Abnormal Fetal Lung of Hoxa1(−/−) Piglets Is Rescued by Maternal Feeding with All-Trans Retinoic Acid

SIMPLE SUMMARY: Proper development of the fetal lung is vital to the survival and healthy growth of pigs after birth, but many factors can disturb the normal growth of the fetal pig lung. In the previous study, we found that the Hoxa1 mutation of g.50111251 G > TC resulted in the congestion and edema of fetal lungs, and all neonatal Hoxa1(−/−) piglets died of respiratory failure during the suckling period. The results of this study showed that supplementing all-trans retinoic acid (ATRA) to pregnant sows alleviated the dyspnea of neonatal Hoxa1(−/−) piglets by increasing the IFN-γ concentration (p < 0.05), airspace area (p < 0.01) and pulmonary microvessel density (p < 0.01); increasing the expression of VEGFD (p < 0.01), PDGFD (p < 0.01), KDR (p < 0.01), ID1 (p < 0.01), and NEDD4 (p < 0.01); and decreasing the septal wall thickness (p < 0.01) and the expression of SFTPC (p < 0.01) and FOXO3 (p < 0.01). ABSTRACT: Neonatal Hoxa1(−/−) piglets were characterized by dyspnea owing to the Hoxa1 mutation, and maternal administration with ATRA alleviated the dyspnea of neonatal Hoxa1(−/−) piglets. The purpose of this experiment was to explore how maternal ATRA administration rescued the abnormal fetal lungs of Hoxa1(−/−) piglets. Samples of the lungs were collected from neonatal Hoxa1(−/−) and non-Hoxa1(−/−) piglets delivered by sows in the control group, and from neonatal Hoxa1(−/−) piglets born by sows administered with ATRA at 4 mg/kg body weight on dpc 12, 13, or 14, respectively. These were used for the analysis of ELISA, histological morphology, immunofluorescence staining, immunohistochemistry staining, and quantitative real-time PCR. The results indicate that the Hoxa1 mutation had adverse impacts on the development of the alveoli and pulmonary microvessels of Hoxa1(−/−) piglets. Maternal administration with ATRA at 4 mg/kg body weight on dpc 14 rescued the abnormal lung development of Hoxa1(−/−) piglets by increasing the IFN-γ concentration (p < 0.05), airspace area (p < 0.01) and pulmonary microvessel density (p < 0.01); increasing the expression of VEGFD (p < 0.01), PDGFD (p < 0.01), KDR (p < 0.01), ID1 (p < 0.01), and NEDD4 (p < 0.01); and decreasing the septal wall thickness (p < 0.01) and the expression of SFTPC (p < 0.01) and FOXO3 (p < 0.01). Maternal administration with ATRA plays a vital role in rescuing the abnormal development of lung of Hoxa1(−/−) fetal piglets.