{"doi":"10.3389/fphys.2023.1129413","title":"The eNAMPT/TLR4 inflammatory cascade drives the severity of intra-amniotic inflammation in pregnancy and predicts infant outcomes","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.","journal":"Frontiers in Physiology","year":2023,"id":370189,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9626,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":688433,"name":"Nancy G. Casanova","orcid":"0000-0002-6363-2414","position":1,"is_corresponding":false},{"id":1129341,"name":"Nahla Zaghloul","orcid":"0000-0001-7172-7395","position":2,"is_corresponding":false},{"id":332034,"name":"Akash Gupta","orcid":"0000-0001-7305-055X","position":3,"is_corresponding":false},{"id":401332,"name":"Marisela Rodriguez","orcid":null,"position":4,"is_corresponding":false},{"id":1129722,"name":"Ian Richard Robbins","orcid":null,"position":5,"is_corresponding":false},{"id":688890,"name":"Carrie L. Kempf","orcid":null,"position":6,"is_corresponding":false},{"id":688435,"name":"Xiaoguang Sun","orcid":"0000-0003-4226-8294","position":7,"is_corresponding":false},{"id":392783,"name":"Jin H. Song","orcid":"0000-0002-0123-2909","position":8,"is_corresponding":false},{"id":688896,"name":"Vivian Reyes Hernon","orcid":null,"position":9,"is_corresponding":false},{"id":688438,"name":"Saad Sammani","orcid":"0000-0002-7933-6388","position":10,"is_corresponding":false},{"id":389496,"name":"Sara M. Camp","orcid":null,"position":11,"is_corresponding":false},{"id":417537,"name":"Alvaro Moreira","orcid":"0000-0003-3455-6608","position":12,"is_corresponding":false},{"id":334160,"name":"Chaur‐Dong Hsu","orcid":"0000-0002-9642-470X","position":13,"is_corresponding":false},{"id":300875,"name":"Joe G. N. Garcia","orcid":"0000-0002-6934-0420","position":14,"is_corresponding":false},{"id":1129721,"name":"Mohamed Ahmed","orcid":null,"position":0,"is_corresponding":true}],"reference_count":102,"raw_metadata":null,"created_at":"2026-07-19T01:15:37.094100Z","pmid":"37415908","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}