Sex-specific differences in neonatal hyperoxic lung injury
Sex-specific differences in neonatal hyperoxic lung injury
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DOI：
10.1152/ajplung.00047.2016
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发表时间：
2016-08-01
影响因子：
4.9
通讯作者：
Moorthy, Bhagavatula
中科院分区：
文献类型：
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作者：
Lingappan, Krithika;Jiang, Weiwu;Moorthy, Bhagavatula
在调整其他混杂因素后，男性被认为是支气管肺发育不良（BPD）发生的独立预测因素。BPD的特征是肺发育停止，肺泡分隔和血管发育明显受损。早产儿性二态性结局的潜在原因尚不清楚。在这项研究中，我们测试的假设，即雄性新生小鼠将更容易受到高氧肺损伤，并将显示更大的停滞在肺泡。将新生雄性和雌性小鼠（C57 BL/6）暴露于高氧[95% FiO（2），出生后第1-5天]，并在PND 7和21实施安乐死。测定肺泡化、肺血管化、炎症和NF-κ B通路的调节程度，并与室内空气对照进行比较。在高氧暴露动物中，巨噬细胞和中性粒细胞浸润显著增加，但与雌性动物相比，雄性动物的增加程度更大。肺形态测定显示，雄性小鼠的平均线性截距（MLI）较高，径向肺泡计数（RAC）较低，因此肺发育阻滞程度较大。与女性相比，高氧暴露后男性血管生成标志物（PECAM 1和VEGFR 2）的表达显著降低。有趣的是，与雄性小鼠相比，雌性小鼠肺中NF-κ B通路的活化增加。这些结果支持性别在该模型中高氧介导的肺损伤中起关键作用的假设。阐明性别特异性的分子机制可能有助于开发新的个体化治疗方法来预防/治疗BPD。
Male sex is considered an independent predictor for the development of bronchopulmonary dysplasia (BPD) after adjusting for other confounders. BPD is characterized by an arrest in lung development with marked impairment of alveolar septation and vascular development. The reasons underlying sexually dimorphic outcomes in premature neonates are not known. In this investigation, we tested the hypothesis that male neonatal mice will be more susceptible to hyperoxic lung injury and will display larger arrest in lung alveolarization. Neonatal male and female mice (C57BL/6) were exposed to hyperoxia [95% FiO(2), postnatal day (PND) 1-5] and euthanized on PND 7 and 21. Extent of alveolarization, pulmonary vascularization, inflammation, and modulation of the NF-kappa B pathway were determined and compared with room air controls. Macrophage and neutrophil infiltration was significantly increased in hyperoxia-exposed animals but was increased to a larger extent in males compared with females. Lung morphometry showed a higher mean linear intercept (MLI) and a lower radial alveolar count (RAC) and therefore greater arrest in lung development in male mice. This was accompanied by a significant decrease in the expression of markers of angiogenesis (PECAM1 and VEGFR2) in males after hyperoxia exposure compared with females. Interestingly, female mice showed increased activation of the NF-kappa B pathway in the lungs compared with males. These results support the hypothesis that sex plays a crucial role in hyperoxia-mediated lung injury in this model. Elucidation of the sex-specific molecular mechanisms may aid in the development of novel individualized therapies to prevent/treat BPD.