Ahmed Mohamed, Casanova Nancy G, Zaghloul Nahla, Gupta Akash, Rodriguez Marisela, Robbins Ian R, Kempf Carrie L, Sun Xiaoguang, Song Jin H, Hernon Vivian Reyes, Sammani Saad, Camp Sara M, Moreira Alvaro, Hsu Chaur-Dong, Garcia Joe G N
Departments of Pediatrics, University of Arizona Health Sciences, Tucson, AZ, United States.
Department of Medicine, University of Arizona Health Sciences, Tucson, AZ, United States.
Front Physiol. 2023 Jun 20;14:1129413. doi: 10.3389/fphys.2023.1129413. eCollection 2023.
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. 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. Human placentas from women with histologically-proven chorioamnionitis exhibited dramatic NAMPT expression compared to placentas without chorioamnionitis. Increased 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. 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.
羊膜内炎症（IAI）或绒毛膜羊膜炎是妊娠常见并发症，可导致严重的孕产妇发病/死亡、早产以及新生儿患慢性肺部疾病如支气管肺发育不良（BPD）的风险。我们研究了细胞外烟酰胺磷酸核糖转移酶（eNAMPT），一种关键的炎症性损伤相关分子模式（DAMP）和Toll样受体4（TLR4）配体，作为降低IAI严重程度和改善不良胎儿/新生儿结局的潜在治疗靶点。对以下样本进行了血液/组织检测：1）经组织学证实患有绒毛膜羊膜炎的女性；2）极低出生体重（VLBW）新生儿；3）IAI的临床前小鼠妊娠模型。对暴露于IAI的妊娠小鼠及其幼崽分组给予eNAMPT中和单克隆抗体（mAb）治疗。与无绒毛膜羊膜炎的胎盘相比，经组织学证实患有绒毛膜羊膜炎的女性的人胎盘显示出显著的烟酰胺磷酸核糖转移酶（NAMPT）表达。VLBW新生儿（出生第5天）全血中表达增加显著预示BPD的发生。与未治疗的经脂多糖（LPS）攻击的母鼠（妊娠第15天）相比，接受eNAMPT mAb治疗的母鼠（妊娠第15/16天）所生幼崽的存活率提高了3倍以上，新生儿肺组织中eNAMPT/细胞因子水平降低，产后第1 - 14天暴露于100%高氧后BPD和肺动脉高压（PH）的发生及严重程度降低。对母体子宫和新生儿心脏组织进行的全基因组基因表达研究证实了eNAMPT mAb诱导炎症通路基因减少。eNAMPT/TLR4炎症通路是妊娠期间IAI病理生物学中一个极具药物开发潜力的因素，eNAMPT中和mAb是减少早产和改善新生儿短期及长期结局的一种新治疗策略。eNAMPT血液表达是早产新生儿慢性肺部疾病早期预测的潜在生物标志物。
