Chen Hui, Liang Zhen-Wei, Wang Zhen-Hua, Zhang Jian-Ping, Hu Bo, Xing Xiang-Bin, Cai Wei-Bin
Department of Obstetrics and Gynecology, Sun Yat-sen Memorial Hospital, Guangdong Province, China.
Key Laboratory of malignant tumor gene regulation and target therapy of Guangdong Higher Education Institutes, Sun Yat-sen Memorial Hospital, Guangdong Province, China.
J Cell Biochem. 2015 Oct;116(10):2313-24. doi: 10.1002/jcb.25182.
Fetal growth restriction (FGR) increases the risk of perinatal death, partly due to defects in lung development. Leptin, a polypeptide hormone, is involved in fetal lung development. We previously demonstrated that treatment with exogenous leptin during gestation significantly promotes fetal lung maturity in the rat model of FGR. In this study, to delineate the molecular pathways through which leptin may enhance fetal lung development, we investigated the impact of leptin treatment on the survival of type II alveolar epithelial cells (AECs), essential leptin-responsive cells involved in lung development, in a rat model of FGR. The rat model of FGR was induced in pregnant Sprague-Dawley rats by partial uterine artery and vein ligation. In vivo and in vitro analyses of fetal lung tissues and freshly-isolated cultured AECs, respectively, showed that leptin protects type II AECs from hypoxia-induced apoptosis. Further molecular studies revealed the role of Akt activation in the leptin-mediated promotion of survival of type II AECs. The data also showed that the anti-apoptotic effects of leptin are dependent on phosphoinositol 3-kinase (PI3K) activation, and involve the down-regulation of caspases 3 and 9, upregulation of pro-survival proteins Bcl-2, and p-Bad, and inhibition of the release of cytochrome c from mitochondria. Taken together, our data suggested that leptin enhances the maturity of fetal lungs by mediating the regulation of caspase-3 and -9 during hypoxia-induced apoptosis of type II AECs and provide support for the potential of leptin as a therapeutic agent for promoting lung development in FGR.
胎儿生长受限（FGR）会增加围产期死亡风险，部分原因是肺部发育缺陷。瘦素是一种多肽激素，参与胎儿肺部发育。我们之前证明，在妊娠期用外源性瘦素治疗可显著促进FGR大鼠模型的胎儿肺成熟。在本研究中，为了阐明瘦素增强胎儿肺发育的分子途径，我们在FGR大鼠模型中研究了瘦素治疗对II型肺泡上皮细胞（AEC）存活的影响，II型肺泡上皮细胞是参与肺发育的重要瘦素反应细胞。通过部分子宫动静脉结扎在怀孕的Sprague-Dawley大鼠中诱导建立FGR大鼠模型。分别对胎儿肺组织和新鲜分离培养的AEC进行体内和体外分析，结果显示瘦素可保护II型AEC免受缺氧诱导的凋亡。进一步的分子研究揭示了Akt激活在瘦素介导的促进II型AEC存活中的作用。数据还表明，瘦素的抗凋亡作用依赖于磷酸肌醇3激酶（PI3K）激活，涉及半胱天冬酶3和9的下调、促生存蛋白Bcl-2和p-Bad的上调，以及抑制细胞色素c从线粒体释放。综上所述，我们的数据表明，瘦素通过在II型AEC缺氧诱导凋亡过程中介导对半胱天冬酶-3和-9的调节来增强胎儿肺成熟，并为瘦素作为促进FGR中肺发育的治疗药物的潜力提供了支持。
