Loss of Growth Differentiation Factor 15 exacerbates lung injury in neonatal mice.

Growth Differentiation Factor 15 (GDF15 is a divergent member of the TGF-β superfamily, and its expression increases under various stress conditions, including inflammation, hyperoxia, and senescence. GDF15 expression is increased in neonatal murine BPD models, and GDF15 loss exacerbates oxidative stress and decreases cellular viability . Our overall hypothesis is that the loss of GDF15 will exacerbate hyperoxic lung injury in the neonatal lung . We exposed neonatal mice and wild-type (WT) controls on a similar background to room air or hyperoxia (95% O) 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 to 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 arrest of alveolarization in the developing lung with loss of female-sex advantage in mice.