Lung dysfunction causes systemic hypoxia in estrogen receptor beta knockout (ERbeta-/-) mice.
Lung dysfunction causes systemic hypoxia in estrogen receptor beta knockout (ERbeta-/-) mice.
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发表时间：
2006
影响因子：
11.1
通讯作者：
A. Morani;R. Barros;O. Imamov;K. Hultenby;A. Arner;M. Warner;J. Gustafsson
中科院分区：
文献类型：
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作者：
A. Morani;R. Barros;O. Imamov;K. Hultenby;A. Arner;M. Warner;J. Gustafsson
雌激素受体β(ERbeta)在I型和II型肺泡上皮细胞以及细支气管上皮细胞中高表达。在成人肺中检测不到ERAlpha。已经有报道称，成年雌性ERbeta基因敲除(ERbeta-/-)小鼠的肺泡较少，弹性反冲减少。在这篇文章中，我们报道，在5个月大的时候，雄性和雌性ERbeta-/-小鼠的肺中都有大面积的未扩张的肺泡。在ERbeta-/-小鼠的肺泡间隔中，胶原蛋白染色增强，并可见异常的胶原纤维团。免疫组织化学分析和Western blotting显示ERbeta-/-小鼠肺小窝蛋白-1表达下调，膜型-1金属蛋白酶、基质金属蛋白酶2(活性形式)和金属蛋白酶组织抑制物2表达增加。低氧诱导因子1α和化学加合物(用Hypoxy探针)免疫组织化学分析显示，在安静条件下，ERbeta-/-小鼠心、前列腺腹侧、卵巢囊、肾脏、肝脏和脑明显缺氧。此外，成年雄性和雌性ERbeta-/-小鼠都不愿在跑步机上跑步，运动后组织缺氧变得非常明显。我们得出结论，ERbeta对于维持肺内细胞外基质成分是必需的，而ERbeta的缺失会导致肺结构异常和全身缺氧。系统性缺氧可能与已报道的ERbeta-/-小鼠左、右心肥厚和全身性高血压有关。
Estrogen receptor beta (ERbeta) is highly expressed in both type I and II pneumocytes as well as bronchiolar epithelial cells. ERalpha is not detectable in the adult lung. Lungs of adult female ERbeta knockout (ERbeta-/-) mice have already been reported to have fewer alveoli and reduced elastic recoil. In this article, we report that, by 5 months of age, there are large areas of unexpanded alveoli in lungs of both male and female ERbeta-/- mice. There is increased staining for collagen and, by EM, abnormal clusters of collagen fibers are seen in the alveolar septa of ERbeta-/- mice. Immunohistochemical analysis and Western blotting with lung membrane fractions of ERbeta-/- mice revealed down-regulation of caveolin-1, increased expression of membrane type-1 metalloproteinase, matrix metalloproteinase 2 (active form), and tissue inhibitors of metalloproteinases 2. Hypoxia, measured by immunohistochemical analysis for hypoxia-inducible factor 1alpha and chemical adducts (with Hypoxyprobe), was evident in the heart, ventral prostate, periovarian sac, kidney, liver, and brain of ERbeta-/- mice under resting conditions. Furthermore, both male and female adult ERbeta-/- mice were reluctant to run on a treadmill and tissue hypoxia became very pronounced after exercise. We conclude that ERbeta is necessary for the maintenance of the extracellular matrix composition in the lung and loss of ERbeta leads to abnormal lung structure and systemic hypoxia. Systemic hypoxia may be responsible for the reported left and right heart ventricular hypertrophy and systemic hypertension in ERbeta-/- mice.