Loss of growth differentiation factor 15 exacerbates lung injury in neonatal mice.

Growth differentiation factor 15 (GDF15) is a divergent member of the transforming growth factor-β (TGF-β) superfamily, and its expression increases under various stress conditions, including inflammation, hyperoxia, and senescence. GDF15 expression is increased in neonatal murine bronchopulmonary dysplasia (BPD) models, and GDF15 loss exacerbates oxidative stress and decreases cellular viability in vitro. Our overall hypothesis is that the loss of GDF15 will exacerbate hyperoxic lung injury in the neonatal lung in vivo. We exposed neonatal mice and wild-type (WT) controls on a similar background to room air or hyperoxia (95% [Formula: see text]) for 5 days after birth. The mice were euthanized on (PND 21). mice had higher mortality and lower body weight than WT mice after exposure to hyperoxia. Hyperoxia exposure adversely impacted alveolarization and lung vascular development, with a greater impact in mice. Interestingly, mice showed lower macrophage count in the lungs compared with WT mice both under room air and after exposure to hyperoxia. Analysis of the lung transcriptome revealed marked divergence in gene expression and enriched biological pathways in WT and mice and differed markedly by biological sex. Notably, pathways related to macrophage activation and myeloid cell homeostasis were negatively enriched in mice. Loss of exacerbates mortality, lung injury, and the phenotype of the arrest of alveolarization in the developing lung with loss of female-sex advantage in mice. We show for the first time that loss of exacerbates mortality, lung injury, and the phenotype of the arrest of alveolarization in the developing lung with loss of female-sex advantage in mice. We also highlight the distinct pulmonary transcriptomic response in the lung including pathways related to macrophage recruitment and activation.