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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Inducible expression of keratinocyte growth factor (KGF) in mice inhibits lung epithelial cell death induced by hyperoxia
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Inducible expression of keratinocyte growth factor (KGF) in mice inhibits lung epithelial cell death induced by hyperoxia

机译：小鼠角质形成细胞生长因子（KGF）的诱导表达抑制高氧诱导的肺上皮细胞死亡

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摘要

Oxidant-induced injury to the lung is associated with extensive damage to the lung epithelium. Instillation of keratinocyte growth factor (KGF) in the lungs of animals protects animals from oxidant-induced injury but the mechanism of protection is not well understood. An inherent problem in studying KGF function in vivo has been that constitutive overexpression of KGF in the lung causes embryonic lethality with extensive pulmonary malformation. Here we report the development of a stringently regulated, tetracycline-inducible, lung-specific transgenic system that allows regulated expression of KGF in the lung without causing developmental abnormalities from leaky KGF expression. By using this system, we show that exposure of KGF-expressing mice to hyperoxia protects the lung epithelium but not the endothelium from cell death in accordance with the selective expression of KGF receptor on epithelial and not on endothelial cells. Investigations of KGF-induced cell survival pathways revealed KGF-induced activation of the multifunctional pro-survival Akt signaling axis both in vitro and in vivo. Inhibition of KGF-induced Akt activation by a dominant-negative mutant of Akt blocked the KGF-mediated protection of epithelial cells exposed to hyperoxia. KGF-induced Akt activation may play an important role in inhibiting lung alveolar cell death thereby preserving the lung architecture and function during oxidative stress.
机译：氧化剂对肺的损伤与肺上皮的广泛损伤有关。在动物的肺中滴入角质形成细胞生长因子（KGF）可以保护动物免受氧化剂诱导的伤害，但保护机理尚不清楚。研究体内KGF功能的一个固有问题是，肺中KGF的组成型过表达会导致胚胎致死性，并伴有广泛的肺畸形。在这里，我们报告了严格调控的，四环素诱导的，肺特异性转基因系统的发展，该系统允许在肺中调节KGF的表达，而不会引起泄漏的KGF表达引起发育异常。通过使用此系统，我们表明，根据KGF受体在上皮而不是在内皮细胞上的选择性表达，将表达KGF的小鼠暴露于高氧可保护肺上皮而不保护内皮免于细胞死亡。对KGF诱导的细胞存活途径的研究揭示了KGF诱导的体外和体内多功能促存活Akt信号轴的激活。 Akt的显性负突变体抑制KGF诱导的Akt激活可阻断KGF介导的对高氧暴露的上皮细胞的保护。 KGF诱导的Akt激活可能在抑制肺泡细胞死亡中起重要作用，从而在氧化应激期间保持肺部结构和功能。

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