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The Impact of Chronic Intrauterine Inflammation on the Physiologic and Neurodevelopmental Consequences of Intermittent Umbilical Cord Occlusion in Fetal Sheep

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Abstract

Objective

To determine the effect of intrauterine inflammation on fetal responses to umbilical cord occlusion (UCO).

Study Design

In pregnant sheep, lipopolysaccharide (LPS) or saline (SAL) was infused intra-amniotically for 4 weeks from 80 days of gestation (d). At 110 d, fetuses were instrumented for UCOs (5 × 2-minutes, 30-minute intervals: LPS + UCO, n = 6; SAL + UCO, n = 8) or no UCO (sham, n = 6) on 117 and 118 d. Tissues were collected at 126 d.

Results

Fetal physiological responses to UCO were similar between LPS + UCO and SAL + UCO. Histologic chorioamnionitis and increased amniotic fluid interleukin 8 (IL-8) were observed in LPS + UCO pregnancies (versus SAL + UCO, P < .05). CNPase-positive oligodendrocyte number in the cerebral white matter was lower in LPS + UCO and SAL + UCO than sham (P < .05); there was no effect on astrocytes or activated microglia/macrophages. Two of the SAL + UCO fetuses had white matter lesions; none were observed in LPS + UCO or sham.

Conclusion

Chronic pre-existing intrauterine inflammation did not exacerbate fetal brain injury induced by intermittent UCO.

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References

  1. Goldenberg RL, Hauth JC, Andrews WW. Intrauterine infection and preterm delivery. N Engl J Med. 2000;342(20):1500–1507.

    Article  CAS  PubMed  Google Scholar 

  2. Romero R, Espinoza J, Gonçalves LF, Kusanovic JP, Friel LA, Nien JK. Inflammation in preterm and term labour and delivery. Semin Fetal Neonatal Med. 2006;11(5):317–326.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Gotsch F, Romero R, Kusanovic JP, et al. The fetal inflammatory response syndrome. Clin Obstetr Gynecol. 2007;50(3):652–683.

    Article  Google Scholar 

  4. Nitsos I, Rees SM, Duncan J, et al. Chronic exposure to intraamniotic lipopolysaccharide affects the ovine fetal brain. J Soc Gynecol Investig. 2006;13(4):239–247.

    Article  CAS  PubMed  Google Scholar 

  5. Moss TJM, Nitsos I, Newnham JP, Ikegami M, Jobe AH. Chorioamnionitis induced by subchorionic endotoxin infusion in sheep. Am J Obstet Gynecol. 2003;189(6):1771–1776.

    Article  CAS  PubMed  Google Scholar 

  6. Moss TJM, Newnham JP, Willett KE, Kramer BW, Jobe AH, Ikegami M. Early gestational intra-amniotic endotoxin: lung function, surfactant, and morphometry. Am J Respir Crit Care Med. 2002;165(6):805–811.

    Article  PubMed  Google Scholar 

  7. Nitsos I, Moss TJM, Cock ML, Harding R, Newnham JP. Fetal responses to intra-amniotic endotoxin in sheep. J Soc Gynecol Investig. 2002;9(2):80–85.

    Article  CAS  PubMed  Google Scholar 

  8. Debillon T, Gras-Leguen C, Vérielle V, et al. Intrauterine infection induces programmed cell death in rabbit periventricular white matter. Pediatr Res. 2000;47(6):736–742.

    Article  CAS  PubMed  Google Scholar 

  9. Duncan JR, Cock ML, Scheerlinck JP, et al. White matter injury after repeated endotoxin exposure in the preterm ovine fetus. Pediatr Res. 2002;52(6):941–949.

    Article  CAS  PubMed  Google Scholar 

  10. Yoon BH, Kim CJ, Romero R, et al. Experimentally induced intrauterine infection causes fetal brain white matter lesions in rabbits. Am J Obstet Gynecol. 1997;177(4):797–802.

    Article  CAS  PubMed  Google Scholar 

  11. Rees S, Mallard C, Breen S, Stringer M, Cock M, Harding R. Fetal brain injury following prolonged hypoxemia and placental insufficiency: a review. Comp Biochem Physiol. 1998;119(3): 653–660.

    Article  CAS  Google Scholar 

  12. Rees S, Stringer M, Just Y, Hooper SB, Harding R. The vulnerability of the fetal sheep brain to hypoxemia at mid-gestation. Brain Res Dev Brain Res. 1997;103(2):103–118.

    Article  CAS  PubMed  Google Scholar 

  13. Duncan JR, Cock ML, Suzuki K, Scheerlinck JP, Harding R, Rees SM. Chronic endotoxin exposure causes brain injury in the ovine fetus in the absence of hypoxemia. J Soc Gynecol Investig. 2006;13(2):87–96.

    Article  CAS  PubMed  Google Scholar 

  14. Nelson KB, Grether JK. Potentially asphyxiating conditions and spastic cerebral palsy in infants of normal birth weight. Am J Obstet Gynecol. 1998;179(2):507–513.

    Article  CAS  PubMed  Google Scholar 

  15. Eklind S, Mallard C, Arvidsson P, Hagberg H. Lipopolysaccharide induces both a primary and a secondary phase of sensitization in the developing rat brain. Pediatr Res. 2005;58(1):112–116.

    Article  CAS  PubMed  Google Scholar 

  16. Eklind S, Mallard C, Leverin AL, et al. Bacterial endotoxin sensitizes the immature brain to hypoxic-ischaemic injury. Eur J Neurosci. 2001;13(6):1101–1106.

    Article  CAS  PubMed  Google Scholar 

  17. Wang X, Hagberg H, Nie C, Zhu C, Ikeda T, Mallard C. Dual role of intrauterine immune challenge on neonatal and adult brain vulnerability to hypoxia-ischemia. J Neuropathol Exp Neurol. 2007;66(6):552–561.

    Article  CAS  PubMed  Google Scholar 

  18. Lehnardt S, Massillon L, Follett P, et al. Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proc Natl Acad Sci USA. 2003;100(14):8514-8519.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Loeliger M, Watson CS, Reynolds JD, et al. Extracellular glutamate levels and neuropathology in cerebral white matter following repeated umbilical cord occlusion in the near term fetal sheep. Neuroscience. 2003;116(3):705–714.

    Article  CAS  PubMed  Google Scholar 

  20. Roelfsema V, Gunn AJ, Fraser M, Quaedackers JS, Bennet L. Cortisol and ACTH responses to severe asphyxia in preterm fetal sheep. Exp Physiol. 2005;90(4):545–555.

    Article  CAS  PubMed  Google Scholar 

  21. Sloboda DM, Moss TJM, Li S, et al. Prenatal betamethasone exposure results in pituitary-adrenal hyporesponsiveness in adult sheep. Am J Physiol Endocrinol Metab. 2007;292(1):E61–E70.

    Article  CAS  PubMed  Google Scholar 

  22. Conradi NG, Muntzing K. Cerebellar foliation in rats. 2. Effects of maternal malnutrition on the formation of fissures in foetal rats. Acta Pathol Microbiol Immunol Scand [A]. 1985;93(6):391–395.

    CAS  Google Scholar 

  23. Haynes RL, Folkerth RD, Keefe RJ, et al. Nitrosative and oxidative injury to premyelinating oligodendrocytes in periventricular leukomalacia. J Neuropathol Exp Neurol. 2003;62(5):441–450.

    Article  PubMed  Google Scholar 

  24. Kramer BW, Moss TJM, Willet KE, et al. Dose and time response after intraamniotic endotoxin in preterm lambs. Am J Respir Crit Care Med. 2001;164(6):982–988.

    Article  CAS  PubMed  Google Scholar 

  25. Wu YW. Systematic review of chorioamnionitis and cerebral palsy. MRDD Res Rev. 2002;8(1):25–29.

    Google Scholar 

  26. Viscardi RM, Muhumuza CK, Rodriguez A, et al. Inflammatory markers in intrauterine and fetal blood and cerebrospinal fluid compartments are associated with adverse pulmonary and neurologic outcomes in preterm infants. Pediatr Res. 2004;55(6): 1009–1017.

    Article  CAS  PubMed  Google Scholar 

  27. Park CW, Moon KC, Park JS, Jun JK, Romero R, Yoon BH. The involvement of human amnion in histologic chorioamnionitis is an indicator that a fetal and an intra-amniotic inflammatory response is more likely and severe: clinical implications. Placenta. 2009;30(1):56–61.

    Article  CAS  PubMed  Google Scholar 

  28. Yoon BH, Romero R, Park JS, et al. Fetal exposure to an intramniotic inflammation and the development of cerebral palsy at the age of three years. Am J Obstet Gynecol. 2000;182(3):675–681.

    Article  CAS  PubMed  Google Scholar 

  29. Green LR, Homan J, White SE, Richardson BS. Cardiovascular and metabolic responses to intermittent umbilical cord occlusion in the preterm ovine fetus. J Soc Gynecol Investig. 1999;6(2):56–63.

    Article  CAS  PubMed  Google Scholar 

  30. Newnham JP, Kallapur SG, Kramer BW, et al. Betamethasone effects on chorioamnionitis induced by intra-amniotic endotoxin in sheep. Am J Obstet Gynecol. 2003;189(5):1458–1466.

    Article  CAS  PubMed  Google Scholar 

  31. Kallapur SG, Nitsos I, Moss TJM, et al. Chronic endotoxin exposure does not cause sustained structural abnormalities in the fetal sheep lungs. Am J Physiol Lung Cell Mol Physiol. 2005;288(5): L966–L974.

    Article  CAS  PubMed  Google Scholar 

  32. Kallapur SG, Jobe AH, Ball MK, et al. Pulmonary and systemic endotoxin tolerance in preterm fetal sheep exposed to chorioamnionitis. J Immunol. 2007;179(12):8491–8499.

    Article  CAS  PubMed  Google Scholar 

  33. Johnston MV, Hagberg H. Sex and the pathogenesis of cerebral palsy. Dev Med Child Neurol. 2007;49(1):74–78.

    Article  PubMed  Google Scholar 

  34. Mayoral SR, Omar G, Penn AA. Sex differences in a hypoxia model of preterm brain damage. Pediatr Res. 2009;66(3):248–253.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Mallard C, Hagberg H. Inflammation-induced preconditioning in the immature brain. Semin Fetal Neonatal Med. 2007;12(4): 280–286.

    Article  PubMed  Google Scholar 

  36. Karikó K, Weissman D, Welsh FA. Inhibition of toll-like receptor and cytokine signaling-a unifying theme in ischemic tolerance. J Cereb Blood Flow Metab. 2004;24(11):1288–1304.

    Article  PubMed  Google Scholar 

  37. Ikeda T, Yang L, Ikenoue T, Mallard C, Hagberg H. Endotoxin-induced hypoxic-ischemic tolerance is mediated by up-regulation of corticosterone in neonatal rat. Pediatr Res. 2006;59(1):56–60.

    Article  CAS  PubMed  Google Scholar 

  38. del Rey A, Furukawa H, Monge-Arditi G, Kabiersch A, Voigt KH, Besedovsky HO. Alterations in the pituitary-adrenal axis of adult mice following neonatal exposure to interleukin-1. Brain Behav Immun. 1996;10(3):235–248.

    Article  PubMed  Google Scholar 

  39. Hodgson DM, Knott B, Walker FR. Neonatal endotoxin exposure influences HPA responsivity and impairs tumor immunity in Fischer 344 rats in adulthood. Pediatr Res. 2001;50(6):750–755.

    Article  CAS  PubMed  Google Scholar 

  40. Reul JM, Stec I, Wiegers GJ, et al. Prenatal immune challenge alters the hypothalamic-pituitary-adrenocortical axis in adult rats. J Clin Invest. 1994;93(6):2600–2607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Samuelsson AM, Ohrn I, Dahlgren J, et al. Prenatal exposure to interleukin-6 results in hypertension and increased hypothalamic-pituitary-adrenal axis activity in adult rats. Endocrinology. 2004;145(11):4897–4911.

    Article  CAS  PubMed  Google Scholar 

  42. Challis JR, Sloboda D, Matthews SG, et al. The fetal placental hypothalamic-pituitary-adrenal (HPA) axis, parturition and post natal health. Mol Cell Endocrinol. 2001;185(1–2):135–144.

    Article  CAS  PubMed  Google Scholar 

  43. Romero R, Gotsch F, Pineles B, Kusanovic JP. Inflammation in pregnancy: its roles in reproductive physiology, obstetrical complications, and fetal injury. Nutr Rev. 2007;65(12 Pt 2): S194–S202.

    Article  PubMed  Google Scholar 

  44. Mallard EC, Williams CE, Johnston BM, Gunning MI, Davis S, Gluckman PD. Repeated episodes of umbilical cord occlusion in fetal sheep lead to preferential damage to the striatum and sensitize the heart to further insults. Pediatr Res. 1995;37(6): 707–713.

    Article  CAS  PubMed  Google Scholar 

  45. Nelson KB. Causative factors in cerebral palsy. Clin Obstet Gyne-col. 2008;51(4):749–762.

    Article  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. School of Women’s and Infants’ Health, The University of Western Australia, Crawley, WA, Australia

    Ilias Nitsos PhD, John P. Newnham MD & Timothy J. M. Moss PhD

  2. Department of Anatomy and Cell Biology, University of Melbourne, Parkville, Victoria, Australia

    Sandra M. Rees PhD

  3. Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia

    Richard Harding DSc

  4. The Ritchie Centre, Monash Institute of Medical Research & Department of Obstetrics and Gynaecology, Monash University, PO Box 5418, 3168, Clayton, VIC, Australia

    Ilias Nitsos PhD

Authors
  1. Ilias Nitsos PhD
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  2. John P. Newnham MD
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  3. Sandra M. Rees PhD
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  4. Richard Harding DSc
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  5. Timothy J. M. Moss PhD
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Correspondence to Timothy J. M. Moss PhD.

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Nitsos, I., Newnham, J.P., Rees, S.M. et al. The Impact of Chronic Intrauterine Inflammation on the Physiologic and Neurodevelopmental Consequences of Intermittent Umbilical Cord Occlusion in Fetal Sheep. Reprod. Sci. 21, 658–670 (2014). https://doi.org/10.1177/1933719111399928

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  • DOI: https://doi.org/10.1177/1933719111399928

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