Neonatology pp 73-94 | Cite as

Prenatal and Postnatal Inflammatory Mechanisms

  • Kirsten GlaserEmail author
  • Christian P. SpeerEmail author
Reference work entry


During the past 20 years, intrauterine infection and inflammation have been identified as significant risk factors in the development of fetal and neonatal morbidity and mortality, as well as adverse long-term outcome in very immature preterm infants. Besides severe infections, immature preterm infants are at high risk for syndromes of dysregulated inflammation including bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), and preterm cerebral white matter disease (WMD). Although pathogenesis is multifactorial, inflammation has been acknowledged as principle mechanism, being caused, sustained, and aggravated by multiple perinatal factors interacting in a multiple-hit sequence. An inflammatory state is presumed to be either initiated prenatally by chorioamnionitis or induced and sustained by pro-inflammatory postnatal conditions, such as oxygen toxicity, mechanical ventilation, and neonatal infection. Perturbation of pro- and anti-inflammatory central signaling pathways and subsequently imbalanced inflammatory responses may lead to severe organ injury affecting parenchymal development during a window of vulnerability. Maturation-dependent factors and genetic predisposition may underlie a particular vulnerability.



Bronchoalveolar lavage fluid


Bronchopulmonary dysplasia




Cerebral palsy


Continuous positive airway pressure


Cerebrospinal fluid


Extremely low birth weight


Early-onset sepsis


Fetal inflammatory response syndrome


Intercellular adhesion molecules






IL-1 receptor antagonist


IL-1 receptor-associated kinase


Late-onset sepsis


Lipopolysaccharide (endotoxin)


Monocyte chemoattractant protein


Macrophage inflammatory protein


Matrix metalloproteinase


Magnetic resonance imaging


Nuclear transcription factor KB


Polymerase chain reaction


Polymorphonuclear cells


Pre-myelinating oligodendrocytes


Pattern recognition receptor


Respiratory distress syndrome


Reactive oxygen species


Surfactant protein


Transforming growth factor-β


Toll-like receptor


Tumor necrosis factor-α


Vascular cell adhesion molecules


Vascular endothelial growth factor


  1. Adams EW, Harrison MC, Counsell SJ, Allsop JM, Kennea NL, Hajnal JV et al (2004) Increased lung water and tissue damage in bronchopulmonary dysplasia. J Pediatr 145:503–507PubMedCrossRefGoogle Scholar
  2. Akira S (2006) TLR signaling. Curr Top Microbiol Immunol 311:1–16PubMedGoogle Scholar
  3. Altiok O, Yasumatsu R, Bingol-Karakoc G, Riese RJ, Stahlman MT, Dwyer W et al (2006) Imbalance between cysteine proteases and inhibitors in a baboon model of bronchopulmonary dysplasia. Am J Respir Crit Care Med 173:318–326PubMedCrossRefGoogle Scholar
  4. Backstrom E, Hogmalm A, Lappalainen U, Bry K (2011) Developmental stage is a major determinant of lung injury in a murine model of bronchopulmonary dysplasia. Pediatr Res 69:312–318PubMedCrossRefGoogle Scholar
  5. Baier RJ, Majid A, Parupia H, Loggins J, Kruger TE (2004) CC chemokine concentrations increase in respiratory distress syndrome and correlate with development of bronchopulmonary dysplasia. Pediatr Pulmonol 37:137–148PubMedCrossRefGoogle Scholar
  6. Barton SK, Moss TJ, Hooper SB, Crossley KJ, Gill AW, Kluckow M et al (2014) Protective ventilation of preterm lambs exposed to acute chorioamnionitis does not reduce ventilation-induced lung or brain injury. PLoS One 9:e112402PubMedCrossRefPubMedCentralGoogle Scholar
  7. Bartram U, Speer CP (2004) The role of transforming growth factor beta in lung development and disease. Chest 125:754–765CrossRefPubMedGoogle Scholar
  8. Benjamin JT, Smith RJ, Halloran BA, Day TJ, Kelly DR, Prince LS (2007) FGF-10 is decreased in bronchopulmonary dysplasia and suppressed by Toll-like receptor activation. Am J Physiol Lung Cell Mol Physiol 292:L550–L558PubMedCrossRefGoogle Scholar
  9. Berger I, Peleg O, Ofek-Shlomai N (2012) Inflammation and early brain injury in term and preterm infants. Isr Med Assoc J 14:318–323PubMedGoogle Scholar
  10. Bersani I, Speer CP (2012) Nosocomial sepsis in neonatal intensive care: inevitable or preventable? Z Geburtshilfe Neonatol 216:186–190PubMedCrossRefGoogle Scholar
  11. Bersani I, Kunzmann S, Speer CP (2013) Immunomodulatory properties of surfactant preparations. Expert Rev Anti Infect Ther 11:99–110PubMedCrossRefGoogle Scholar
  12. Bhandari V (2010) Hyperoxia-derived lung damage in preterm infants. Semin Fetal Neonatal Med 15:223–229PubMedCrossRefPubMedCentralGoogle Scholar
  13. Bhandari V, Elias JA (2006) Cytokines in tolerance to hyperoxia-induced injury in the developing and adult lung. Free Radic Biol Med 41:4–18PubMedCrossRefGoogle Scholar
  14. Blackwell TS, Hipps AN, Yamamoto Y, Han W, Barham WJ, Ostrowski MC et al (2011) NF-kappaB signaling in fetal lung macrophages disrupts airway morphogenesis. J Immunol 187:2740–2747PubMedCrossRefPubMedCentralGoogle Scholar
  15. Boghossian NS, Page GP, Bell EF, Stoll BJ, Murray JC, Cotten CM et al (2013) Late-onset sepsis in very low birth weight infants from singleton and multiple-gestation births. J Pediatr 162:1120–1124, 1124 e1121PubMedCrossRefPubMedCentralGoogle Scholar
  16. Bose CL, Dammann CE, Laughon MM (2008) Bronchopulmonary dysplasia and inflammatory biomarkers in the premature neonate. Arch Dis Child Fetal Neonatal Ed 93:F455–F461PubMedCrossRefGoogle Scholar
  17. Bose CL, Laughon MM, Allred EN, O’Shea TM, Van Marter LJ, Ehrenkranz RA et al (2013) Systemic inflammation associated with mechanical ventilation among extremely preterm infants. Cytokine 61:315–322PubMedCrossRefGoogle Scholar
  18. Brehmer F, Bendix I, Prager S, van de Looij Y, Reinboth BS, Zimmermanns J et al (2012) Interaction of inflammation and hyperoxia in a rat model of neonatal white matter damage. PLoS One 7:e49023PubMedCrossRefPubMedCentralGoogle Scholar
  19. Brew N, Hooper SB, Allison BJ, Wallace MJ, Harding R (2011) Injury and repair in the very immature lung following brief mechanical ventilation. Am J Physiol Lung Cell Mol Physiol 301:L917–L926PubMedCrossRefGoogle Scholar
  20. Brochu ME, Girard S, Lavoie K, Sebire G (2011) Developmental regulation of the neuroinflammatory responses to LPS and/or hypoxia-ischemia between preterm and term neonates: an experimental study. J Neuroinflammation 8:55PubMedCrossRefPubMedCentralGoogle Scholar
  21. Cai Z, Pang Y, Lin S, Rhodes PG (2003) Differential roles of tumor necrosis factor-alpha and interleukin-1 beta in lipopolysaccharide-induced brain injury in the neonatal rat. Brain Res 975:37–47PubMedCrossRefGoogle Scholar
  22. Cederqvist K, Sorsa T, Tervahartiala T, Maisi P, Reunanen K, Lassus P et al (2001) Matrix metalloproteinases-2, -8, and -9 and TIMP-2 in tracheal aspirates from preterm infants with respiratory distress. Pediatrics 108:686–692PubMedCrossRefGoogle Scholar
  23. Chetty A, Cao GJ, Severgnini M, Simon A, Warburton R, Nielsen HC (2008) Role of matrix metalloprotease-9 in hyperoxic injury in developing lung. Am J Physiol Lung Cell Mol Physiol 295:L584–L592PubMedCrossRefPubMedCentralGoogle Scholar
  24. Chew LJ, DeBoy CA (2015) Pharmacological approaches to intervention in hypomyelinating and demyelinating white matter pathology. Neurol. pii: S0028-3908(15)00266-X. [Epub ahead of print]PubMedCrossRefGoogle Scholar
  25. Curtis MA, Kam M, Nannmark U, Anderson MF, Axell MZ, Wikkelso C et al (2007) Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension. Science 315:1243–1249PubMedCrossRefGoogle Scholar
  26. D’Alquen D, Kramer BW, Seidenspinner S, Marx A, Berg D, Groneck P et al (2005) Activation of umbilical cord endothelial cells and fetal inflammatory response in preterm infants with chorioamnionitis and funisitis. Pediatr Res 57:263–269PubMedCrossRefGoogle Scholar
  27. D’Angio CT, Maniscalco WM (2002) The role of vascular growth factors in hyperoxia-induced injury to the developing lung. Front Biosci 7:d1609–d1623PubMedCrossRefGoogle Scholar
  28. Dammann O, Leviton A (2014) Intermittent or sustained systemic inflammation and the preterm brain. Pediatr Res 75:376–380PubMedCrossRefGoogle Scholar
  29. Danan C, Franco ML, Jarreau PH, Dassieu G, Chailley-Heu B, Bourbon J et al (2002) High concentrations of keratinocyte growth factor in airways of premature infants predicted absence of bronchopulmonary dysplasia. Am J Respir Crit Care Med 165:1384–1387PubMedCrossRefGoogle Scholar
  30. Dommergues MA, Patkai J, Renauld JC, Evrard P, Gressens P (2000) Proinflammatory cytokines and interleukin-9 exacerbate excitotoxic lesions of the newborn murine neopallium. Ann Neurol 47:54–63PubMedCrossRefGoogle Scholar
  31. Dong Y, Speer CP (2015) Late-onset neonatal sepsis: recent developments. Arch Dis Child Fetal Neonatal Ed 100:F257–F263PubMedCrossRefGoogle Scholar
  32. Eklind S, Mallard C, Arvidsson P, Hagberg H (2005) Lipopolysaccharide induces both a primary and a secondary phase of sensitization in the developing rat brain. Pediatr Res 58:112–116PubMedCrossRefGoogle Scholar
  33. Ericson JE, Laughon MM (2015) Chorioamnionitis: implications for the neonate. Clin Perinatol 42:155–165, ixPubMedCrossRefGoogle Scholar
  34. Fan X, Heijnen CJ, van der Kooij MA, Groenendaal F, van Bel F (2009) The role and regulation of hypoxia-inducible factor-1alpha expression in brain development and neonatal hypoxic-ischemic brain injury. Brain Res Rev 62:99–108PubMedCrossRefGoogle Scholar
  35. Garcia-Munoz Rodrigo F, Galan Henriquez G, Figueras Aloy J, Garcia-Alix Perez A (2014) Outcomes of very-low-birth-weight infants exposed to maternal clinical chorioamnionitis: a multicentre study. Neonatology 106:229–234PubMedCrossRefGoogle Scholar
  36. Garcia-Ramallo E, Marques T, Prats N, Beleta J, Kunkel SL, Godessart N (2002) Resident cell chemokine expression serves as the major mechanism for leukocyte recruitment during local inflammation. J Immunol 169:6467–6473PubMedCrossRefGoogle Scholar
  37. Genc MR, Onderdonk A (2011) Endogenous bacterial flora in pregnant women and the influence of maternal genetic variation. BJOG 118:154–163PubMedCrossRefGoogle Scholar
  38. Gerber CE, Bruchelt G, Stegmann H, Schweinsberg F, Speer CP (1999) Presence of bleomycin-detectable free iron in the alveolar system of preterm infants. Biochem Biophys Res Commun 257:218–222PubMedCrossRefGoogle Scholar
  39. Girard S, Kadhim H, Roy M, Lavoie K, Brochu ME, Larouche A et al (2009) Role of perinatal inflammation in cerebral palsy. Pediatr Neurol 40:168–174PubMedCrossRefGoogle Scholar
  40. Girard S, Sebire H, Brochu ME, Briota S, Sarret P, Sebire G (2012) Postnatal administration of IL-1Ra exerts neuroprotective effects following perinatal inflammation and/or hypoxic-ischemic injuries. Brain Behav Immun 26:1331–1339PubMedCrossRefPubMedCentralGoogle Scholar
  41. Glaser K, Speer CP (2013) Toll-like receptor signaling in neonatal sepsis and inflammation: a matter of orchestration and conditioning. Expert Rev Clin Immunol 9:1239–1252PubMedCrossRefGoogle Scholar
  42. Goldenberg RL, Andrews WW, Goepfert AR, Faye-Petersen O, Cliver SP, Carlo WA et al (2008) The Alabama Preterm Birth Study: umbilical cord blood Ureaplasma urealyticum and Mycoplasma hominis cultures in very preterm newborn infants. Am J Obstet Gynecol 198(43):e41–e45Google Scholar
  43. Groneck P, Gotze-Speer B, Oppermann M, Eiffert H, Speer CP (1994) Association of pulmonary inflammation and increased microvascular permeability during the development of bronchopulmonary dysplasia: a sequential analysis of inflammatory mediators in respiratory fluids of high-risk preterm neonates. Pediatrics 93:712–718PubMedGoogle Scholar
  44. Guo H, Zhou H, Lu J, Qu Y, Yu D, Tong Y (2016) Vascular endothelial growth factor: an attractive target in the treatment of hypoxic/ischemic brain injury. Neural Regen Res 11:174–179PubMedCrossRefPubMedCentralGoogle Scholar
  45. Hallman M, Curstedt T, Halliday HL, Saugstad OD, Speer CP (2013) Better neonatal outcomes: oxygen, surfactant and drug delivery. Preface. Neonatology 103:316–319PubMedCrossRefGoogle Scholar
  46. Harju K, Glumoff V, Hallman M (2001) Ontogeny of toll-like receptors Tlr2 and Tlr4 in mice. Pediatr Res 49:81–83PubMedCrossRefGoogle Scholar
  47. Harju K, Ojaniemi M, Rounioja S, Glumoff V, Paananen R, Vuolteenaho R et al (2005) Expression of toll-like receptor 4 and endotoxin responsiveness in mice during perinatal period. Pediatr Res 57:644–648PubMedCrossRefGoogle Scholar
  48. Hartling L, Liang Y, Lacaze-Masmonteil T (2012) Chorioamnionitis as a risk factor for bronchopulmonary dysplasia: a systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed 97:F8–F17PubMedCrossRefGoogle Scholar
  49. He Z, Zhu Y, Jiang H (2009) Inhibiting toll-like receptor 4 signaling ameliorates pulmonary fibrosis during acute lung injury induced by lipopolysaccharide: an experimental study. Respir Res 10:126PubMedCrossRefPubMedCentralGoogle Scholar
  50. Hillman NH, Moss TJ, Nitsos I, Kramer BW, Bachurski CJ, Ikegami M et al (2008) Toll-like receptors and agonist responses in the developing fetal sheep lung. Pediatr Res 63:388–393PubMedCrossRefGoogle Scholar
  51. Hillman NH, Nitsos I, Berry C, Pillow JJ, Kallapur SG, Jobe AH (2011) Positive end-expiratory pressure and surfactant decrease lung injury during initiation of ventilation in fetal sheep. Am J Physiol Lung Cell Mol Physiol 301:L712–L720PubMedCrossRefPubMedCentralGoogle Scholar
  52. Hines EA, Sun X (2014) Tissue crosstalk in lung development. J Cell Biochem 115:1469–1477PubMedCrossRefGoogle Scholar
  53. Hogmalm A, Bry M, Strandvik B, Bry K (2014) IL-1beta expression in the distal lung epithelium disrupts lung morphogenesis and epithelial cell differentiation in fetal mice. Am J Physiol Lung Cell Mol Physiol 306:L23–L34PubMedCrossRefGoogle Scholar
  54. Huusko JM, Karjalainen MK, Mahlman M, Haataja R, Kari MA, Andersson S et al (2014) A study of genes encoding cytokines (IL6, IL10, TNF), cytokine receptors (IL6R, IL6ST), and glucocorticoid receptor (NR3C1) and susceptibility to bronchopulmonary dysplasia. BMC Med Genet 15:120PubMedCrossRefPubMedCentralGoogle Scholar
  55. Inatomi T, Oue S, Ogihara T, Hira S, Hasegawa M, Yamaoka S et al (2012) Antenatal exposure to Ureaplasma species exacerbates bronchopulmonary dysplasia synergistically with subsequent prolonged mechanical ventilation in preterm infants. Pediatr Res 71:267–273PubMedCrossRefGoogle Scholar
  56. Jaarsma AS, Braaksma MA, Geven WB, van Oeveren W, Bambang Oetomo S (2004) Activation of the inflammatory reaction within minutes after birth in ventilated preterm lambs with neonatal respiratory distress syndrome. Biol Neonate 86:1–5PubMedCrossRefGoogle Scholar
  57. Jobe AH (2011) The new bronchopulmonary dysplasia. Curr Opin Pediatr 23:167–172PubMedCrossRefPubMedCentralGoogle Scholar
  58. Jones CA, Cayabyab RG, Kwong KY, Stotts C, Wong B, Hamdan H et al (1996) Undetectable interleukin (IL)-10 and persistent IL-8 expression early in hyaline membrane disease: a possible developmental basis for the predisposition to chronic lung inflammation in preterm newborns. Pediatr Res 39:966–975PubMedCrossRefGoogle Scholar
  59. Kaindl AM, Favrais G, Gressens P (2009) Molecular mechanisms involved in injury to the preterm brain. J Child Neurol 24:1112–1118PubMedCrossRefPubMedCentralGoogle Scholar
  60. Kallapur SG, Jobe AH, Ikegami M, Bachurski CJ (2003) Increased IP-10 and MIG expression after intra-amniotic endotoxin in preterm lamb lung. Am J Respir Crit Care Med 167:779–786PubMedCrossRefGoogle Scholar
  61. Kemp MW (2014) Preterm birth, intrauterine infection, and fetal inflammation. Front Immunol 5:574PubMedCrossRefPubMedCentralGoogle Scholar
  62. Khwaja O, Volpe JJ (2008) Pathogenesis of cerebral white matter injury of prematurity. Arch Dis Child Fetal Neonatal Ed 93:F153–F161PubMedCrossRefPubMedCentralGoogle Scholar
  63. Kim KS (2003) Pathogenesis of bacterial meningitis: from bacteraemia to neuronal injury. Nat Rev Neurosci 4:376–385CrossRefPubMedGoogle Scholar
  64. Kim CJ, Romero R, Chaemsaithong P, Chaiyasit N, Yoon BH, Kim YM (2015) Acute chorioamnionitis and funisitis: definition, pathologic features, and clinical significance. Am J Obstet Gynecol 213:S29–S52PubMedCrossRefPubMedCentralGoogle Scholar
  65. Kolb M, Margetts PJ, Anthony DC, Pitossi F, Gauldie J (2001) Transient expression of IL-1beta induces acute lung injury and chronic repair leading to pulmonary fibrosis. J Clin Invest 107:1529–1536PubMedCrossRefPubMedCentralGoogle Scholar
  66. Kollmann TR, Crabtree J, Rein-Weston A, Blimkie D, Thommai F, Wang XY et al (2009) Neonatal innate TLR-mediated responses are distinct from those of adults. J Immunol 183:7150–7160PubMedCrossRefPubMedCentralGoogle Scholar
  67. Kollmann TR, Levy O, Montgomery RR, Goriely S (2012) Innate immune function by Toll-like receptors: distinct responses in newborns and the elderly. Immunity 37:771–783PubMedCrossRefPubMedCentralGoogle Scholar
  68. Korzeniewski SJ, Romero R, Cortez J, Pappas A, Schwartz AG, Kim CJ et al (2014) A “multi-hit” model of neonatal white matter injury: cumulative contributions of chronic placental inflammation, acute fetal inflammation and postnatal inflammatory events. J Perinat Med 42:731–743PubMedCrossRefPubMedCentralGoogle Scholar
  69. Kramer BW, Moss TJ, Willet KE, Newnham JP, Sly PD, Kallapur SG et al (2001) Dose and time response after intraamniotic endotoxin in preterm lambs. Am J Respir Crit Care Med 164:982–988PubMedCrossRefGoogle Scholar
  70. Kramer BW, Kramer S, Ikegami M, Jobe AH (2002) Injury, inflammation, and remodeling in fetal sheep lung after intra-amniotic endotoxin. Am J Physiol Lung Cell Mol Physiol 283:L452–L459PubMedCrossRefGoogle Scholar
  71. Kramer BW, Ladenburger A, Kunzmann S, Speer CP, Been JV, van Iwaarden JF et al (2009) Intravenous lipopolysaccharide-induced pulmonary maturation and structural changes in fetal sheep. Am J Obstet Gynecol 200:195 e191–110CrossRefGoogle Scholar
  72. Kroon AA, Wang J, Huang Z, Cao L, Kuliszewski M, Post M (2010) Inflammatory response to oxygen and endotoxin in newborn rat lung ventilated with low tidal volume. Pediatr Res 68:63–69PubMedCrossRefGoogle Scholar
  73. Kuang PP, Zhang XH, Rich CB, Foster JA, Subramanian M, Goldstein RH (2007) Activation of elastin transcription by transforming growth factor-beta in human lung fibroblasts. Am J Physiol Lung Cell Mol Physiol 292:L944–L952PubMedCrossRefGoogle Scholar
  74. Kunig AM, Balasubramaniam V, Markham NE, Seedorf G, Gien J, Abman SH (2006) Recombinant human VEGF treatment transiently increases lung edema but enhances lung structure after neonatal hyperoxia. Am J Physiol Lung Cell Mol Physiol 291:L1068–L1078PubMedCrossRefGoogle Scholar
  75. Kunzmann S, Seher A, Kramer BW, Schenk R, Schutze N, Jakob F et al (2008) Connective tissue growth factor does not affect transforming growth factor-beta 1-induced Smad3 phosphorylation and T lymphocyte proliferation inhibition. Int Arch Allergy Immunol 147:152–160PubMedCrossRefGoogle Scholar
  76. Lal CV, Ambalavanan N (2015) Genetic predisposition to bronchopulmonary dysplasia. Semin Perinatol 39:584–591PubMedCrossRefGoogle Scholar
  77. Lassus P, Heikkila P, Andersson LC, von Boguslawski K, Andersson S (2003) Lower concentration of pulmonary hepatocyte growth factor is associated with more severe lung disease in preterm infants. J Pediatr 143:199–202PubMedCrossRefGoogle Scholar
  78. Lee Y, Kim HJ, Choi SJ, Oh SY, Kim JS, Roh CR et al (2015) Is there a stepwise increase in neonatal morbidities according to histological stage (or grade) of acute chorioamnionitis and funisitis?: effect of gestational age at delivery. J Perinat Med 43:259–267PubMedGoogle Scholar
  79. Leviton A, Allred EN, Kuban KC, Hecht JL, Onderdonk AB, O’Shea TM et al (2010) Microbiologic and histologic characteristics of the extremely preterm infant’s placenta predict white matter damage and later cerebral palsy. The ELGAN study. Pediatr Res 67:95–101PubMedCrossRefPubMedCentralGoogle Scholar
  80. Levy BD, Serhan CN (2014) Resolution of acute inflammation in the lung. Annu Rev Physiol 76:467–492PubMedCrossRefGoogle Scholar
  81. Levy O, Wynn JL (2014) A prime time for trained immunity: innate immune memory in newborns and infants. Neonatology 105:136–141PubMedCrossRefGoogle Scholar
  82. Li WJ, Mao FX, Chen HJ, Qian LH, Buzby JS (2015) Treatment with UDP-glucose, GDNF, and memantine promotes SVZ and white matter self-repair by endogenous glial progenitor cells in neonatal rats with ischemic PVL. Neuroscience 284:444–458PubMedCrossRefGoogle Scholar
  83. Lozano SM, Newnam KM (2016) Modalities of mechanical ventilation: volume-targeted versus pressure-limited. Adv Neonatal Care 16:99–107PubMedCrossRefGoogle Scholar
  84. Lukkarinen H, Hogmalm A, Lappalainen U, Bry K (2009) Matrix metalloproteinase-9 deficiency worsens lung injury in a model of bronchopulmonary dysplasia. Am J Respir Cell Mol Biol 41:59–68PubMedCrossRefGoogle Scholar
  85. Martin RJ, Fanaroff AA (2013) The preterm lung and airway: past, present, and future. Pediatr Neonatol 54:228–234PubMedCrossRefGoogle Scholar
  86. May M, Marx A, Seidenspinner S, Speer CP (2004) Apoptosis and proliferation in lungs of human fetuses exposed to chorioamnionitis. Histopathology 45:283–290PubMedCrossRefGoogle Scholar
  87. Mesples B, Plaisant F, Gressens P (2003) Effects of interleukin-10 on neonatal excitotoxic brain lesions in mice. Brain Res Dev Brain Res 141:25–32PubMedCrossRefGoogle Scholar
  88. Miller JD, Benjamin JT, Kelly DR, Frank DB, Prince LS (2010) Chorioamnionitis stimulates angiogenesis in saccular stage fetal lungs via CC chemokines. Am J Physiol Lung Cell Mol Physiol 298:L637–L645PubMedCrossRefPubMedCentralGoogle Scholar
  89. Morley CJ (2010) CPAP and low oxygen saturation for very preterm babies? N Engl J Med 362:2024–2026PubMedCrossRefGoogle Scholar
  90. Murch SH, Costeloe K, Klein NJ, MacDonald TT (1996a) Early production of macrophage inflammatory protein-1 alpha occurs in respiratory distress syndrome and is associated with poor outcome. Pediatr Res 40:490–497PubMedCrossRefGoogle Scholar
  91. Murch SH, Costeloe K, Klein NJ, Rees H, McIntosh N, Keeling JW et al (1996b) Mucosal tumor necrosis factor-alpha production and extensive disruption of sulfated glycosaminoglycans begin within hours of birth in neonatal respiratory distress syndrome. Pediatr Res 40:484–489PubMedCrossRefGoogle Scholar
  92. Nanthakumar N, Meng D, Goldstein AM, Zhu W, Lu L, Uauy R et al (2011) The mechanism of excessive intestinal inflammation in necrotizing enterocolitis: an immature innate immune response. PLoS One 6:e17776PubMedCrossRefPubMedCentralGoogle Scholar
  93. Narimanbekov IO, Rozycki HJ (1995) Effect of IL-1 blockade on inflammatory manifestations of acute ventilator-induced lung injury in a rabbit model. Exp Lung Res 21:239–254PubMedCrossRefGoogle Scholar
  94. Nguyen CN, Schnulle PM, Chegini N, Luo X, Koenig JM (2010) Neonatal neutrophils with prolonged survival secrete mediators associated with chronic inflammation. Neonatology 98:341–347PubMedCrossRefPubMedCentralGoogle Scholar
  95. Nguyen HA, Rajaram MV, Meyer DA, Schlesinger LS (2012) Pulmonary surfactant protein A and surfactant lipids upregulate IRAK-M, a negative regulator of TLR-mediated inflammation in human macrophages. Am J Physiol Lung Cell Mol Physiol 303:L608–L616PubMedCrossRefPubMedCentralGoogle Scholar
  96. Normann E, Lacaze-Masmonteil T, Eaton F, Schwendimann L, Gressens P, Thebaud B (2009) A novel mouse model of Ureaplasma-induced perinatal inflammation: effects on lung and brain injury. Pediatr Res 65:430–436PubMedCrossRefGoogle Scholar
  97. O’Carroll SJ, Kho DT, Wiltshire R, Nelson V, Rotimi O, Johnson R et al (2015) Pro-inflammatory TNFalpha and IL-1beta differentially regulate the inflammatory phenotype of brain microvascular endothelial cells. J Neuroinflammation 12:131PubMedCrossRefPubMedCentralGoogle Scholar
  98. O’Hare FM, William Watson R, Molloy EJ (2013) Toll-like receptors in neonatal sepsis. Acta Paediatr 102:572–578PubMedCrossRefGoogle Scholar
  99. Paananen R, Husa AK, Vuolteenaho R, Herva R, Kaukola T, Hallman M (2009) Blood cytokines during the perinatal period in very preterm infants: relationship of inflammatory response and bronchopulmonary dysplasia. J Pediatr 154:39–43 e33PubMedCrossRefGoogle Scholar
  100. Pang Y, Rodts-Palenik S, Cai Z, Bennett WA, Rhodes PG (2005) Suppression of glial activation is involved in the protection of IL-10 on maternal E. coli induced neonatal white matter injury. Brain Res Dev Brain Res 157:141–149PubMedCrossRefGoogle Scholar
  101. Prince LS, Dieperink HI, Okoh VO, Fierro-Perez GA, Lallone RL (2005) Toll-like receptor signaling inhibits structural development of the distal fetal mouse lung. Dev Dyn 233:553–561PubMedCrossRefGoogle Scholar
  102. Reyburn B, Martin RJ, Prakash YS, MacFarlane PM (2012) Mechanisms of injury to the preterm lung and airway: implications for long-term pulmonary outcome. Neonatology 101:345–352PubMedCrossRefPubMedCentralGoogle Scholar
  103. Ricard JD, Dreyfuss D, Saumon G (2001) Production of inflammatory cytokines in ventilator-induced lung injury: a reappraisal. Am J Respir Crit Care Med 163:1176–1180PubMedCrossRefGoogle Scholar
  104. Sarelius IH, Glading AJ (2015) Control of vascular permeability by adhesion molecules. Tissue Barriers 3:e985954PubMedCrossRefGoogle Scholar
  105. Saugstad OD (2005) Oxidative stress in the newborn – a 30-year perspective. Biol Neonate 88:228–236PubMedCrossRefGoogle Scholar
  106. Schmitz T, Ritter J, Mueller S, Felderhoff-Mueser U, Chew LJ, Gallo V (2011) Cellular changes underlying hyperoxia-induced delay of white matter development. J Neurosci 31:4327–4344PubMedCrossRefPubMedCentralGoogle Scholar
  107. Smith RE (1996) Chemotactic cytokines mediate leukocyte recruitment in fibrotic lung disease. Biol Signals 5:223–231PubMedCrossRefGoogle Scholar
  108. Speer CP (2006a) Inflammation and bronchopulmonary dysplasia: a continuing story. Semin Fetal Neonatal Med 11:354–362PubMedCrossRefGoogle Scholar
  109. Speer CP (2006b) Pulmonary inflammation and bronchopulmonary dysplasia. J Perinatol 26(Suppl 1):S57–S62; discussion S63–54PubMedCrossRefGoogle Scholar
  110. Speer CP (2009) Chorioamnionitis, postnatal factors and proinflammatory response in the pathogenetic sequence of bronchopulmonary dysplasia. Neonatology 95:353–361PubMedCrossRefGoogle Scholar
  111. Speer CP (2011) Neonatal respiratory distress syndrome: an inflammatory disease? Neonatology 99:316–319PubMedCrossRefGoogle Scholar
  112. Speer CP, Pabst MJ, Hedegaard HB, Rest RF, Johnston RB Jr (1984) Enhanced release of oxygen metabolites by monocyte-derived macrophages exposed to proteolytic enzymes: activity of neutrophil elastase and cathepsin G. J Immunol 133:2151–2156PubMedGoogle Scholar
  113. Speer CP, Gahr M, Wieland M, Eber S (1988) Phagocytosis-associated functions in neonatal monocyte-derived macrophages. Pediatr Res 24:213–216PubMedCrossRefGoogle Scholar
  114. Speer CP, Ruess D, Harms K, Herting E, Gefeller O (1993) Neutrophil elastase and acute pulmonary damage in neonates with severe respiratory distress syndrome. Pediatrics 91:794–799PubMedGoogle Scholar
  115. Stoll BJ, Hansen NI, Sanchez PJ, Faix RG, Poindexter BB, Van Meurs KP et al (2011) Early onset neonatal sepsis: the burden of group B Streptococcal and E. coli disease continues. Pediatrics 127:817–826PubMedCrossRefPubMedCentralGoogle Scholar
  116. Stridh L, Smith PL, Naylor AS, Wang X, Mallard C (2011) Regulation of toll-like receptor 1 and -2 in neonatal mice brains after hypoxia-ischemia. J Neuroinflammation 8:45PubMedCrossRefPubMedCentralGoogle Scholar
  117. Stridh L, Ek CJ, Wang X, Nilsson H, Mallard C (2013) Regulation of toll-like receptors in the choroid plexus in the immature brain after systemic inflammatory stimuli. Transl Stroke Res 4:220–227PubMedCrossRefPubMedCentralGoogle Scholar
  118. Strunk T, Doherty D, Jacques A, Simmer K, Richmond P, Kohan R et al (2012) Histologic chorioamnionitis is associated with reduced risk of late-onset sepsis in preterm infants. Pediatrics 129:e134–e141PubMedCrossRefGoogle Scholar
  119. Strunk T, Inder T, Wang X, Burgner D, Mallard C, Levy O (2014) Infection-induced inflammation and cerebral injury in preterm infants. Lancet Infect Dis 14:751–762PubMedCrossRefPubMedCentralGoogle Scholar
  120. Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140:805–820CrossRefGoogle Scholar
  121. Thebaud B, Abman SH (2007) Bronchopulmonary dysplasia: where have all the vessels gone? Roles of angiogenic growth factors in chronic lung disease. Am J Respir Crit Care Med 175:978–985PubMedCrossRefPubMedCentralGoogle Scholar
  122. Thebaud B, Ladha F, Michelakis ED, Sawicka M, Thurston G, Eaton F et al (2005) Vascular endothelial growth factor gene therapy increases survival, promotes lung angiogenesis, and prevents alveolar damage in hyperoxia-induced lung injury: evidence that angiogenesis participates in alveolarization. Circulation 112:2477–2486PubMedCrossRefGoogle Scholar
  123. Thomas W, Speer CP (2011) Chorioamnionitis: important risk factor or innocent bystander for neonatal outcome? Neonatology 99:177–187PubMedCrossRefGoogle Scholar
  124. Thomas W, Speer CP (2014) Chorioamnionitis is essential in the evolution of bronchopulmonary dysplasia – the case in favour. Paediatr Respir Rev 15:49–52PubMedGoogle Scholar
  125. Thomas W, Seidenspinner S, Kawczynska-Leda N, Kramer BW, Chmielnicka-Kopaczyk M, Marx A et al (2008) Systemic fetal inflammation and reduced concentrations of macrophage migration inhibitory factor in tracheobronchial aspirate fluid of extremely premature infants. Am J Obstet Gynecol 198(64):e61–e66Google Scholar
  126. Turunen R, Nupponen I, Siitonen S, Repo H, Andersson S (2006) Onset of mechanical ventilation is associated with rapid activation of circulating phagocytes in preterm infants. Pediatrics 117:448–454PubMedCrossRefGoogle Scholar
  127. Ueda K, Cho K, Matsuda T, Okajima S, Uchida M, Kobayashi Y et al (2006) A rat model for arrest of alveolarization induced by antenatal endotoxin administration. Pediatr Res 59:396–400PubMedCrossRefGoogle Scholar
  128. Varughese R, Nayak JL, LoMonaco M, O’Reilly MA, Ryan RM, D’Angio CT (2003) Effects of hyperoxia on tumor necrosis factor alpha and Grobeta expression in newborn rabbit lungs. Lung 181:335–346PubMedCrossRefGoogle Scholar
  129. Viscardi RM (2012) Perinatal inflammation and lung injury. Semin Fetal Neonatal Med 17:30–35PubMedCrossRefGoogle Scholar
  130. Viscardi RM (2014) Ureaplasma species: role in neonatal morbidities and outcomes. Arch Dis Child Fetal Neonatal Ed 99:F87–F92PubMedCrossRefGoogle Scholar
  131. Viscardi RM, Muhumuza CK, Rodriguez A, Fairchild KD, Sun CC, Gross GW et al (2004) Inflammatory markers in intrauterine and fetal blood and cerebrospinal fluid compartments are associated with adverse pulmonary and neurologic outcomes in preterm infants. Pediatr Res 55:1009–1017PubMedCrossRefGoogle Scholar
  132. Volpe JJ (2008) Postnatal sepsis, necrotizing entercolitis, and the critical role of systemic inflammation in white matter injury in premature infants. J Pediatr 153:160–163PubMedCrossRefPubMedCentralGoogle Scholar
  133. Vuichard D, Ganter MT, Schimmer RC, Suter D, Booy C, Reyes L et al (2005) Hypoxia aggravates lipopolysaccharide-induced lung injury. Clin Exp Immunol 141:248–260PubMedCrossRefPubMedCentralGoogle Scholar
  134. Wagenaar GT, ter Horst SA, van Gastelen MA, Leijser LM, Mauad T, van der Velden PA et al (2004) Gene expression profile and histopathology of experimental bronchopulmonary dysplasia induced by prolonged oxidative stress. Free Radic Biol Med 36:782–801PubMedCrossRefGoogle Scholar
  135. Wesche H, Gao X, Li X, Kirschning CJ, Stark GR, Cao Z (1999) IRAK-M is a novel member of the Pelle/interleukin-1 receptor-associated kinase (IRAK) family. J Biol Chem 274:19403–19410PubMedCrossRefGoogle Scholar
  136. Wilson MR, Choudhury S, Takata M (2005) Pulmonary inflammation induced by high-stretch ventilation is mediated by tumor necrosis factor signaling in mice. Am J Physiol Lung Cell Mol Physiol 288:L599–L607PubMedCrossRefGoogle Scholar
  137. Wu YW (2002) Systematic review of chorioamnionitis and cerebral palsy. Ment Retard Dev Disabil Res Rev 8:25–29PubMedCrossRefGoogle Scholar
  138. Yamamoto M, Takeda K (2010) Current views of toll-like receptor signaling pathways. Gastroenterol Res Pract 2010:240365PubMedCrossRefPubMedCentralGoogle Scholar
  139. Yi M, Jankov RP, Belcastro R, Humes D, Copland I, Shek S et al (2004) Opposing effects of 60% oxygen and neutrophil influx on alveologenesis in the neonatal rat. Am J Respir Crit Care Med 170:1188–1196PubMedCrossRefGoogle Scholar
  140. Yoon BH, Romero R, Jun JK, Park KH, Park JD, Ghezzi F et al (1997) Amniotic fluid cytokines (interleukin-6, tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-8) and the risk for the development of bronchopulmonary dysplasia. Am J Obstet Gynecol 177:825–830PubMedCrossRefGoogle Scholar
  141. Yu KH, Li J, Snyder M, Shaw GM, O’Brodovich HM (2016) The genetic predisposition to bronchopulmonary dysplasia. Curr Opin Pediatr 28:318–323PubMedCrossRefPubMedCentralGoogle Scholar
  142. Zhang J, Zhou J, Xu B, Chen C, Shi W (2015) Different expressions of TLRs and related factors in peripheral blood of preterm infants. Int J Clin Exp Med 8:4108–4114PubMedPubMedCentralGoogle Scholar
  143. Zhao Y, Gilmore BJ, Young SL (1997) Expression of transforming growth factor-beta receptors during hyperoxia-induced lung injury and repair. Am J Physiol 273:L355–L362PubMedGoogle Scholar
  144. Zlotnik A, Yoshie O (2012) The chemokine superfamily revisited. Immunity 36:705–716PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.University Children’s HospitalUniversity of WürzburgWürzburgGermany

Personalised recommendations