分析突出了缺氧和 HIF 介导途径的作用，我们得出结论，靶向 HIF-VEGF 信号通路中的分子在慢性 OM 的治疗中具有治疗潜力。
