A mouse model of otitis media identifies HB-EGF as a mediator of inflammation-induced mucosal proliferation.
A mouse model of otitis media identifies HB-EGF as a mediator of inflammation-induced mucosal proliferation.
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DOI：
10.1371/journal.pone.0102739
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Ryan AF
中科院分区：
文献类型：
--
作者：
Suzukawa K;Tomlin J;Pak K;Chavez E;Kurabi A;Baird A;Wasserman SI;Ryan AF
中耳炎是最常见的儿科感染之一。虽然治疗通常没有困难，但多达20%的儿童可能会进展为长期并发症，包括听力损失、言语和语言发育障碍、学业成绩低下和不可逆转的疾病。中耳黏膜增生是急性中耳炎的后遗症之一，具有重要的临床意义。了解生长因子在粘膜增生中的中介作用可能会导致对这种疾病及其后遗症的新的治疗干预措施的发展。通过对急性中耳炎过程中mRNA表达的全基因组基因阵列分析，我们确定了生长因子的表达动力学与其在时间上的相关。然后，我们测试了这些因子在体外刺激粘膜上皮生长的能力，并确定了活性因子的蛋白质水平和体内组织分布。从基因芯片中，我们确定了7个候选生长因子，它们上调了与粘膜增生相关的mRNA表达动力学。在这七种药物中，只有HB-EGF(肝素结合表皮生长因子)在体外诱导了显著的粘膜上皮增生。免疫印迹法检测HB-EGF蛋白在体内的表达，证实HB-EGF蛋白在接种细菌后6~24小时高表达，免疫组织化学显示中耳上皮细胞和浸润性淋巴细胞产生HB-EGF蛋白。我们的数据表明HB-EGF在中耳炎期间中耳粘膜上皮的增生中起着积极的作用。这些结果表明，针对HB-EGF的治疗可以改善中耳炎期间的粘膜生长，从而减少这种儿童疾病的有害后遗症。
Otitis media is one of the most common pediatric infections. While it is usually treated without difficulty, up to 20% of children may progress to long-term complications that include hearing loss, impaired speech and language development, academic underachievement, and irreversible disease. Hyperplasia of middle ear mucosa contributes to the sequelae of acute otitis media and is of important clinical significance. Understanding the role of growth factors in the mediation of mucosal hyperplasia could lead to the development of new therapeutic interventions for this disease and its sequelae. From a whole genome gene array analysis of mRNA expression during acute otitis media, we identified growth factors with expression kinetics temporally related to hyperplasia. We then tested these factors for their ability to stimulate mucosal epithelial growth in vitro, and determined protein levels and histological distribution in vivo for active factors. From the gene array, we identified seven candidate growth factors with upregulation of mRNA expression kinetics related to mucosal hyperplasia. Of the seven, only HB-EGF (heparin-binding-epidermal growth factor) induced significant mucosal epithelial hyperplasia in vitro. Subsequent quantification of HB-EGF protein expression in vivo via Western blot analysis confirmed that the protein is highly expressed from 6 hours to 24 hours after bacterial inoculation, while immunohistochemistry revealed production by middle ear epithelial cells and infiltrating lymphocytes. Our data suggest an active role for HB-EGF in the hyperplasia of the middle ear mucosal epithelium during otitis media. These results imply that therapies targeting HB-EGF could ameliorate mucosal growth during otitis media, and thereby reduce detrimental sequelae of this childhood disease.
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影响因子：
7.8
作者：
Lai, W H;Cameron, P H;Wada, I;Doherty, J J 2nd;Kay, D G;Posner, B I;Bergeron, J J
通讯作者：
Bergeron, J J
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Junttila, TT;Sundvall, M;Elenius, K
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