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Published on: December 17, 2014
Loss of growth differentiation factor 15 exacerbates lung injury in neonatal mice
Faeq Al-Mudares1, Manuel Cantu Gutierrez2, Abiud Cantu2
1Section of Neonatology, Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas, United States.
Insights
Loss of Growth Differentiation Factor 15 (GDF15) worsens neonatal lung injury and mortality from hyperoxia. This study reveals GDF15 deficiency impairs lung development and macrophage function, particularly in females.
Area of Science:
- Pulmonary Medicine
- Neonatal Research
- Molecular Biology
- Immunology
Background:
- Growth Differentiation Factor 15 (GDF15) expression rises under stress, including in neonatal bronchopulmonary dysplasia (BPD) models.
- GDF15 deficiency in vitro increases oxidative stress and reduces cell viability.
- The role of GDF15 in neonatal hyperoxic lung injury in vivo remains unclear.
Purpose of the Study:
- To investigate the hypothesis that GDF15 loss exacerbates hyperoxic lung injury in neonatal mice.
- To analyze the impact of GDF15 deficiency on lung development, mortality, and immune cell response under hyperoxia.
Main Methods:
- Neonatal GDF15-deficient (Gdf15-/-) and wild-type (WT) mice were exposed to room air or 95% oxygen for 5 days.
- Mice were assessed at postnatal day 21 (PND 21) for mortality, body weight, lung alveolarization, and vascular development.
- Pulmonary macrophage counts and lung transcriptome were analyzed to identify differential gene expression and biological pathways.
Main Results:
- Gdf15-/- mice exhibited higher mortality and reduced body weight following hyperoxia compared to WT controls.
- Hyperoxia impaired alveolarization and lung vascular development more severely in Gdf15-/- mice.
- Gdf15-/- mice showed decreased lung macrophage counts and altered gene expression, particularly in pathways related to macrophage activation and myeloid cell homeostasis, with a loss of the typical female-sex advantage.
Conclusions:
- Loss of GDF15 exacerbates hyperoxic lung injury, mortality, and arrested alveolar development in neonatal mice.
- GDF15 deficiency significantly impacts pulmonary immune responses, particularly macrophage function and homeostasis.
- The absence of GDF15 eliminates the protective female-sex advantage observed in lung injury models.
Abstract:
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 Gdf15-/- 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 postnatal day 21 (PND 21). Gdf15-/- 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 Gdf15-/- mice. Interestingly, Gdf15-/- 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 Gdf15-/- mice and differed markedly by biological sex. Notably, pathways related to macrophage activation and myeloid cell homeostasis were negatively enriched in Gdf15-/- mice. Loss of Gdf15 exacerbates mortality, lung injury, and the phenotype of the arrest of alveolarization in the developing lung with loss of female-sex advantage in Gdf15-/- mice.NEW & NOTEWORTHY We show for the first time that loss of Gdf15 exacerbates mortality, lung injury, and the phenotype of the arrest of alveolarization in the developing lung with loss of female-sex advantage in Gdf15-/- mice. We also highlight the distinct pulmonary transcriptomic response in the Gdf15-/- lung including pathways related to macrophage recruitment and activation.
