The Protective Effect And Mechanism Of Nuclear Factor Erythroid 2 Related Factor 2 On Lung Development In Intrauterine Growth Restriction

Intrauterine growth restriction(IUGR)is a common complication of pregnancy.Despite continuous improvement in neonatal care,it is still the main cause of stillbirth,neonatal death and short-term and long-term morbidity of newborns worldwide,and a serious public health problem.IUGR is a systemic disease that has adverse effects on all organs,especially the lung.Placental dysfunction generally occurs in the second half of pregnancy,when the acinar and alveoli are developing,so the distal lungs are most susceptible to IUGR.At the same time,lung development is not complete at birth and must continue after birth,which makes the lung vulnerable to injury.There are still many limitations in current medical care methods,and new treatment directions are urgently needed.Inflammation and oxidative stress are known mechanisms of IUGR damage.Nuclear factor erythroid 2 related factor 2(Nrf2)is an important transcription factor that not only regulates these two pathological phenomena,but also is closely related to pyroptosis,a newly discovered mode of inflammatory cell death.This study aimed to study the protective effect of Nrf2 on lung development in IUGR offspring and its mechanism.While the etiology of IUGR varies,its downstream effects are ultimately fetal hypoxia.Therefore,maternal hypoxia model provides a direct method to study the pathological mechanism of IUGR.In this study,hypoxia-induced IUGR mice were used to investigate its mechanism.By measuring body weight and brain/liver ratio for four consecutive weeks,IUGR mice were found to have abnormal growth and development,decreased birth weight,catch-up growth and brain retention effect.At 2 weeks of age,the lung tissue was abnormal and pulmonary angiogenesis decreased.The levels of IL-1β and IL-6 in lung tissue on the day of birth were negatively correlated with birth weight.Lung tissue inflammation,oxidative stress and pyroptosis occurred at 2 weeks of age,and Nrf2 was blocked from entering the nucleus and could not play its physiological function.Human placental transcriptome data also showed that GSDMD was highly expressed in IUGR placenta.In conclusion,Nrf2 has a protective effect on hypoxia-induced IUGR lung injury.Promote Nrf2 nuclear transposition can inhibit pyroptosis and relieve IUGR-induced pulmonary dysplasia.Nrf2 knockout mice were further used to verify the protective effect of Nrf2 on IUGR.It was found that the growth restriction of IUGR mice after Nrf2 knockout was increased,and the live fetus rate and birth weight were further reduced.At 2 weeks of age,lung structural damage worsened and Vascular Endothelial Growth Factor α/Vascular Endothelial Growth Factor Receptor 2(VEGFα/VEGFR2)pathway was abnormally activated.Nrf2 knockout mice had compensatory antioxidant activity at 2 weeks of age and decompensated at 4 weeks of age,with increased oxidative stress.The m RNA and protein levels of pyroptosis related molecules in lung tissue of mice at 2 weeks of age showed that the pyroptosis was aggravated by Nrf2 knockout.String protein-protein interaction analysis showed that there was an interaction between Nrf2 and pyroptosis related molecules.Overexpression of Nrf2 on 293 T cells inhibited the expression of the key pyroptosis molecule GSDMD,and the binding of Nrf2 to the promoter region of GSDMD was confirmed by double luciferase reporter gene assay.In conclusion,Nrf2 has a protective effect on hypoxia-induced IUGR lung development.Promoting Nrf2 nuclear transposition can inhibit pyroptosis and alleviate IUGR lung injury.