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首页> 美国卫生研究院文献>American Journal of Physiology - Lung Cellular and Molecular Physiology >Hypoxia-induced alveolar epithelial-mesenchymal transition requires mitochondrial ROS and hypoxia-inducible factor 1
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Hypoxia-induced alveolar epithelial-mesenchymal transition requires mitochondrial ROS and hypoxia-inducible factor 1

机译：低氧诱导的肺泡上皮-间质转化需要线粒体ROS和低氧诱导因子1

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Patients with acute lung injury develop hypoxia, which may lead to lung dysfunction and aberrant tissue repair. Recent studies have suggested that epithelial-mesenchymal transition (EMT) contributes to pulmonary fibrosis. We sought to determine whether hypoxia induces EMT in alveolar epithelial cells (AEC). We found that hypoxia induced the expression of α-smooth muscle actin (α-SMA) and vimentin and decreased the expression of E-cadherin in transformed and primary human, rat, and mouse AEC, suggesting that hypoxia induces EMT in AEC. Both severe hypoxia and moderate hypoxia induced EMT. The reactive oxygen species (ROS) scavenger Euk-134 prevented hypoxia-induced EMT. Moreover, hypoxia-induced expression of α-SMA and vimentin was prevented in mitochondria-deficient ρ0 cells, which are incapable of ROS production during hypoxia. CoCl2 and dimethyloxaloylglycine, two compounds that stabilize hypoxia-inducible factor (HIF)-α under normoxia, failed to induce α-SMA expression in AEC. Furthermore, overexpression of constitutively active HIF-1α did not induce α-SMA. However, loss of HIF-1α or HIF-2α abolished induction of α-SMA mRNA during hypoxia. Hypoxia increased the levels of transforming growth factor (TGF)-β1, and preincubation of AEC with SB431542, an inhibitor of the TGF-β1 type I receptor kinase, prevented the hypoxia-induced EMT, suggesting that the process was TGF-β1 dependent. Furthermore, both ROS and HIF-α were necessary for hypoxia-induced TGF-β1 upregulation. Accordingly, we have provided evidence that hypoxia induces EMT of AEC through mitochondrial ROS, HIF, and endogenous TGF-β1 signaling.
机译：急性肺损伤患者会出现缺氧，这可能导致肺功能障碍和组织异常修复。最近的研究表明上皮-间质转化（EMT）有助于肺纤维化。我们试图确定缺氧是否在肺泡上皮细胞（AEC）中诱导EMT。我们发现，低氧诱导转化的和原代人，大鼠和小鼠AEC中α-平滑肌肌动蛋白（α-SMA）和波形蛋白的表达，并降低E-钙粘蛋白的表达，表明低氧诱导AEC中的EMT。严重缺氧和中度缺氧均可诱发EMT。活性氧（ROS）清除剂Euk-134可防止缺氧诱导的EMT。此外，在缺氧的线粒体缺乏ρ 0 细胞中，低氧诱导的α-SMA和波形蛋白的表达被阻止，而缺氧时不能产生ROS。 CoCl2和二甲基草酰甘氨酸，这两种在常氧下可稳定缺氧诱导因子（HIF）-α的化合物，均无法诱导AEC中的α-SMA表达。此外，组成型活性HIF-1α的过表达不会诱导α-SMA。然而，缺氧期间HIF-1α或HIF-2α的丧失消除了对α-SMAmRNA的诱导。缺氧增加了转化生长因子（TGF）-β1的水平，AEC与T431-β1型IGF受体激酶抑制剂SB431542的预温育可防止缺氧诱导的EMT，提示该过程是TGF-β1依赖性的。此外，ROS和HIF-α对于缺氧诱导的TGF-β1上调都是必需的。因此，我们提供了证据，低氧通过线粒体ROS，HIF和内源性TGF-β1信号传导诱导AEC的EMT。

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