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.
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DOI：
10.1371/journal.pgen.1002336
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发表时间：
2011-10
期刊：
影响因子：
4.5
通讯作者：
Brown SD
中科院分区：
文献类型：
--
作者：
Cheeseman MT;Tyrer HE;Williams D;Hough TA;Pathak P;Romero MR;Hilton H;Bali S;Parker A;Vizor L;Purnell T;Vowell K;Wells S;Bhutta MF;Potter PK;Brown SD
渗出性中耳炎（OME）是儿童听力损失的最常见原因，但相关的遗传途径和机制尚未完全了解。用鼓膜造孔管进行中耳通气是儿童最常见的外科手术，也是慢性OME的最佳治疗方法，但其作用机制仍不确定。由于缺氧是发炎微环境的共同特征，因此缺氧的缓和可能是重要的促成机制。我们研究了缺氧和缺氧诱导因子（HIF）介导的反应在Junbo和Jeff小鼠突变模型，发展自发性慢性中耳炎的发生。我们发现，杰夫和Junbo小鼠体内标记与pimonidazole表现出细胞缺氧的炎性细胞在泡腔，和Junbo中耳粘膜也缺氧。与Jeff相比，Junbo的大疱液炎性细胞数量更多，炎性基因网络的上调更明显。Hif-1α基因在大疱液炎性细胞中表达升高，其靶基因Vegfa在Junbo和Jeff中表达上调。因此，我们研究了小分子VEGFR信号抑制剂（PTK 787，SU-11248和BAY 43-9006）和通过用17-DMAG抑制其伴侣蛋白HSP 90来稳定HIF在Junbo中的作用。我们发现，这两类抑制剂显着降低听力损失和大疱液的发生，并VEGFR抑制剂调节炎症中耳粘膜中的血管生成和淋巴管生成。HSP 90和VEGFR信号抑制剂在Junbo模型中抑制OM的有效性暗示HIF介导的VEGF在OM发病机制中起关键作用。我们对Junbo和Jeff突变体的分析突出了缺氧和HIF介导的通路的作用，我们得出结论，HIF-VEGF信号通路中的靶向分子在治疗慢性OM中具有治疗潜力。渗出性中耳炎（OME）是儿童听力损失的最常见原因，使用耳鼻喉科治疗仍然是儿童最常见的外科手术。从人群研究中已知慢性形式的OM具有重要的遗传成分，但对所涉及的潜在基因或途径知之甚少。我们分析了两种慢性OM小鼠模型，Junbo和Jeff突变体，发现两者都表现出缺氧和缺氧诱导因子（HIF）介导的反应。在突变中耳中存在炎症通路的上调，并且在Junbo中调节Hif-1α的细胞因子升高。HIF-1α水平在中耳以及HIF的下游靶点（如Vegfa）中升高。我们探索了Junbo突变体中HSP 90和VEGF受体信号传导小分子抑制剂的影响，发现使用VEGF受体抑制剂可以显着减少听力损失、大疱液的发生，并缓解炎症中耳粘膜的血管变化。Junbo和Jeff突变体的研究表明缺氧和HIF介导的通路在OM发病机制中的作用，并且它表明靶向HIF-VEGF通路可能代表慢性OM治疗干预的新方法。
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. Otitis media with effusion (OME) is the commonest cause of hearing loss in children, and treatment using grommets remains the commonest surgical procedure in children. Chronic forms of OM are known from human population studies to have a significant genetic component, but little is known of the underlying genes or pathways involved. We have analyzed two chronic OM mouse models, the Junbo and Jeff mutants, and have found that both demonstrate hypoxia and hypoxia-inducible factor (HIF) mediated responses. There is upregulation of inflammatory pathways in the mutant middle ears and in Junbo elevation of cytokines that modulate Hif-1α. Hif-1α levels are raised in the middle ear as well as downstream targets of HIF such as Vegfa. We explored the effects of small-molecule inhibitors of HSP90 and VEGF receptor signaling in the Junbo mutant and found significant reductions in hearing loss, the occurrence of bulla fluid, and moderation of vascular changes in the inflamed middle ear mucosa with the VEGF receptor inhibitors. The study of the Junbo and Jeff mutants demonstrates the role of hypoxia and HIF mediated pathways in OM pathogenesis, and it indicates that targeting the HIF–VEGF pathway may represent a novel approach to therapeutic intervention in chronic OM.
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影响因子：
1.4
作者：
Chae, SW;Kim, SJ;Jung, HH
通讯作者：
Jung, HH
影响因子：
3.6
作者：
GIEBINK, GS;JUHN, SK;LE, CT
通讯作者：
LE, CT
影响因子：
--
作者：
Casselbrant, ML;Mandel, EM;Ferrell, RE
通讯作者：
Ferrell, RE
DOI：
10.1016/0165-5876(89)90051-7
发表时间：
1989-07-01
影响因子：
1.5
作者：
DAVIDSON, J;HYDE, ML;ALBERTI, PW
通讯作者：
ALBERTI, PW
影响因子：
3.3
作者：
Duval, Martine;Le Boeuf, Fabrice;Gratton, Jean-Philippe
通讯作者：
Gratton, Jean-Philippe