The eNAMPT/TLR4 inflammatory cascade drives the severity of intra-amniotic inflammation in pregnancy and predicts infant outcomes

作者：Mohamed Ahmed, Nancy G. Casanova, Nahla Zaghloul, Akash Gupta, Marisela Rodriguez, Ian Richard Robbins, Carrie L. Kempf, Xiaoguang Sun, Jin H. Song, Vivian Reyes Hernon, Saad Sammani, Sara M. Camp, Alvaro Moreira, Chaur‐Dong Hsu, Joe G. N. Garcia · 发表于：Frontiers in Physiology · 年份：2023 · DOI：10.3389/fphys.2023.1129413 · 被引用次数：7 · 研究领域：Neonatal Respiratory Health Research、Preterm Birth and Chorioamnionitis、Pregnancy and preeclampsia studies

Introduction: Intra-amniotic inflammation (IAI) or chorioamnionitis is a common complication of pregnancy producing significant maternal morbidity/mortality, premature birth and neonatal risk of chronic lung diseases such as bronchopulmonary dysplasia (BPD). We examined eNAMPT (extracellular nicotinamide phosphoribosyltransferase), a critical inflammatory DAMP and TLR4 ligand, as a potential therapeutic target to reduce IAI severity and improve adverse fetal/neonatal outcomes. Methods: Blood/tissue samples were examined in: 1) women with histologically-proven chorioamnionitis, 2) very low birth weight (VLBW) neonates, and 3) a preclinical murine pregnancy model of IAI. Groups of pregnant IAI-exposed mice and pups were treated with an eNAMPT-neutralizing mAb. Results: Human placentas from women with histologically-proven chorioamnionitis exhibited dramatic NAMPT expression compared to placentas without chorioamnionitis. Increased NAMPT expression in whole blood from VLBW neonates (day 5) significantly predicted BPD development. Compared to untreated LPS-challenged murine dams (gestational day 15), pups born to eNAMPT mAb-treated dams (gestational days 15/16) exhibited a > 3-fold improved survival, reduced neonate lung eNAMPT/cytokine levels, and reduced development and severity of BPD and pulmonary hypertension (PH) following postnatal exposure to 100% hyperoxia days 1–14. Genome-wide gene expression studies of maternal uterine and neonatal cardiac tissues corroborated ...