Neonatal epithelial hypoxia inducible factor-1α expression regulates the response of the lung to experimental asthma.
Neonatal epithelial hypoxia inducible factor-1α expression regulates the response of the lung to experimental asthma.
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新生儿上皮缺氧诱导因子-1α 表达调节肺对实验性哮喘的反应。
DOI：
10.1152/ajplung.00193.2011
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
LaPres,JohnJ
中科院分区：
文献类型：
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作者：
Greenwood,KristaK;Proper,StevenP;Saini,Yogesh;Bramble,LoriA;Jackson-Humbles,DavenN;Wagner,JamesG;Harkema,JackR;LaPres,JohnJ
变应性气道疾病的特征在于辅助性T细胞2型介导的气道炎症和气道高反应性。关于缺氧介导的信号传导在疾病进展中的作用知之甚少。为了解决这一知识缺口，建立了一种小鼠模型，其中多西环素暴露诱导肺的肺泡II型和Clara细胞中缺氧诱导因子-1 α的功能缺失。当缺氧诱导因子-1 α在出生后肺发育早期被诱导缺失时，小鼠对过敏性气道疾病的卵清蛋白模型表现出增强的反应。与卵白蛋白处理的对照小鼠相比，这些缺氧诱导因子-1 α缺陷小鼠表现出细胞浸润增加，灌洗液和实质中嗜酸性粒细胞增多，以及T辅助细胞2型细胞因子增加。此外，与对照组相比，这些缺氧诱导因子-1 α缺陷小鼠显示气道阻力增加。有趣的是，如果缺氧诱导因子-1 α的缺失在成年早期被诱导，则没有观察到加重的表型。总之，这些结果表明，上皮缺氧诱导因子-1 α在建立肺的先天免疫中起重要作用，并且在出生后发育早期，转录因子中的上皮特异性缺陷增加了卵白蛋白激发后炎症和功能性气道阻力的严重程度。最后，这些结果可能解释了在早产儿中观察到的一些慢性呼吸道病理学，特别是那些接受补充氧气的早产儿。这种早期的高氧暴露，来自正常的环境和补充氧气，可能会抑制正常的缺氧诱导因子-1 α信号传导，模拟所描述的功能缺失。
Allergic airway disease is characterized by a T helper type 2 cell-mediated airway inflammation and airway hyperresponsiveness. Little is known about the role of hypoxia-mediated signaling in the progression of the disease. To address this knowledge gap, a mouse model was created in which doxycycline exposure induces the functional deletion of hypoxia inducible factor-1α from alveolar type II and Clara cells of the lung. When hypoxia inducible factor-1α deletion was induced during the early postnatal development period of the lung, the mice displayed an enhanced response to the ovalbumin model of allergic airway disease. These hypoxia inducible factor-1α-deficient mice exhibit increased cellular infiltrates, eosinophilia in the lavage fluid and parenchyma, and T helper type 2 cytokines, as compared with ovalbumin-treated control mice. Moreover, these hypoxia inducible factor-1α-deficient mice display increased airway resistance when compared with their control counterparts. Interestingly, if the loss of hypoxia inducible factor-1α was induced in early adulthood, the exacerbated phenotype was not observed. Taken together, these results suggest that epithelial hypoxia inducible factor-1α plays an important role in establishing the innate immunity of the lung and epithelial-specific deficiency in the transcription factor, during early postnatal development, increases the severity of inflammation and functional airway resistance, following ovalbumin challenge. Finally, these results might explain some of the chronic respiratory pathology observed in premature infants, especially those that receive supplemental oxygen. This early hyperoxic exposure, from normal ambient and supplemental oxygen, would presumably inhibit normal hypoxia inducible factor-1α signaling, mimicking the functional deletion described.