Neonatology pp 1619-1639 | Cite as

Inflammatory Mediators in Neonatal Asphyxia and Infection

  • Kaoru OkazakiEmail author
  • Akira Nishida
  • Hirokazu Kimura
Reference work entry


Inflammatory mediators, such as inflammatory cytokines, are closely associated with neonatal diseases, including neonatal asphyxia (NA) and infection. The pathophysiology of NA may be mainly responsible for ischemia-reperfusion injuries, leading to the damage of tissue and organs via the production of aberrant inflammatory mediators, including cytokines. Excessive cytokine production may be associated with the activation of innate immunity, leading to further exacerbation of NA. In addition, pathogenic organisms can induce an acute/excessive inflammatory response through phagocyte activation with cytokine storm. Thus, these unbalanced immunological responses may induce inflammation and tissue damage in NA and infection. Furthermore, to compensate for cytokine imbalance, anti-inflammatory cytokines may be induced. Possible causes include the fact that preterm and term neonates are susceptible to NA and infection due to their lack of an adequate immune system. Therefore, given such a milieu, proper balanced cytokine production may influence the outcome of patients with NA and infection. From these aspects, we describe the relationships between inflammatory mediators in NA and infection in this chapter.



Antigen-presenting cells


Antimicrobial proteins and peptides


Blood-brain barrier


Bactericidal/permeability-increasing proteins




Compensatory anti-inflammatory response syndrome


Central nervous system


C-reactive protein


Damage-associated with molecular patterns




Fetus inflammatory response syndrome


Granulocyte-colony-stimulating factor


Granulocyte-macrophage colony-stimulating factor

HMGB1 protein

High-mobility group box 1 protein




Immunoglobulin G




Mixed anti-inflammatory response syndrome


Monocyte chemoattractant protein-1


Macrophage inflammatory protein


Matrix metalloproteinases


Neonatal asphyxia


Nuclear factor kappa-B


Nitric oxide




Pattern recognition receptors


Regulated on activation, normal T cell expressed and secreted


Reactive oxygen species


Systemic inflammatory response syndrome


Transforming growth factor


Toll-like receptors


Tumor necrosis factor


Triggering receptor expressed on myeloid cells-1


Vascular endothelial growth factor


  1. Abraham E, Arcaroli J, Carmody A et al (2000) HMG-1 as a mediator of acute lung inflammation. J Immunol 165:2950–2954PubMedCrossRefGoogle Scholar
  2. Adib-Conquy M, Cavaillon J-M (2009) Compensatory anti-inflammatory response syndrome. Thromb Haemost 101:36–47PubMedCrossRefGoogle Scholar
  3. Akdis M, Burgler S, Crameri R et al (2011) Interleukins, from 1 to 37, and interferon-gamma: receptors, functions, and roles in diseases. J Allergy Clin Immunol 127:701–721, e701–770CrossRefPubMedGoogle Scholar
  4. Ala Y, Palluy O, Favero J et al (1992) Hypoxia/reoxygenation stimulates endothelial cells to promote interleukin-1 and interleukin-6 production. Effects of free radical scavengers. Agents Actions 37:134–139PubMedCrossRefGoogle Scholar
  5. Aly H, Khashaba MT, El-Ayouty M et al (2006) IL-1β, IL-6 and TNF-α and outcomes of neonatal hypoxic ischemic encephalopathy. Brain Dev 28:178–182PubMedCrossRefGoogle Scholar
  6. Aly H, Hassanein S, Nada A et al (2009) Vascular endothelial growth factor in neonates with perinatal asphyxia. Brain Dev 31:600–604PubMedCrossRefGoogle Scholar
  7. Baggiolini M (1998) Chemokines and leukocyte traffic. Nature 392:565–568PubMedCrossRefGoogle Scholar
  8. Baranova O, Miranda LF, Pichiule P et al (2007) Neuron-specific inactivation of the hypoxia inducible factor 1α increases brain injury in a mouse model of transient focal cerebral ischemia. J Neurosci 27:6320–6332PubMedCrossRefGoogle Scholar
  9. Belderbos ME, Levy O, Meyaard L et al (2013) Plasma-mediated immune suppression: a neonatal perspective. Pediatr Allergy Immunol 24:102–113PubMedCrossRefGoogle Scholar
  10. Bianchi ME (2007) DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol 81:1–5CrossRefPubMedGoogle Scholar
  11. Bona E, Andersson AL, Blomgren K et al (1999) Chemokine and inflammatory cell response to hypoxia-ischemia in immature rats. Pediatr Res 45:500–509PubMedCrossRefGoogle Scholar
  12. Bonizzi G, Karin M (2004) The two NF-κB activation pathways and their role in innate and adaptive immunity. Trends Immunol 25:280–288CrossRefPubMedGoogle Scholar
  13. Brochu ME, Girard S, Lavoie K et al (2011) Developmental regulation of the neuroinflammatory responses to LPS and/or hypoxia-ischemia between preterm and term neonates: an experimental study. J Neuroinflammation 8:55PubMedPubMedCentralCrossRefGoogle Scholar
  14. Brocklehurst P, Farrell B, King A et al (2011) Treatment of neonatal sepsis with intravenous immune globulin. N Engl J Med 365:1201–1211PubMedCrossRefGoogle Scholar
  15. Carr R, Modi N, Dore C (2003) G-CSF and GM-CSF for treating or preventing neonatal infections. Cochrane Database Syst Rev Cd003066Google Scholar
  16. Castellheim A, Brekke OL, Espevik T et al (2009) Innate immune responses to danger signals in systemic inflammatory response syndrome and sepsis. Scand J Immunol 69:479–491PubMedCrossRefGoogle Scholar
  17. Chalak LF, Sanchez PJ, Adams-Huet B et al (2014) Biomarkers for severity of neonatal hypoxic-ischemic encephalopathy and outcomes in newborns receiving hypothermia therapy. J Pediatr 164:468–474.e461PubMedCrossRefGoogle Scholar
  18. Chapados I, Lee T-F, Chik CL et al (2011) Hydrocortisone administration increases pulmonary artery pressure in asphyxiated newborn piglets reoxygenated with 100% oxygen. Eur J Pharmacol 652:111–116PubMedCrossRefGoogle Scholar
  19. Chavez-Valdez R, Kovell L, Ahlawat R et al (2013) Opioids and clonidine modulate cytokine production and opioid receptor expression in neonatal immune cells. J Perinatol Off J Calif Perinat Assoc 33:374–382CrossRefGoogle Scholar
  20. Chiesa C, Pellegrini G, Panero A et al (2003) Umbilical cord interleukin-6 levels are elevated in term neonates with perinatal asphyxia. Eur J Clin Invest 33:352–358PubMedCrossRefGoogle Scholar
  21. Chirico V, Lacquaniti A, Salpietro V et al (2014) High-mobility group box 1 (HMGB1) in childhood: from bench to bedside. Eur J Pediatr 173:1123–1136PubMedCrossRefGoogle Scholar
  22. Cuenca AG, Wynn JL, Moldawer LL et al (2013) Role of innate immunity in neonatal infection. Am J Perinatol 30:105–112PubMedPubMedCentralCrossRefGoogle Scholar
  23. Derugin N, Wendland M, Muramatsu K et al (2000) Evolution of brain injury after transient middle cerebral artery occlusion in neonatal rats. Stroke 31:1752–1761PubMedCrossRefGoogle Scholar
  24. Dinarello CA (1998) Interleukin-1, interleukin-1 receptors and interleukin-1 receptor antagonist. Int Rev Immunol 16:457–499PubMedCrossRefGoogle Scholar
  25. Døllner H, Vatten L, Halgunset J et al (2002) Histologic chorioamnionitis and umbilical serum levels of pro-inflammatory cytokines and cytokine inhibitors. BJOG Int J Obstet Gynaecol 109:534–539CrossRefGoogle Scholar
  26. Dubovy P, Brazda V, Klusakova I et al (2013) Bilateral elevation of interleukin-6 protein and mRNA in both lumbar and cervical dorsal root ganglia following unilateral chronic compression injury of the sciatic nerve. J Neuroinflammation 10:55PubMedPubMedCentralCrossRefGoogle Scholar
  27. Epstein FHMD, Goldenberg RLMD, Hauth JCMD et al (2000) Intrauterine infection and preterm delivery. N Engl J Med 342:1500–1507CrossRefGoogle Scholar
  28. Ergenekon E, Gücüyener K, Erbaş D et al (2004) Cerebrospinal fluid and serum vascular endothelial growth factor and nitric oxide levels in newborns with hypoxic ischemic encephalopathy. Brain Dev 26:283–286PubMedCrossRefGoogle Scholar
  29. Fan X, Heijnen CJ, Van Der Kooij MA et al (2009) The role and regulation of hypoxia-inducible factor-1α expression in brain development and neonatal hypoxic–ischemic brain injury. Brain Res Rev 62:99–108PubMedPubMedCentralCrossRefGoogle Scholar
  30. Fauchère J-C, Koller BM, Tschopp A et al (2015) Safety of early high-dose recombinant erythropoietin for neuroprotection in very preterm infants. J Pediatr 167:52–57.e53PubMedCrossRefGoogle Scholar
  31. Felderhoff-Mueser U, Schmidt OI, Oberholzer A et al (2005) IL-18: a key player in neuroinflammation and neurodegeneration? Trends Neurosci 28:487–493PubMedCrossRefGoogle Scholar
  32. Fellman V, Raivio KO (1997) Reperfusion injury as the mechanism of brain damage after perinatal asphyxia. Pediatr Res 41:599–606PubMedCrossRefGoogle Scholar
  33. Feng Y, Rhodes PG, Bhatt AJ (2008) Neuroprotective effects of vascular endothelial growth factor following hypoxic ischemic brain injury in neonatal rats. Pediatr Res 64:370–374PubMedCrossRefGoogle Scholar
  34. Feng Y, Rhodes PG, Liu H et al (2009) Dexamethasone induces neurodegeneration but also up-regulates vascular endothelial growth factor A in neonatal rat brains. Neuroscience 158:823–832PubMedCrossRefGoogle Scholar
  35. Fisher CJ Jr, Dhainaut JF, Opal SM et al (1994) Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group. JAMA 271:1836–1843PubMedCrossRefGoogle Scholar
  36. Fisher CJ Jr, Agosti JM, Opal SM et al (1996) Treatment of septic shock with the tumor necrosis factor receptor: Fc fusion protein. The Soluble TNF Receptor Sepsis Study Group. N Engl J Med 334:1697–1702PubMedCrossRefGoogle Scholar
  37. Fiuza C, Bustin M, Talwar S et al (2003) Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells. Blood 101:2652–2660CrossRefPubMedGoogle Scholar
  38. Fotopoulos S, Mouchtouri A, Xanthou G et al (2005) Inflammatory chemokine expression in the peripheral blood of neonates with perinatal asphyxia and perinatal or nosocomial infections. Acta Paediatr 94:800–806PubMedCrossRefGoogle Scholar
  39. Galasso JM, Liu Y, Szaflarski J et al (2000) Monocyte chemoattractant protein-1 is a mediator of acute excitotoxic injury in neonatal rat brain. Neuroscience 101:737–744PubMedCrossRefGoogle Scholar
  40. Gantert M, Been JV, Gavilanes AWD et al (2010) Chorioamnionitis: a multiorgan disease of the fetus[quest]. J Perinatol Off J Calif Perinat Assoc 30:S21–S30CrossRefGoogle Scholar
  41. Gomez R, Romero R, Ghezzi F et al (1998) The fetal inflammatory response syndrome. Am J Obstet Gynecol 179:194–202PubMedCrossRefGoogle Scholar
  42. Gotsch F, Romero R, Kusanovic JP et al (2007) The fetal inflammatory response syndrome. Clin Obstet Gynecol 50:652–683PubMedCrossRefGoogle Scholar
  43. Hedtjarn M, Leverin AL, Eriksson K et al (2002) Interleukin-18 involvement in hypoxic-ischemic brain injury. J Neurosci Off J Soc Neurosci 22:5910–5919CrossRefGoogle Scholar
  44. Hedtjärn M, Mallard C, Arvidsson P et al (2004) White matter injury in the immature brain: role of interleukin-18. Neurosci Lett 373:16–20CrossRefGoogle Scholar
  45. Hotchkiss RS, Monneret G, Payen D (2013a) Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis 13:260–268PubMedPubMedCentralCrossRefGoogle Scholar
  46. Hotchkiss RS, Monneret G, Payen D (2013b) Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol 13:862–874PubMedPubMedCentralCrossRefGoogle Scholar
  47. Hotoura E, Giapros V, Kostoula A et al (2011) Tracking changes of lymphocyte subsets and pre-inflammatory mediators in full-term neonates with suspected or documented infection. Scand J Immunol 73:250–255PubMedCrossRefGoogle Scholar
  48. Irakam A, Miskolci V, Vancurova I et al (2002) Dose-related inhibition of proinflammatory cytokine release from neutrophils of the newborn by dexamethasone, betamethasone, and hydrocortisone. Biol Neonate 82:89–95PubMedCrossRefGoogle Scholar
  49. Jenkins DD, Rollins LG, Perkel JK et al (2012) Serum cytokines in a clinical trial of hypothermia for neonatal hypoxic-ischemic encephalopathy. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 32:1888–1896CrossRefGoogle Scholar
  50. Jeong SJ, Han SH, Kim CO et al (2013) Anti-vascular endothelial growth factor antibody attenuates inflammation and decreases mortality in an experimental model of severe sepsis. Crit Care 17:R97PubMedPubMedCentralCrossRefGoogle Scholar
  51. Kaandorp JJ, Van Bel F, Veen S et al (2012) Long-term neuroprotective effects of allopurinol after moderate perinatal asphyxia: follow-up of two randomised controlled trials. Arch Dis Child Fetal Neonatal Ed 97:F162–F166PubMedCrossRefGoogle Scholar
  52. Kelen D, Robertson NJ (2010) Experimental treatments for hypoxic ischaemic encephalopathy. Early Hum Dev 86:369–377PubMedCrossRefGoogle Scholar
  53. Kim CJ, Romero R, Chaemsaithong P et al (2015) Acute chorioamnionitis and funisitis: definition, pathologic features, and clinical significance. Am J Obstet Gynecol 213:S29–S52PubMedPubMedCentralCrossRefGoogle Scholar
  54. Kollmann TR, Crabtree J, Rein-Weston A et al (2009) Neonatal innate TLR-mediated responses are distinct from those of adults. J Immunol 183:7150–7160PubMedPubMedCentralCrossRefGoogle Scholar
  55. Komine-Kobayashi M, Zhang N, Liu M et al (2006) Neuroprotective effect of recombinant human granulocyte colony-stimulating factor in transient focal ischemia of mice. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 26:402–413CrossRefGoogle Scholar
  56. Kondo M, Itoh S, Isobe K et al (2000) Chemiluminescence because of the production of reactive oxygen species in the lungs of newborn piglets during resuscitation periods after asphyxiation load. Pediatr Res 47:524–527PubMedCrossRefGoogle Scholar
  57. Leung DW, Cachianes G, Kuang WJ et al (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science (New York, NY) 246:1306–1309CrossRefGoogle Scholar
  58. Levy O, Wynn JL (2014) A prime time for trained immunity: innate immune memory in newborns and infants. Neonatology 105:136–141PubMedPubMedCentralCrossRefGoogle Scholar
  59. Levy MM, Fink MP, Marshall JC et al (2003) 2001 SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions conference. Crit Care Med 31:1250–1256CrossRefPubMedGoogle Scholar
  60. Li L, Mbride DW, Doycheva D et al (2015) G-CSF attenuates neuroinflammation and stabilizes the blood–brain barrier via the PI3K/Akt/GSK-3β signaling pathway following neonatal hypoxia-ischemia in rats. Exp Neurol 272:135–144PubMedPubMedCentralCrossRefGoogle Scholar
  61. Liu F, Mccullough LD (2013) Inflammatory responses in hypoxic ischemic encephalopathy. Acta Pharmacol Sin 34:1121–1130PubMedPubMedCentralCrossRefGoogle Scholar
  62. Lv H, Wang Q, Wu S et al (2015) Neonatal hypoxic ischemic encephalopathy-related biomarkers in serum and cerebrospinal fluid. Clin Chim Acta 450:282–297PubMedCrossRefGoogle Scholar
  63. Marodi L (2001) IL-12 and IFN-gamma deficiencies in human neonates. Pediatr Res 49:316PubMedCrossRefGoogle Scholar
  64. Maroso M, Balosso S, Ravizza T et al (2011) Interleukin-1 type 1 receptor/toll-like receptor signalling in epilepsy: the importance of IL-1beta and high-mobility group box 1. J Intern Med 270:319–326PubMedCrossRefGoogle Scholar
  65. Matsui T, Kida H, Iha T et al (2014) Effects of hypothermia on ex vivo microglial production of pro- and anti-inflammatory cytokines and nitric oxide in hypoxic-ischemic brain-injured mice. Folia Neuropathol Assoc Pol Neuropathol Med Res Cent Pol Acad Sci 52:151–158Google Scholar
  66. Mesples B, Plaisant F, Gressens P (2003) Effects of interleukin-10 on neonatal excitotoxic brain lesions in mice. Dev Brain Res 141:25–32CrossRefGoogle Scholar
  67. Miossec P, Korn T, Kuchroo VK (2009) Interleukin-17 and type 17 helper T cells. N Engl J Med 361:888–898PubMedCrossRefGoogle Scholar
  68. Mizuno K, Hida H, Masuda T et al (2008) Pretreatment with low doses of erythropoietin ameliorates brain damage in periventricular leukomalacia by targeting late oligodendrocyte progenitors: a rat model. Neonatology 94:255–266PubMedCrossRefGoogle Scholar
  69. Murphy BP, Inder TE, Huppi PS et al (2001) Impaired cerebral cortical gray matter growth after treatment with dexamethasone for neonatal chronic lung disease. Pediatrics 107:217–221PubMedCrossRefGoogle Scholar
  70. Nakamura S, Kusaka T, Koyano K et al (2014) Relationship between early changes in cerebral blood volume and electrocortical activity after hypoxic-ischemic insult in newborn piglets. Brain Dev 36:563–571PubMedCrossRefGoogle Scholar
  71. Ng PC, Li K, Chui KM et al (2007) IP-10 is an early diagnostic marker for identification of late-onset bacterial infection in preterm infants. Pediatr Res 61:93–98PubMedCrossRefGoogle Scholar
  72. Ohlsson A, Lacy JB (2015) Intravenous immunoglobulin for suspected or proven infection in neonates. Cochrane Database Syst Rev 3, Cd001239Google Scholar
  73. Okazaki K, Nishida A, Kato M et al (2006) Elevation of cytokine concentrations in asphyxiated neonates. Biol Neonate 89:183–189PubMedCrossRefGoogle Scholar
  74. Okazaki K, Kondo M, Kato M et al (2008a) Temporal alterations in concentrations of sera cytokines/chemokines in sepsis due to group B streptococcus infection in a neonate. Jpn J Infect Dis 61:382–385PubMedGoogle Scholar
  75. Okazaki K, Kondo M, Kato M et al (2008b) Elevation of high-mobility group box 1 concentration in asphyxiated neonates. Neonatology 94:105–109PubMedCrossRefGoogle Scholar
  76. Okazaki K, Kusaka T, Kondo M et al (2012) Temporal alteration of serum G-CSF and VEGF levels in perinatal asphyxia treated with head cooling. Cytokine 60:812–814PubMedCrossRefGoogle Scholar
  77. Okazaki K, Kusaka T, Kondo M, Kimura H (2015) Pathophysiological roles of cytokines in the brain during perinatal asphyxia. Ann Pediatr Child Health 3:1030Google Scholar
  78. Osuchowski MF, Welch K, Siddiqui J et al (2006) Circulating cytokine/inhibitor profiles reshape the understanding of the SIRS/CARS continuum in sepsis and predict mortality. J Immunol 177:1967–1974PubMedCrossRefGoogle Scholar
  79. Osuchowski MF, Craciun F, Weixelbaumer KM et al (2012) Sepsis chronically in MARS: systemic cytokine responses are always mixed regardless of the outcome, magnitude, or phase of sepsis. J Immunol 189:4648–4656PubMedPubMedCentralCrossRefGoogle Scholar
  80. Pammi M, Abrams SA (2015) Oral lactoferrin for the prevention of sepsis and necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev 2, Cd007137Google Scholar
  81. Pober JS, Sessa WC (2007) Evolving functions of endothelial cells in inflammation. Nat Rev Immunol 7:803–815CrossRefPubMedGoogle Scholar
  82. Qian L, Weng XW, Chen W et al (2014) TREM-1 as a potential therapeutic target in neonatal sepsis. Int J Clin Exp Med 7:1650–1658PubMedPubMedCentralGoogle Scholar
  83. Rangarajan V, Juul SE (2014) Erythropoietin: emerging role of erythropoietin in neonatal neuroprotection. Pediatr Neurol 51:481–488PubMedPubMedCentralCrossRefGoogle Scholar
  84. Roka A, Beko G, Halasz J et al (2013) Changes in serum cytokine and cortisol levels in normothermic and hypothermic term neonates after perinatal asphyxia. Inflamm Res 62:81–87PubMedCrossRefGoogle Scholar
  85. Romero R, Chaemsaithong P, Korzeniewski SJ et al (2016) Clinical chorioamnionitis at term II: the intra-amniotic inflammatory response. J Perinat Med 44:5–22PubMedPubMedCentralGoogle Scholar
  86. Rosenberg GA (2009) Matrix metalloproteinases and their multiple roles in neurodegenerative diseases. Lancet Neurol 8:205–216PubMedCrossRefGoogle Scholar
  87. Rossol M, Heine H, Meusch U et al (2011) LPS-induced cytokine production in human monocytes and macrophages. Crit Rev™ Immunol 31:379–446CrossRefGoogle Scholar
  88. Sahni R, Sanocka UM (2008) Hypothermia for hypoxic-ischemic encephalopathy. Clin Perinatol 35:717–734, viPubMedCrossRefGoogle Scholar
  89. Saraiva M, O’garra A (2010) The regulation of IL-10 production by immune cells. Nat Rev Immunol 10:170–181CrossRefPubMedGoogle Scholar
  90. Savman K, Blennow M, Gustafson K et al (1998) Cytokine response in cerebrospinal fluid after birth asphyxia. Pediatr Res 43:746–751CrossRefPubMedGoogle Scholar
  91. Schelonka RL, Maheshwari A, Carlo WA et al (2011) T cell cytokines and the risk of blood stream infection in extremely low birth weight infants. Cytokine 53:249–255PubMedCrossRefGoogle Scholar
  92. Schlager GW, Griesmaier E, Wegleiter K et al (2011) Systemic G-CSF treatment does not improve long-term outcomes after neonatal hypoxic–ischaemic brain injury. Exp Neurol 230:67–74PubMedCrossRefGoogle Scholar
  93. Seo JW, Kim JH, Kim JH et al (2012) Time-dependent effects of hypothermia on microglial activation and migration. J Neuroinflammation 9:164PubMedPubMedCentralCrossRefGoogle Scholar
  94. Sharma AA, Jen R, Butler A et al (2012) The developing human preterm neonatal immune system: a case for more research in this area. Clin Immunol 145:61–68PubMedPubMedCentralCrossRefGoogle Scholar
  95. Shozushima T, Takahashi G, Matsumoto N et al (2011) Usefulness of presepsin (sCD14-ST) measurements as a marker for the diagnosis and severity of sepsis that satisfied diagnostic criteria of systemic inflammatory response syndrome. J Infect Chemother Off J Jpn Soc Chemother 17:764–769CrossRefGoogle Scholar
  96. Si QS, Nakamura Y, Kataoka K (1997) Hypothermic suppression of microglial activation in culture: inhibition of cell proliferation and production of nitric oxide and superoxide. Neuroscience 81:223–229PubMedCrossRefGoogle Scholar
  97. Sood BG, Shankaran S, Schelonka RL et al (2012) Cytokine profiles of preterm neonates with fungal and bacterial sepsis. Pediatr Res 72:212–220PubMedPubMedCentralCrossRefGoogle Scholar
  98. Sprung CL, Annane D, Keh D et al (2008) Hydrocortisone therapy for patients with septic shock. N Engl J Med 358:111–124PubMedCrossRefGoogle Scholar
  99. Verrotti A, Basciani F, Trotta D et al (2001) Effect of anticonvulsant drugs on interleukins-1, -2 and -6 and monocyte chemoattractant protein-1. Clin Exp Med 1:133–136PubMedCrossRefGoogle Scholar
  100. Volpe JJ (2001) Perinatal brain injury: from pathogenesis to neuroprotection. Ment Retard Dev Disabil Res Rev 7:56–64PubMedCrossRefGoogle Scholar
  101. Wynn J, Cornell TT, Wong HR et al (2010) The host response to sepsis and developmental impact. Pediatrics 125:1031–1041PubMedPubMedCentralCrossRefGoogle Scholar
  102. Yamaguchi M, Okamoto K, Kusano T et al (2015) The effects of xanthine oxidoreductase inhibitors on oxidative stress markers following global brain ischemia reperfusion injury in C57BL/6 mice. PLoS One 10, e0133980PubMedPubMedCentralCrossRefGoogle Scholar
  103. Yang KD, Liou WY, Lee CS et al (1992) Effects of phenobarbital on leukocyte activation: membrane potential, actin polymerization, chemotaxis, respiratory burst, cytokine production, and lymphocyte proliferation. J Leukoc Biol 52:151–156PubMedCrossRefGoogle Scholar
  104. Yossuck P, Nightengale BJ, Fortney JE et al (2008) Effect of morphine sulfate on neonatal neutrophil chemotaxis. Clin J Pain 24:76–82PubMedCrossRefGoogle Scholar
  105. Zhang ZG, Zhang L, Tsang W et al (2002) Correlation of VEGF and angiopoietin expression with disruption of blood–brain barrier and angiogenesis after focal cerebral ischemia. J Cereb Blood Flow Metab 22:379–392PubMedCrossRefGoogle Scholar
  106. Zhang J, Takahashi HK, Liu K et al (2011) Anti-high mobility group box-1 monoclonal antibody protects the blood-brain barrier from ischemia-induced disruption in rats. Stroke 42:1420–1428PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of NeonatologyTokyo Metropolitan Children’s Medical CenterTokyoJapan
  2. 2.Infectious Diseases Surveillance CenterNational Institute of Infectious DiseasesTokyoJapan

Section editors and affiliations

  • Robert D. Christensen
    • 1
  1. 1.Intermountain HealthcareSalt Lake CityUSA

Personalised recommendations