Zhang Yuhao, Jiang Weiwu, Wang Lihua, Lingappan Krithika
Department of Pediatrics, Section of Neonatology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.
Department of Pediatrics, Section of Neonatology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.
Toxicol Appl Pharmacol. 2017 Oct 1;332:8-14. doi: 10.1016/j.taap.2017.07.016. Epub 2017 Jul 20.
Male premature neonates are more susceptible than females to the development of bronchopulmonary dysplasia (BPD). The reasons underlying sexually dimorphic outcomes in premature neonates are not known. GDF15 (Growth and differentiation factor 15) is a secreted cytokine and plays a role in cell proliferation, apoptosis, and angiogenesis. In this study, we sought to elucidate the sex-specific expression of Gdf15 in the lung in vivo in neonatal hyperoxic lung injury and its regulation by Hif-1α, and to delineate the differences in GDF15 expression in male and female human umbilical venous endothelial cells in an in vitro model of oxygen toxicity. Following hyperoxia exposure (95% FiO, PND (postnatal day 1-5: saccular stage of lung development), neonatal male mice (C57BL/6) show increased GDF15 and decreased HIF-1α expression compared to female mice. For the in vitro experiments, male and female HUVECs were exposed to room air condition (21% O2, 5% CO) or in hyperoxia condition (95% O2, 5% CO) for up to 72h. Male HUVECs had greater expression of GDF15 mRNA and protein. To study the inter-relationship between GDF15 and HIF-1α, we measured the expression of GDF15 in H441 cells after HIF-1α knockdown using promoter dual luciferase reporter assay, which showed that HIF-1α and GDF15 expression are inversely related under normoxia and hyperoxia. The results indicate that sex differences exist in the expression and modulation of GDF15 by HIF-1α in neonatal hyperoxic injury both in vivo and in vitro. These differences could explain in part the mechanisms behind sex-specific differences in BPD.
男性早产新生儿比女性更容易发生支气管肺发育不良（BPD）。早产新生儿出现性别差异结局的潜在原因尚不清楚。生长分化因子15（GDF15）是一种分泌型细胞因子，在细胞增殖、凋亡和血管生成中发挥作用。在本研究中，我们试图阐明新生儿高氧肺损伤时体内肺组织中Gdf15的性别特异性表达及其受缺氧诱导因子-1α（Hif-1α）的调控，并在氧毒性体外模型中描绘男性和女性人脐静脉内皮细胞中GDF15表达的差异。在高氧暴露后（吸入氧分数95%，出生后第1 - 5天：肺发育的囊状期），与雌性小鼠相比，新生雄性小鼠（C57BL/6）的GDF15表达增加，HIF-1α表达降低。在体外实验中，将雄性和雌性人脐静脉内皮细胞暴露于室空气条件（21% O₂，5% CO₂）或高氧条件（95% O₂，5% CO₂）下长达72小时。雄性人脐静脉内皮细胞的GDF15 mRNA和蛋白表达更高。为了研究GDF15与HIF-1α之间的相互关系，我们使用启动子双荧光素酶报告基因检测法测量了HIF-1α敲低后H441细胞中GDF15的表达，结果表明在常氧和高氧条件下HIF-1α与GDF15的表达呈负相关。结果表明，在新生儿高氧损伤的体内和体外实验中，GDF15的表达及其受HIF-1α的调控存在性别差异。这些差异可能部分解释了BPD性别特异性差异背后的机制。
