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

Mohamed Ahmed, Nancy G. Casanova, Nahla Zaghloul, Akash Gupta, Marisela Rodriguez, Ian R. 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

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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 eNAMPT mAb-induced reductions in inflammatory pathway genes. Discussion: The eNAMPT/TLR4 inflammatory pathway is a highly druggable contributor to IAI pathobiology during pregnancy with the eNAMPT-neutralizing mAb a novel therapeutic strategy to decrease premature delivery and improve short- and long-term neonatal outcomes. eNAMPT blood expression is a potential biomarker for early prediction of chronic lung disease among premature neonates.

Original languageEnglish (US)
Article number1129413
JournalFrontiers in Physiology
Volume14
DOIs
StatePublished - 2023

Keywords

  • bronchopulmonary dysplasia (BPD)
  • damage-associated molecular pattern protein (DAMP)
  • eNAMPT
  • intra-amniotic inflammation (IAI)
  • mAb
  • preterm birth

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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