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

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.

[1]  C. Bime,et al.  Involvement of eNAMPT/TLR4 inflammatory signaling in progression of non-alcoholic fatty liver disease, steatohepatitis, and fibrosis , 2023, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[2]  S. Mustafa,et al.  Development of a Peripheral Blood Transcriptomic Gene Signature to Predict Bronchopulmonary Dysplasia. , 2022, American journal of physiology. Lung cellular and molecular physiology.

[3]  J. Dagvadorj,et al.  eNAMPT/TLR4 inflammatory cascade activation is a key contributor to SLE Lung vasculitis and alveolar hemorrhage , 2022, Journal of translational autoimmunity.

[4]  C. Karmonik,et al.  eNAMPT Neutralization Preserves Lung Fluid Balance and Reduces Acute Renal Injury in Porcine Sepsis/VILI-Induced Inflammatory Lung Injury , 2022, Frontiers in Physiology.

[5]  L. Cancio,et al.  eNAMPT neutralization reduces preclinical ARDS severity via rectified NFkB and Akt/mTORC2 signaling , 2022, Scientific Reports.

[6]  J. Garcia,et al.  A Humanized Monoclonal Antibody Targeting Extracellular Nicotinamide Phosphoribosyltransferase Prevents Aggressive Prostate Cancer Progression , 2021, Pharmaceuticals.

[7]  Y. Lussier,et al.  Endothelial eNAMPT drives EndMT and preclinical PH: rescue by an eNAMPT-neutralizing mAb , 2021, Pulmonary circulation.

[8]  R. Pique-Regi,et al.  The amniotic fluid cell-free transcriptome in spontaneous preterm labor , 2021, Scientific Reports.

[9]  Zhonglin Liu,et al.  Involvement of eNAMPT/TLR4 signaling in murine radiation pneumonitis: protection by eNAMPT neutralization. , 2021, Translational research : the journal of laboratory and clinical medicine.

[10]  Xingyu Gao,et al.  MiR-34a suppression targets Nampt to ameliorate bone marrow mesenchymal stem cell senescence by regulating NAD+-Sirt1 pathway , 2021, Stem cell research & therapy.

[11]  V. Bhandari,et al.  miR34a: A Novel small Molecule Regulator with a Big role in Bronchopulmonary Dysplasia. , 2021, American journal of physiology. Lung cellular and molecular physiology.

[12]  C. Bime,et al.  Strategies to DAMPen COVID-19-mediated lung and systemic inflammation and vascular injury , 2020, Translational Research.

[13]  Zhonglin Liu,et al.  Endothelial eNAMPT amplifies pre-clinical acute lung injury: efficacy of an eNAMPT-neutralising monoclonal antibody , 2020, European Respiratory Journal.

[14]  Xiaoguang Sun,et al.  Role of secreted extracellular nicotinamide phosphoribosyltransferase (eNAMPT) in prostate cancer progression: Novel biomarker and therapeutic target , 2020, EBioMedicine.

[15]  S. Kallapur,et al.  Immunobiology of Acute Chorioamnionitis , 2020, Frontiers in Immunology.

[16]  Y. Lussier,et al.  Development of a biomarker mortality risk model in acute respiratory distress syndrome , 2019, Critical Care.

[17]  B. Jacobsson,et al.  Nicotinamide phosphoribosyltransferase and intra-amniotic inflammation in preterm prelabor rupture of membranes , 2019, The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians.

[18]  Amanda M. Brown,et al.  IL-1 receptor antagonist therapy mitigates placental dysfunction and perinatal injury following Zika virus infection. , 2019, JCI insight.

[19]  R. Keller,et al.  Recent advances in antenatal factors predisposing to bronchopulmonary dysplasia. , 2018, Seminars in perinatology.

[20]  R. Savani.  Modulators of inflammation in Bronchopulmonary Dysplasia. , 2018, Seminars in perinatology.

[21]  F. Zlámal,et al.  Umbilical cord blood and maternal visfatin (PBEF/NAMPT) concentrations in preterm birth with and without preterm premature rupture of membranes , 2018, The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians.

[22]  R. Weiss,et al.  Lipopolysaccharide‐induced maternal inflammation induces direct placental injury without alteration in placental blood flow and induces a secondary fetal intestinal injury that persists into adulthood , 2018, American journal of reproductive immunology.

[23]  N. Salomonis,et al.  IL-1 signaling mediates intrauterine inflammation and chorio-decidua neutrophil recruitment and activation. , 2018, JCI insight.

[24]  J. Postberg,et al.  Neonatal exposure to hyperoxia leads to persistent disturbances in pulmonary histone signatures associated with NOS3 and STAT3 in a mouse model , 2018, Clinical epigenetics.

[25]  B. Shivanna,et al.  Bronchopulmonary dysplasia: A review of pathogenesis and pathophysiology. , 2017, Respiratory medicine.

[26]  R. Dweik,et al.  Nicotinamide Phosphoribosyltransferase Promotes Pulmonary Vascular Remodeling and Is a Therapeutic Target in Pulmonary Arterial Hypertension , 2017, Circulation.

[27]  X. Hou,et al.  Antenatal Suppression of IL-1 Protects against Inflammation-Induced Fetal Injury and Improves Neonatal and Developmental Outcomes in Mice , 2017, The Journal of Immunology.

[28]  S. Chemtob,et al.  Sterile inflammation and pregnancy complications: a review. , 2016, Reproduction.

[29]  S. Hintz,et al.  Early neurodevelopmental outcomes of extremely preterm infants. , 2016, Seminars in perinatology.

[30]  G. Gardener,et al.  Neonatal outcomes after prelabour rupture of membranes before 24 weeks' gestation , 2016, Journal of paediatrics and child health.

[31]  A. Jobe,et al.  Lipopolysaccharide-Induced Chorioamnionitis Promotes IL-1–Dependent Inflammatory FOXP3+ CD4+ T Cells in the Fetal Rhesus Macaque , 2016, The Journal of Immunology.

[32]  L. Schieve,et al.  Population impact of preterm birth and low birth weight on developmental disabilities in US children. , 2016, Annals of epidemiology.

[33]  X. Ni,et al.  Novel Noncompetitive IL-1 Receptor–Biased Ligand Prevents Infection- and Inflammation-Induced Preterm Birth , 2015, The Journal of Immunology.

[34]  M. Wallace,et al.  Perinatal inflammation: a common factor in the early origins of cardiovascular disease? , 2015, Clinical science.

[35]  Jieling Zhao,et al.  Unique Toll-Like Receptor 4 Activation by NAMPT/PBEF Induces NFκB Signaling and Inflammatory Lung Injury , 2015, Scientific Reports.

[36]  J. Salmon,et al.  Prevention of Defective Placentation and Pregnancy Loss by Blocking Innate Immune Pathways in a Syngeneic Model of Placental Insufficiency , 2015, The Journal of Immunology.

[37]  Steven L Salzberg,et al.  HISAT: a fast spliced aligner with low memory requirements , 2015, Nature Methods.

[38]  B. Haglund,et al.  Perinatal conditions related to growth restriction and inflammation are associated with an increased risk of bronchopulmonary dysplasia , 2015, Acta paediatrica.

[39]  E. Miller,et al.  Inhibition of Cxcr 1 and 2 Delays Preterm Delivery and Reduces Neonatal Mortality in a Mouse Model of Chorioamnionitis , 2014 .

[40]  M. Elovitz,et al.  IL‐1 Receptor Blockade Prevents Fetal Cortical Brain Injury but Not Preterm Birth in a Mouse Model of Inflammation‐Induced Preterm Birth and Perinatal Brain Injury , 2014, American journal of reproductive immunology.

[41]  S. Kenyon,et al.  Antibiotics for preterm rupture of membranes. , 2013, The Cochrane database of systematic reviews.

[42]  Clara-Cecilie Günther,et al.  Gene Expression Profiling in Preterm Infants: New Aspects of Bronchopulmonary Dysplasia Development , 2013, PloS one.

[43]  J. Garcia,et al.  Mechanical stress induces pre-B-cell colony-enhancing factor/NAMPT expression via epigenetic regulation by miR-374a and miR-568 in human lung endothelium. , 2013, American journal of respiratory cell and molecular biology.

[44]  T. Hara,et al.  Serum neutrophil gelatinase-associated lipocalin as a predictor of the development of bronchopulmonary dysplasia in preterm infants. , 2013, Early human development.

[45]  L. Sarno,et al.  Chorioamnionitis and prematurity: a critical review , 2012, The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians.

[46]  A. Jobe.  Effects of chorioamnionitis on the fetal lung. , 2012, Clinics in perinatology.

[47]  Ann-Beth Moller,et al.  National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications , 2012, The Lancet.

[48]  Steven L Salzberg,et al.  Fast gapped-read alignment with Bowtie 2 , 2012, Nature Methods.

[49]  W. Carlo,et al.  Prospective Analysis of Pulmonary Hypertension in Extremely Low Birth Weight Infants , 2012, Pediatrics.

[50]  M. Hallman,et al.  Influence of Common Non-Synonymous Toll-like Receptor 4 Polymorphisms on Bronchopulmonary Dysplasia and Prematurity in Human Infants , 2012, PloS one.

[51]  N. Zaghloul,et al.  Extracellular Superoxide Dismutase Overexpression Can Reverse the Course of Hypoxia-Induced Pulmonary Hypertension , 2012, Molecular medicine.

[52]  L. Hartling,et al.  Chorioamnionitis as a risk factor for bronchopulmonary dysplasia: a systematic review and meta-analysis , 2011, Archives of Disease in Childhood: Fetal and Neonatal Edition.

[53]  M. O’Reilly,et al.  Neonatal hyperoxia causes pulmonary vascular disease and shortens life span in aging mice. , 2011, The American journal of pathology.

[54]  B. Kramer.  Chorioamnionitis – New Ideas from Experimental Models , 2011, Neonatology.

[55]  T. Agorastos,et al.  Serum vaspin levels in normal pregnancy in comparison with non-pregnant women. , 2011, European journal of endocrinology.

[56]  S. Renaud,et al.  Spontaneous Pregnancy Loss Mediated by Abnormal Maternal Inflammation in Rats Is Linked to Deficient Uteroplacental Perfusion , 2011, The Journal of Immunology.

[57]  Cole Trapnell,et al.  Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. , 2010, Nature biotechnology.

[58]  P. Austin,et al.  Optimal caliper widths for propensity-score matching when estimating differences in means and differences in proportions in observational studies , 2010, Pharmaceutical statistics.

[59]  J. Folkman,et al.  Maternal preeclampsia predicts the development of bronchopulmonary dysplasia. , 2010, The Journal of pediatrics.

[60]  M. Lepage,et al.  IL-1 Receptor Antagonist Protects against Placental and Neurodevelopmental Defects Induced by Maternal Inflammation , 2010, The Journal of Immunology.

[61]  S. Welty,et al.  Deficits in lung alveolarization and function after systemic maternal inflammation and neonatal hyperoxia exposure. , 2010, Journal of applied physiology.

[62]  R. Ehrenkranz,et al.  Fetal Growth Restriction and Chronic Lung Disease Among Infants Born Before the 28th Week of Gestation , 2009, Pediatrics.

[63]  J. Pillow,et al.  IL-1 mediates pulmonary and systemic inflammatory responses to chorioamnionitis induced by lipopolysaccharide. , 2009, American journal of respiratory and critical care medicine.

[64]  R. Romero,et al.  Maternal plasma visfatin in preterm labor , 2009, The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians.

[65]  K. Sarafidis,et al.  Clara cell secretory protein (CC16) as a peripheral blood biomarker of lung injury in ventilated preterm neonates , 2008, European Journal of Pediatrics.

[66]  Carol Friedman,et al.  Information theory applied to the sparse gene ontology annotation network to predict novel gene function , 2007, ISMB/ECCB.

[67]  Assuring Healthy Outcomes,et al.  Preterm Birth : Causes , Consequences , and Prevention , 2005 .

[68]  S. Witkin,et al.  Preterm labor is induced by intraamniotic infusions of interleukin-1beta and tumor necrosis factor-alpha but not by interleukin-6 or interleukin-8 in a nonhuman primate model. , 2006, American journal of obstetrics and gynecology.

[69]  T. Ogihara,et al.  Plasma KL-6 Predicts the Development and Outcome of Bronchopulmonary Dysplasia , 2006, Pediatric Research.

[70]  Changlian Zhu,et al.  Disruption of interleukin-18, but not interleukin-1, increases vulnerability to preterm delivery and fetal mortality after intrauterine inflammation. , 2006, The American journal of pathology.

[71]  Gordon K. Smyth,et al.  Empirical array quality weights in the analysis of microarray data , 2006, BMC Bioinformatics.

[72]  M. Mahendroo,et al.  Signaling via the type I IL-1 and TNF receptors is necessary for bacterially induced preterm labor in a murine model. , 2006, American journal of obstetrics and gynecology.

[73]  Han-Suk Kim,et al.  Increase of interleukin‐6 in tracheal aspirate at birth: A predictor of subsequent bronchopulmonary dysplasia in preterm infants , 2006, Acta paediatrica.

[74]  E. Dempsey,et al.  Outcome of neonates less than 30 weeks gestation with histologic chorioamnionitis. , 2005, American journal of perinatology.

[75]  Jean YH Yang,et al.  Bioconductor: open software development for computational biology and bioinformatics , 2004, Genome Biology.

[76]  R. Redline,et al.  Amniotic Infection Syndrome: Nosology and Reproducibility of Placental Reaction Patterns , 2003, Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society.

[77]  R. Lamont.  Infection in the prediction and antibiotics in the prevention of spontaneous preterm labour and preterm birth , 2003, Minerva ginecologica.

[78]  C. Lockwood.  Predicting premature delivery--no easy task. , 2002, The New England journal of medicine.

[79]  S. Witkin,et al.  Indomethacin blocks interleukin 1beta-induced myometrial contractions in pregnant rhesus monkeys. , 2000, American journal of obstetrics and gynecology.

[80]  U. Thome,et al.  Comparison of Pulmonary Inflammatory Mediators in Preterm Infants Treated with Intermittent Positive Pressure Ventilation or High Frequency Oscillatory Ventilation 1 , 1998, Pediatric Research.

[81]  Roberto Romero,et al.  The fetal inflammatory response syndrome. , 1998, American journal of obstetrics and gynecology.

[82]  K. Watterberg,et al.  Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops. , 1996, Pediatrics.

[83]  R. Romero,et al.  Systemic administration of interleukin-1 induces preterm parturition in mice. , 1991, American journal of obstetrics and gynecology.

[84]  W. Tooley,et al.  Epidemiology of bronchopulmonary dysplasia. , 1979, The Journal of pediatrics.

[85]  Xiaoguang Sun,et al.  Direct Extracellular NAMPT Involvement in Pulmonary Hypertension and Vascular Remodeling Transcriptional Regulation by SOX and HIF-2 a , 2020 .

[86]  R. Beigi,et al.  Committee Opinion No. 712: Intrapartum Management of Intraamniotic Infection. , 2017, Obstetrics and gynecology.

[87]  I. Kahramanoglu,et al.  Comparison of two different antibiotic regimens for the prophylaxisis of cases with preterm premature rupture of membranes: a randomized clinical trial. , 2016, Ginekologia polska.

[88]  B. Poindexter,et al.  Early pulmonary vascular disease in preterm infants at risk for bronchopulmonary dysplasia. , 2015, American journal of respiratory and critical care medicine.

[89]  Joy E. Lawn,et al.  Born too soon: the global action report on preterm birth , 2012 .

[90]  L. Monte,et al.  [Bronchopulmonary dysplasia]. , 2005, Jornal de pediatria.

[91]  Susumu Goto,et al.  The KEGG resource for deciphering the genome , 2004, Nucleic Acids Res..

[92]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .