{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T03:10:12Z","timestamp":1791688212678,"version":"4.3.4"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,3,3]],"date-time":"2021-03-03T00:00:00Z","timestamp":1614729600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R35-GM118097"],"award-info":[{"award-number":["R35-GM118097"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Morbidity and mortality associated with neonatal sepsis remains a healthcare crisis. PD1<jats:sup>\u2212\/\u2212<\/jats:sup> neonatal mice endured experimental sepsis, in the form of cecal slurry (CS), and showed improved rates of survival compared to wildtype (WT) counterparts. End-organ injury, particularly of the lung, contributes to the devastation set forth by neonatal sepsis. PDL1<jats:sup>\u2212\/\u2212<\/jats:sup> neonatal mice, in contrast to PD1<jats:sup>\u2212\/\u2212<\/jats:sup> neonatal mice did not have a significant improvement in survival after CS. Because of this, we focused subsequent studies on the impact of PD1 gene deficiency on lung injury. Here, we observed that at 24 h post-CS (but not at 4 or 12 h) there was a marked increase in pulmonary edema (PE), neutrophil influx, myeloperoxidase (MPO) levels, and cytokine expression sham (Sh) WT mice. Regarding pulmonary endothelial cell (EC) adhesion molecule expression, we observed that Zona occludens-1 (ZO-1) within the cell shifted from a membranous location to a peri-nuclear location after CS in WT murine cultured ECs at 24hrs, but remained membranous among PD1<jats:sup>\u2212\/\u2212<\/jats:sup> lungs. To expand the scope of this inquiry, we investigated human neonatal lung tissue. We observed that the lungs of human newborns exposed to intrauterine infection had significantly higher numbers of PD1<jats:sup>+<\/jats:sup> cells compared to specimens who died from non-infectious causes. Together, these data suggest that PD1\/PDL1, a pathway typically thought to govern adaptive immune processes in adult animals, can modulate the largely innate neonatal pulmonary immune response to experimental septic insult. The potential future significance of this area of study includes that PD1\/PDL1 checkpoint proteins may be viable therapeutic targets in the septic neonate.<\/jats:p>","DOI":"10.3389\/fimmu.2021.634529","type":"journal-article","created":{"date-parts":[[2021,3,3]],"date-time":"2021-03-03T04:49:05Z","timestamp":1614746945000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Survival and Pulmonary Injury After Neonatal Sepsis: PD1\/PDL1's Contributions to Mouse and Human Immunopathology"],"prefix":"10.3389","volume":"12","author":[{"given":"Eleanor A.","family":"Fallon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Shiang","family":"Chung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daithi S.","family":"Heffernan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaping","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monique E.","family":"De Paepe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfred","family":"Ayala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,3,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1016\/j.bpobgyn.2016.05.008","article-title":"Ending preventable maternal and newborn deaths due to infection","volume":"36","author":"Desale","year":"2016","journal-title":"Best Pract Res Clin Obstet Gynaecol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"342","DOI":"10.15585\/mmwr.mm6513a2","article-title":"Varying estimates of sepsis mortality using death certificates and administrative codes\u2013United States, 1999-2014","volume":"65","author":"Epstein","year":"2016","journal-title":"MMWR Morb Mortal Wkly Rep"},{"key":"B3","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.jinf.2016.11.006","article-title":"Hospital-related cost of sepsis: a systematic review","volume":"74","author":"Arefian","year":"2016","journal-title":"J Infect"},{"key":"B4","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1089\/sur.2016.184","article-title":"Age and its impact on outcomes with intra-abdominal infection","volume":"18","author":"Farmer","year":"2017","journal-title":"Surg Infect."},{"key":"B5","doi-asserted-by":"publisher","first-page":"798","DOI":"10.1097\/PCC.0000000000000225","article-title":"Pediatric severe sepsis in U.S. children's hospitals","volume":"15","author":"Balamuth","year":"2014","journal-title":"Pediatr Crit Care Med"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1115","DOI":"10.1542\/peds.2015-0434","article-title":"Annual summary of vital statistics: 2012-2013","volume":"135","author":"Osterman","year":"2015","journal-title":"Pediatrics"},{"key":"B7","doi-asserted-by":"publisher","first-page":"706","DOI":"10.1093\/ije\/dyl043","article-title":"Estimating the causes of 4 million neonatal deaths in the year 2000","volume":"35","author":"Lawn","year":"2006","journal-title":"Int J Epidemiol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1097\/PCC.0000000000000157","article-title":"Time for a neonatal-specific consensus definition for sepsis","volume":"15","author":"Wynn","year":"2014","journal-title":"Pediatr Crit Care Med"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/imm.12454","article-title":"Is the developmentally immature immune response in paediatric sepsis a recapitulation of immune tolerance?","volume":"145","year":"2015","journal-title":"Immunology"},{"key":"B10","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1016\/j.molmed.2014.01.002","article-title":"The new normal: immunomodulatory agents against sepsis immune suppression","volume":"20","author":"Hutchins","year":"2014","journal-title":"Trends Mol Med"},{"key":"B11","doi-asserted-by":"publisher","first-page":"854","DOI":"10.1038\/nrd1854","article-title":"Animal models of sepsis: setting the stage","volume":"4","author":"Buras","year":"2005","journal-title":"Nat Rev Drug Discov"},{"key":"B12","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1186\/1757-7241-20-54","article-title":"Acute lung injury and the acute respiratory distress syndrome in the injured patient","volume":"20","author":"Bakowitz","year":"2012","journal-title":"Scand J Trauma Resusc Emerge Med"},{"key":"B13","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1189\/jlb.4MA1213-647RR","article-title":"Active players in resolution of shock\/sepsis induced indirect lung injury: immunomodulatory effects of Tregs and PD-1","volume":"96","author":"Tang","year":"2014","journal-title":"J Leukoc Biol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1165\/rcmb.2013-0148OC","article-title":"Neutrophil-endothelial interactions mediate angiopoietin-2-associated pulmonary endothelial cell dysfunction in indirect acute lung injury in mice","volume":"50","author":"Lomas-Neira","year":"2014","journal-title":"Am J Respir Cell Mol Biol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"e88501","DOI":"10.1371\/journal.pone.0088501","article-title":"Pulmonary microvascular albumin leak is associated with endothelial cell death in murine sepsis-induced lung injury in vivo","volume":"9","author":"Gill","year":"2014","journal-title":"PLoS ONE"},{"key":"B16","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1097\/SLA.0b013e31823433ca","article-title":"Mechanisms of indirect acute lung injury: a novel role for the coinhibitory receptor, programmed death-1","volume":"255","author":"Monaghan","year":"2012","journal-title":"Ann Surg"},{"key":"B17","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1097\/SHK.0b013e31825de6a3","article-title":"Programmed death 1 expression as a marker for immune and physiological dysfunction in the critically ill surgical patient","volume":"38","author":"Monaghan","year":"2012","journal-title":"Shock"},{"key":"B18","doi-asserted-by":"publisher","first-page":"L51","DOI":"10.1152\/ajplung.00028.2005","article-title":"Role of alveolar macrophage and migrating neutrophils in hemorrhage-induced priming for ALI subsequent to septic challenge","volume":"290","author":"Lomas-Neira","year":"2006","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"3926","DOI":"10.3791\/3926","article-title":"Use of animal model of sepsis to evaluate novel herbal therapies","author":"Li","year":"2012","journal-title":"J Vis Exp."},{"key":"B20","doi-asserted-by":"publisher","first-page":"G917","DOI":"10.1152\/ajpgi.00422.2013","article-title":"Animal models of gastrointestinal and liver diseases. Animal models of necrotizing enterocolitis: pathophysiology, translational relevance, and challenges","volume":"306","author":"Lu","year":"2014","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1271","DOI":"10.1016\/S0140-6736(06)69525-1","article-title":"Necrotising enterocolitis","volume":"368","author":"Lin","year":"2006","journal-title":"Lancet"},{"key":"B22","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1097\/00024382-199403000-00008","article-title":"Porcine peritoneal sepsis: modeling for clinical relevance","volume":"1","author":"Kazarian","year":"1994","journal-title":"Shock"},{"key":"B23","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1097\/SHK.0b013e3180556d09","article-title":"Increased mortality and altered immunity in neonatal sepsis produced by generalized peritonitis","volume":"28","author":"Wynn","year":"2007","journal-title":"Shock"},{"key":"B24","doi-asserted-by":"publisher","first-page":"3887","DOI":"10.1002\/j.1460-2075.1992.tb05481.x","article-title":"Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death","volume":"11","author":"Ishida","year":"1992","journal-title":"EMBO J"},{"key":"B25","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1093\/intimm\/dxs098","article-title":"PD-1 is a novel regulator of human B-cell activation","volume":"25","author":"Thibult","year":"2013","journal-title":"Int Immunol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1186\/s12967-016-1071-x","article-title":"Soluble programmed cell death receptor-1 (sPD-1): a potential biomarker with anti-inflammatory properties in human and experimental acute respiratory distress syndrome (ARDS)","volume":"14","author":"Monaghan","year":"2016","journal-title":"J Transl Med"},{"key":"B27","doi-asserted-by":"publisher","first-page":"6303","DOI":"10.1073\/pnas.0809422106","article-title":"PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis","volume":"106","author":"Huang","year":"2009","journal-title":"Proc Natl Acad Sci USA"},{"key":"B28","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1016\/j.surg.2016.11.008","article-title":"Improved survival after induction of sepsis by cecal slurry in PD-1 knockout murine neonates","volume":"36","author":"Young","year":"2016","journal-title":"Surgery"},{"key":"B29","doi-asserted-by":"publisher","first-page":"830","DOI":"10.2119\/molmed.2016.00150","article-title":"A novel role for programmed cell death receptor ligand-1 (PD-L1) in sepsis-induced intestinal dysfunction","volume":"22","author":"Wu","year":"2017","journal-title":"Mol Med"},{"key":"B30","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1097\/SHK.0b013e3181cf70fb","article-title":"Deficiency of Bid protein reduces sepsis-induced apoptosis and inflammation, while improving septic survival","volume":"34","author":"Chung","year":"2010","journal-title":"Shock"},{"key":"B31","doi-asserted-by":"publisher","first-page":"840","DOI":"10.1016\/j.jamcollsurg.2007.02.023","article-title":"Beneficial versus detrimental effects of neutrophils are determined by the nature of the insult","volume":"204","author":"Perl","year":"2007","journal-title":"J Am Coll Surg"},{"key":"B32","doi-asserted-by":"publisher","first-page":"276","DOI":"10.1097\/00005373-200208000-00015","article-title":"Mechanism of immune dysfunction in sepsis: inducible nitric oxide-meditated alterations in p38 MAPK activation","volume":"53","author":"Song","year":"2002","journal-title":"J Trauma"},{"key":"B33","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1159\/000448808","article-title":"Cl-Amidine prevents histone 3 citrullination and neutrophil extracellular trap formation, and improves survival in a murine sepsis model","volume":"9","author":"Biron","year":"2017","journal-title":"J Innate Immun"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1901313","DOI":"10.1183\/13993003.01313-2019","article-title":"Culture of pulmonary artery endothelial cells from pulmonary artery catheter balloon tips: considerations for use in pulmonary vascular disease","volume":"55","author":"Ventetuolo","year":"2020","journal-title":"Eur Respir J"},{"key":"B35","doi-asserted-by":"publisher","first-page":"L1091","DOI":"10.1152\/ajplung.00421.2003","article-title":"Barrier dysfunction and RhoA activation are blunted by homocysteine and adenosine in pulmonary endothelium","volume":"287","author":"Harrington","year":"2004","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1164\/rccm.200506-927OC","article-title":"Growth of pulmonary microvasculature in ventilated preterm infants","volume":"173","author":"De Paepe","year":"2006","journal-title":"Am J Respir Crit Care Med"},{"key":"B37","doi-asserted-by":"publisher","first-page":"L801","DOI":"10.1152\/ajplung.00108.2019","article-title":"Blockade of endothelial, but not epithelial, cell expression of PD-L1 following severe shock attenuates the development of indirect acute lung injury in mice","volume":"318","author":"Xu","year":"2020","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"B38","doi-asserted-by":"publisher","first-page":"3030","DOI":"10.3389\/fimmu.2018.03030","article-title":"Novel role for PD-1:PD-L1 as mediator of pulmonary vascular endothelial cell functions in pathogenesis of indirect ARDS in mice","volume":"9","author":"Lomas-Neira","year":"2018","journal-title":"Front Immunol"},{"key":"B39","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1002\/ppul.22818","article-title":"Postmortem lung volume\/body weight standards for term and preterm infants","volume":"49","author":"De Paepe","year":"2014","journal-title":"Pediatr Pulmonol"},{"key":"B40","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1083\/jcb.103.3.755","article-title":"Identification of ZO-1: a high molecular weight polypeptide associated with the tight junction (zonula occludens) in a variety of epithelia","volume":"103","author":"Stevenson","year":"1986","journal-title":"J Cell Biol"},{"key":"B41","first-page":"11","article-title":"Tissue-specific expression of occludin, zona occludens-1, and junction adhesion molecule A in the duodenum, ileum, colon, kidney, liver, lung, brain, and skeletal muscle of C57BL mice","volume":"64","author":"Hwang","year":"2013","journal-title":"J Physiol Pharmacol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1016\/j.imlet.2016.08.011","article-title":"Identification of CD177 as the most dysregulated parameter in a microarray study of purified neutrophils from septic shock patients","volume":"178","author":"Demaret","year":"2016","journal-title":"Immunol Lett"},{"key":"B43","doi-asserted-by":"publisher","first-page":"2092","DOI":"10.1182\/blood-2017-03-768507","article-title":"CD177 modulates human neutrophil migration through activation-mediated integrin and chemoreceptor regulation","volume":"130","author":"Bai","year":"2017","journal-title":"Blood"},{"key":"B44","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1007\/s00109-018-1646-5","article-title":"Impact of toll-like receptor 4 stimulation on human neonatal neutrophil spontaneous migration, transcriptomics, and cytokine production","volume":"96","author":"Raymond","year":"2018","journal-title":"J Mol Med."},{"key":"B45","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1016\/j.trsl.2017.08.003","article-title":"Neutrophil chemotaxis and transcriptomics in term and preterm neonates","volume":"190","author":"Raymond","year":"2017","journal-title":"Transl Res."},{"key":"B46","doi-asserted-by":"publisher","first-page":"e94404","DOI":"10.1371\/journal.pone.0094404","article-title":"Host responses to sepsis vary in different low-lethality murine models","volume":"9","author":"Gentile","year":"2014","journal-title":"PLoS ONE"},{"key":"B47","doi-asserted-by":"publisher","first-page":"e0186819","DOI":"10.1371\/journal.pone.0186819","article-title":"Analysis of PD-1 expression in the monocyte subsets from non-septic and septic preterm neonates","volume":"12","author":"Zasada","year":"2017","journal-title":"PLoS ONE"},{"key":"B48","doi-asserted-by":"publisher","first-page":"2283","DOI":"10.1016\/S0002-9440(10)64504-X","article-title":"Shock-induced neutrophil mediated priming for acute lung injury in mice: divergent effects of TLR-4 and TLR-4\/FasL deficiency","volume":"161","author":"Ayala","year":"2002","journal-title":"Am J Pathol"},{"key":"B49","doi-asserted-by":"publisher","first-page":"R99","DOI":"10.1186\/cc10112","article-title":"Programmed death-1 levels correlate with increased mortality, nosocomial infection and immune dysfunctions in septic shock patients","volume":"15","author":"Guignant","year":"2011","journal-title":"Crit Care"},{"key":"B50","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1016\/j.canlet.2019.05.026","article-title":"The anthelmintic flubendazole blocks human melanoma growth and metastasis and suppresses programmed cell death protein-1 and myeloid-derived suppressor cell accumulation","volume":"459","author":"Li","year":"2019","journal-title":"Cancer Lett"},{"key":"B51","doi-asserted-by":"publisher","first-page":"1469","DOI":"10.3389\/fimmu.2017.01469","article-title":"Program cell death receptor-1-mediated invariant natural killer t-cell control of peritoneal macrophage modulates survival in neonatal sepsis","volume":"8","author":"Fallon","year":"2017","journal-title":"Front Immunol"},{"key":"B52","doi-asserted-by":"publisher","first-page":"833","DOI":"10.3389\/fimmu.2018.00833","article-title":"Activation of invariant natural killer T cells redirects the inflammatory response in neonatal sepsis","volume":"9","author":"Bolognese","year":"2018","journal-title":"Front Immunol"},{"key":"B53","doi-asserted-by":"publisher","first-page":"780","DOI":"10.1055\/s-0040-1710522","article-title":"COVID-19 and Neonatal respiratory care: current evidence and practical approach","volume":"37","author":"Shalish","year":"2020","journal-title":"Am J Perinatol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.634529\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,3]],"date-time":"2021-03-03T04:49:08Z","timestamp":1614746948000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.634529\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,3]]},"references-count":53,"alternative-id":["10.3389\/fimmu.2021.634529"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.634529","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,3]]},"article-number":"634529"}}