Sex-specific differences in neonatal hyperoxic lung injury

Abstract

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% FiO2, postnatal day (PND) 1-5] and euthanized on PND 7 and 21. Extent of alveolarization, pulmonary vascularization, inflammation, and modulation of the NF-κB 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-κB 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.

Sex-specific differences in the modulation of Growth Differentiation Factor 15 (GDF15) by hyperoxia in vivo and in vitro : Role of Hif-1α

“…Blockade of prolyl hydroxylase stabilizes HIF, and leads to increases in VEGF, PEC AM-1 levels and angiogenesis in human microvascular endothelial cells exposed to hyperoxia (Asikainen et al, 2005). In our study, HIF-1α mRNA levels were increased in female neonatal mice exposed to hyperoxia at PND7 and were decreased in male mice at PND21 which was consistent with our previous findings of decreased lung vascular development in male mice at the same time point (Lingappan et al, 2016). HIF-1α was also decreased upon exposure to hyperoxia under in vitro conditions (Figures 2 and 4).…”

“…The sex in neonatal mouse pups was determined by both the anogenital distance and pigmentation in the anogenital region method (Wolterink-Donselaar et al, 2009). In younger mice, the sex was reconfirmed with PCR analysis for the Sry gene in genomic DNA obtained from mouse-tail clips as described before (Lingappan et al, 2016). …”

“…Sex-specific differences in injury patterns have been observed both in vivo and in vitro models. Male neonatal mice (C57BL/6J) exposed to hyperoxia (PND1-5, 95% FiO 2 ) show greater arrest in alveolarization and vascular development when compared to females (Lingappan et al, 2016). Male human umbilical venous endothelial cells have decreased survival, greater oxidative stress and impairment in angiogenesis compared to similarly exposed female cells (Zhang and Lingappan, 2017).…”

Differential sex-specific effects of oxygen toxicity in human umbilical vein endothelial cells

“…Data from our laboratory and those of other investigators have shown sex-specific modulation of NF-κB pathway [7–9]. In a model of neonatal hyperoxic lung injury, we showed that there was a greater arrest in lung development (alveolarization and angiogenesis) in male mice.…”

“…Interestingly, female mice showed increased activation of the NF-κB pathway in the lungs compared to males. The larger decrease in angiogenesis in males exposed to hyperoxia may have been in part due to decreased NF-κB activation [9]…”