Intrauterine inflammation-induced neonatal lung injury via succinic acid-mediated alveolar epithelial E-cadherin downregulation.

Intrauterine inflammation is associated with lung injury in offspring and long-term adverse pulmonary outcomes, but the underlying mechanism remains elusive. This study aimed to investigate the underlying molecular mechanism from the perspective of metabolites. Pregnant C57BL/6 mice received an intraperitoneal injection of LPS on gestational day 12.5 to establish an intrauterine inflammation model. The results showed that prenatal LPS exposure induced bronchopulmonary dysplasia (BPD)-like alveolar simplification. Then, by LC/MS untargeted metabolomics analysis, succinic acid was found to be elevated in murine placentas and preterm human umbilical cord blood with intrauterine inflammation. Besides, the expression of succinate dehydrogenase B subunit (Sdhb), a key catalytic enzyme of succinic acid, was downregulated in the murine placentas with intrauterine inflammation. Tail intravenous administration of Sdhb siRNA led to the accumulation of succinic acid in the placenta and aggravated LPS-induced lung injury in the offspring. In offspring mice, intrauterine inflammation decreased E-cadherin levels in lung tissue, which were further reduced by Sdhb siRNA injection. Conversely, overexpression of E-cadherin alleviated inflammation-induced lung injury. In vitro experiments revealed that succinic acid downregulated E-cadherin expression in alveolar epithelial cells through the PI3K/Akt/Hif-1α pathway. Succinic acid also indirectly downregulated the E-cadherin expression in alveolar epithelial cells by inducing macrophage M2 polarization and the production of Tgf-β1. In conclusion, this study demonstrates that succinic acid is a critical mediator of intrauterine inflammation-induced lung injury in offspring.NEW & NOTEWORTHY Intrauterine inflammation induces the accumulation of succinic acid in the placenta, which subsequently downregulated E-cadherin expression in the alveolar epithelial cells, thereby contributing to lung injury.