Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Antenatal inflammation and lung injury: prenatal origin of neonatal disease

Journal of Perinatology volume 28, pages S21–S27 (2008)Cite this article

Abstract

Introduction:

Antenatal inflammation in utero may be associated with lung injury and subsequent aberrant lung development resulting in bronchopulmonary dysplasia (BPD). BPD has become a developmental disease with a uniform arrest in lung development.

Study Design:

The role of antenatal inflammation in the induction of lung injury was explored in a sheep model suitable for the study of lung development with respect to human development. Chorioamnionitis was induced by a single injection of endotoxin into the amniotic cavity under ultrasound guidance.

Result:

Endotoxin-induced chorioamnionitis caused a cascade of lung injury, pulmonary inflammation and remodeling in the fetal lung similar to lung injury previously described in adult animal models. The structural changes in the fetal lung after chorioamnionitis showed little to no fibrosis and alveolar/microvascular simplification similar to new BPD. The identified cytokine networks and regulators may explain the absence of fibrosis and lung simplification after strictly intra-uterine inflammation.

Conclusion:

The mechanisms of antenatal inflammation in the fetal lung were multifactorial and could be antenatally modulated. Fetal pulmonary inflammation was temporarily suppressed by maternal glucocorticoid therapy. However, pulmonary inflammation could be augmented postnatally by resuscitation, oxygen toxicity, mechanical ventilation and pulmonary and systemic infection, which opens a broad window of clinical options.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Northway WH, Rosan RC, Porter DY . Pulmonary disease following respirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia. N Engl J Med 1967; 276: 357–368.

    Article  Google Scholar 

  2. Northway WH, Moss RB, Carlisle KB, Parker BR, Popp RL, Pitlick PT et al. Late pulmonary sequelae of bronchopulmonary dysplasia. N Engl J Med 1990; 323: 1793–1799.

    Article  Google Scholar 

  3. Husain AN, Siddiqui NH, Stocker JT . Pathology of arrested acinar development in postsurfactant bronchopulmonary dysplasia. Hum Pathol 1998; 29: 710–717.

    Article  CAS  Google Scholar 

  4. Jobe AH . The new BPD: an arrest of lung development. Pediatr Res 1999; 46: 641–643.

    Article  CAS  Google Scholar 

  5. Jobe AH, Bancalari E . Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001; 163: 1723–1729.

    Article  CAS  Google Scholar 

  6. Burri PH . Structural aspects of postnatal lung development—alveolar formation and growth. Biol Neonate 2006; 89: 313–322.

    Article  Google Scholar 

  7. Speer CP . Inflammation and bronchopulmonary dysplasia: a continuing story. Semin Fetal Neonatal Med 2006; 11: 354–362.

    Article  Google Scholar 

  8. Schmidt B, Cao L, Mackensen-Haen S, Kendziorra H, Klingel K, Speer CP . Chorioamnionitis and inflammation of the fetal lung. Am J Obstet Gynecol 2001; 185: 173–177.

    Article  CAS  Google Scholar 

  9. Groneck P, Schmale J, Soditt V, Stutzer H, Gotze-Speer B, Speer CP . Bronchoalveolar inflammation following airway infection in preterm infants with chronic lung disease. Pediatr Pulmonol 2001; 31: 331–338.

    Article  CAS  Google Scholar 

  10. Groneck P, Gotze-Speer B, Oppermann M, Eiffert H, Speer CP . 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 1994; 93: 712–718.

    CAS  PubMed  Google Scholar 

  11. Speer CP, Ruess D, Harms K, Herting E, Gefeller O . Neutrophil elastase and acute pulmonary damage in neonates with severe respiratory distress syndrome. Pediatrics 1993; 91: 794–799.

    CAS  PubMed  Google Scholar 

  12. Groneck P, Speer CP . Inflammatory mediators and bronchopulmonary dysplasia. Arch Dis Child Fetal Neonatal Ed 1995; 73: F1–F3.

    Article  CAS  Google Scholar 

  13. Costeloe K, Hennessy E, Gibson AT, Marlow N, Wilkinson AR . The EPICure study: outcomes to discharge from hospital for infants born at the threshold of viability. Pediatrics 2000; 106: 659–671.

    Article  CAS  Google Scholar 

  14. Watterberg KL, Gerdes JS, Cole CH, Aucott SW, Thilo EH, Mammel MC et al. Prophylaxis of early adrenal insufficiency to prevent bronchopulmonary dysplasia: a multicenter trial. Pediatrics 2004; 114: 1649–1657.

    Article  Google Scholar 

  15. Kent A, Dahlstrom JE . Chorioamnionitis/funisitis and the development of bronchopulmonary dysplasia. J Paediatr Child Health 2004; 40: 356–359.

    Article  CAS  Google Scholar 

  16. Stoll BJ, Hansen N, Fanaroff AA, Wright LL, Carlo WA, Ehrenkranz RA et al. Changes in pathogens causing early-onset sepsis in very-low-birth-weight infants. N Engl J Med 2002; 347: 240–247.

    Article  Google Scholar 

  17. Watterberg KL, Demers LM, Scott SM, Murphy S . Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops. Pediatrics 1996; 97: 210–215.

    CAS  PubMed  Google Scholar 

  18. Van Marter LJ, Dammann O, Allred EN, Leviton A, Pagano M, Moore M et al. Chorioamnionitis, mechanical ventilation, and postnatal sepsis as modulators of chronic lung disease in preterm infants. J Pediatr 2002; 140: 171–176.

    Article  Google Scholar 

  19. Andrews WW, Goldenberg RL, Faye-Petersen O, Cliver S, Goepfert AR, Hauth JC . The Alabama Preterm Birth Study: polymorphonuclear and mononuclear cell placental infiltrations, other markers of inflammation, and outcomes in 23- to 32-week preterm newborn infants. Am J Obstet Gynecol 2006; 195: 803–808.

    Article  CAS  Google Scholar 

  20. Jobe AH, Kramer BW, Moss TJ, Newnham JP, Ikegami M . Decreased indicators of lung injury with continuous positive expiratory pressure in preterm lambs. Pediatr Res 2002; 52: 387–392.

    Article  Google Scholar 

  21. Speer CP, Harms K, Herting E, Neumann N, Curstedt T, Robertson B . Early versus late surfactant replacement therapy in severe respiratory distress syndrome. Lung 1990; 168 (suppl): 870–876.

    Article  Google Scholar 

  22. Ramanathan R, Rasmussen MR, Gerstmann DR, Finer N, Sekar K . A randomized, multicenter masked comparison trial of poractant alfa (Curosurf) versus beractant (Survanta) in the treatment of respiratory distress syndrome in preterm infants. Am J Perinatol 2004; 21: 109–119.

    Article  Google Scholar 

  23. Zimmermann LJ, Janssen DJ, Tibboel D, Hamvas A, Carnielli VP . Surfactant metabolism in the neonate. Biol Neonate 2005; 87: 296–307.

    Article  CAS  Google Scholar 

  24. Epaud R, Ikegami M, Whitsett JA, Jobe AH, Weaver TE, Akinbi HT . Surfactant protein B inhibits endotoxin-induced lung inflammation. Am J Respir Cell Mol Biol 2003; 28: 373–378.

    Article  CAS  Google Scholar 

  25. Ikegami M, Whitsett JA, Martis PC, Weaver TE . Reversibility of lung inflammation caused by SP-B deficiency. Am J Physiol Lung Cell Mol Physiol 2005; 289: L962–L970.

    Article  CAS  Google Scholar 

  26. van Iwaarden JF, Claassen E, Jeurissen SH, Haagsman HP, Kraal G . Alveolar macrophages, surfactant lipids, and surfactant protein B regulate the induction of immune responses via the airways. Am J Respir Cell Mol Biol 2001; 24: 452–458.

    Article  CAS  Google Scholar 

  27. Baur FM, Brenner B, Goetze-Speer B, Neu S, Speer CP . Natural porcine surfactant (Curosurf) down-regulates mRNA of tumor necrosis factor-alpha (TNF-alpha) and TNF-alpha type II receptor in lipopolysaccharide-stimulated monocytes. Pediatr Res 1998; 44: 32–36.

    Article  CAS  Google Scholar 

  28. Speer CP, Gotze B, Curstedt T, Robertson B . Phagocytic functions and tumor necrosis factor secretion of human monocytes exposed to natural porcine surfactant (Curosurf). Pediatr Res 1991; 30: 69–74.

    Article  CAS  Google Scholar 

  29. Kramer BW, Jobe AH, Ikegami M . Monocyte function in preterm, term, and adult sheep. Pediatr Res 2003; 54: 52–57.

    Article  Google Scholar 

  30. Akei H, Whitsett JA, Buroker M, Ninomiya T, Tatsumi H, Weaver TE et al. Surface tension influences cell shape and phagocytosis in alveolar macrophages. Am J Physiol Lung Cell Mol Physiol 2006; 291: L572–L579.

    Article  CAS  Google Scholar 

  31. Pringle KC . Human fetal lung development and related animal models. Clin Obstet Gynecol 1986; 29: 502–513.

    Article  CAS  Google Scholar 

  32. Kramer BW, Kramer S, Ikegami M, Jobe AH . Injury, inflammation, and remodeling in fetal sheep lung after intra-amniotic endotoxin. Am J Physiol Lung Cell Mol Physiol 2002; 283: L452–L459.

    Article  CAS  Google Scholar 

  33. Kramer BW, Moss TJ, Willet KE, Newnham JP, Sly PD, Kallapur SG et al. Dose and time response after intraamniotic endotoxin in preterm lambs. Am J Respir Crit Care Med 2001; 164: 982–988.

    Article  CAS  Google Scholar 

  34. Abman SH . Bronchopulmonary dysplasia: ‘a vascular hypothesis’. Am J Respir Crit Care Med 2001; 164: 1755–1756.

    Article  CAS  Google Scholar 

  35. Kramer BW, Kaemmerer U, Kapp M, Herbst D, Marx A, Berg D et al. Decreased expression of angiogenic factors in placentas with chorioamnionitis after preterm birth. Pediatr Res 2005; 58: 607–612.

    Article  CAS  Google Scholar 

  36. Kallapur SG, Jobe AH, Ikegami M, Bachurski CJ . Increased IP-10 and MIG expression after intra-amniotic endotoxin in preterm lamb lung. Am J Respir Crit Care Med 2003; 167: 779–786.

    Article  Google Scholar 

  37. Kallapur SG, Bachurski CJ, Le Cras TD, Joshi SN, Ikegami M, Jobe AH . Vascular changes after intra-amniotic endotoxin in preterm lamb lungs. Am J Physiol Lung Cell Mol Physiol 2004; 287: L1178–L1185.

    Article  CAS  Google Scholar 

  38. Willet KE, Jobe AH, Ikegami M, Newnham J, Brennan S, Sly PD . Antenatal endotoxin and glucocorticoid effects on lung morphometry in preterm lambs. Pediatr Res 2000; 48: 782–788.

    Article  CAS  Google Scholar 

  39. Kunzmann S, Speer CP, Jobe AH, Kramer BW . Antenatal inflammation induced TGF-{beta}1 but suppressed CTGF in preterm lungs. Am J Physiol Lung Cell Mol Physiol 2007; 292: L223–L231.

    Article  CAS  Google Scholar 

  40. McDevitt TM, Gonzales LW, Savani RC, Ballard PL . Role of endogenous TGF-beta in glucocorticoid-induced lung type II cell differentiation. Am J Physiol Lung Cell Mol Physiol 2007; 292: L249–L257.

    Article  CAS  Google Scholar 

  41. Friedrichsen S, Heuer H, Christ S, Winckler M, Brauer D, Bauer K et al. CTGF expression during mouse embryonic development. Cell Tissue Res 2003; 312: 175–188.

    CAS  PubMed  Google Scholar 

  42. Kwong KY, Niang S, Literat A, Zhu NL, Ramanathan R, Jones CA et al. Expression of transforming growth factor beta (TGF-b1) by human preterm lung inflammatory cells. Life Sci 2006; 79: 2349–2356.

    Article  CAS  Google Scholar 

  43. Coalson JJ . Pathology of new bronchopulmonary dysplasia. Semin Neonatol 2003; 8: 73–81.

    Article  Google Scholar 

  44. Bachurski CJ, Ross GF, Ikegami M, Kramer BW, Jobe AH . Intra-amniotic endotoxin increases pulmonary surfactant proteins and induces SP-B processing in fetal sheep. Am J Physiol Lung Cell Mol Physiol 2001; 280: L279–L285.

    Article  CAS  Google Scholar 

  45. Jobe AH, Newnham JP, Willet KE, Moss TJ, Gore Ervin M, Padbury JF et al. Endotoxin-induced lung maturation in preterm lambs is not mediated by cortisol. Am J Respir Crit Care Med 2000; 162: 1656–1661.

    Article  CAS  Google Scholar 

  46. Jobe AH, Newnham JP, Willet KE, Sly P, Ervin MG, Bachurski C et al. Effects of antenatal endotoxin and glucocorticoids on the lungs of preterm lambs. Am J Obstet Gynecol 2000; 182: 401–408.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  48. Duncan JR, Cock ML, Scheerlinck JP, Westcott KT, McLean C, Harding R et al. White matter injury after repeated endotoxin exposure in the preterm ovine fetus. Pediatr Res 2002; 52: 941–949.

    Article  CAS  Google Scholar 

  49. Kallapur SG, Willet KE, Jobe AH, Ikegami M, Bachurski CJ . Intra-amniotic endotoxin: chorioamnionitis precedes lung maturation in preterm lambs. Am J Physiol Lung Cell Mol Physiol 2001; 280: L527–L536.

    Article  CAS  Google Scholar 

  50. Moss TJ, Nitsos I, Kramer BW, Ikegami M, Newnham JP, Jobe AH . Intra-amniotic endotoxin induces lung maturation by direct effects on the developing respiratory tract in preterm sheep. Am J Obstet Gynecol 2002; 187: 1059–1065.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  52. Wilson TC, Bachurski CJ, Ikegami M, Jobe AH, Kallapur SG . Pulmonary and systemic induction of SAA3 after ventilation and endotoxin in preterm lambs. Pediatr Res 2005; 58: 1204–1209.

    Article  CAS  Google Scholar 

  53. Newnham JP, Kallapur SG, Kramer BW, Moss TJ, Nitsos I, Ikegami M et al. Betamethasone effects on chorioamnionitis induced by intra-amniotic endotoxin in sheep. Am J Obstet Gynecol 2003; 189: 1458–1466.

    Article  CAS  Google Scholar 

  54. Kramer BW, Jobe AH . The clever fetus: responding to inflammation to minimize lung injury. Biol Neonate 2005; 88: 202–207.

    Article  Google Scholar 

  55. Dollner H, Vatten L, Halgunset J, Rahimipoor S, Austgulen R . Histologic chorioamnionitis and umbilical serum levels of pro-inflammatory cytokines and cytokine inhibitors. BJOG 2002; 109: 534–539.

    Article  Google Scholar 

  56. Bry K, Lappalainen U, Hallman M . Intraamniotic interleukin-1 accelerates surfactant protein synthesis in fetal rabbits and improves lung stability after premature birth. J Clin Invest 1997; 99: 2992–2999.

    Article  CAS  Google Scholar 

  57. Willet KE, Kramer BW, Kallapur SG, Ikegami M, Newnham JP, Moss TJ et al. Intra-amniotic injection of IL-1 induces inflammation and maturation in fetal sheep lung. Am J Physiol Lung Cell Mol Physiol 2002; 282: L411–L420.

    Article  CAS  Google Scholar 

  58. Sosenko IR, Kallapur SG, Nitsos I, Moss TJ, Newnham JP, Ikegami M et al. IL-1alpha causes lung inflammation and maturation by direct effects on preterm fetal lamb lungs. Pediatr Res 2006; 60: 294–298.

    Article  CAS  Google Scholar 

  59. Ikegami M, Moss TJ, Kallapur SG, Mulrooney N, Kramer BW, Nitsos I et al. Minimal lung and systemic responses to TNF-alpha in preterm sheep. Am J Physiol Lung Cell Mol Physiol 2003; 285: L121–L129.

    Article  CAS  Google Scholar 

  60. Kallapur SG, Moss TJ, Ikegami M, Jasman RL, Newnham JP, Jobe AH . Recruited inflammatory cells mediate endotoxin-induced lung maturation in preterm fetal lambs. Am J Respir Crit Care Med 2005; 172: 1315–1321.

    Article  Google Scholar 

  61. Vayrynen O, Glumoff V, Hallman M . Regulation of surfactant proteins by LPS and proinflammatory cytokines in fetal and newborn lung. Am J Physiol Lung Cell Mol Physiol 2002; 282: L803–L810.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  63. Halliday HL . Evidence-based neonatal care. Best Pract Res Clin Obstet Gynaecol 2005; 19: 155–166.

    Article  Google Scholar 

  64. Newnham JP, Moss TJ, Padbury JF, Willet KE, Ikegami M, Ervin MG et al. The interactive effects of endotoxin with prenatal glucocorticoids on short-term lung function in sheep. Am J Obstet Gynecol 2001; 185: 190–197.

    Article  CAS  Google Scholar 

  65. Kallapur SG, Kramer BW, Moss TJ, Newnham JP, Jobe AH, Ikegami M et al. Maternal glucocorticoids increase endotoxin-induced lung inflammation in preterm lambs. Am J Physiol Lung Cell Mol Physiol 2003; 284: L633–L642.

    Article  CAS  Google Scholar 

  66. Kramer BW, Ikegami M, Moss TJ, Nitsos I, Newnham JP, Jobe AH . Antenatal betamethasone changes cord blood monocyte responses to endotoxin in preterm lambs. Pediatr Res 2004; 55: 764–768.

    Article  CAS  Google Scholar 

  67. Ikegami M, Jobe AH . Postnatal lung inflammation increased by ventilation of preterm lambs exposed antenatally to Escherichia coli endotoxin. Pediatr Res 2002; 52: 356–362.

    Article  Google Scholar 

  68. Speer CP . Pre- and postnatal inflammatory mechanisms in chronic lung disease of preterm infants. Paediatr Respir Rev 2004; 5 (suppl A): S241–S244.

    Article  Google Scholar 

  69. Jobe AH, Ikegami M . Antenatal infection/inflammation and postnatal lung maturation and injury. Respir Res 2001; 2: 27–32.

    Article  CAS  Google Scholar 

  70. Kramer BW, Ikegami M, Jobe AH . Intratracheal endotoxin causes systemic inflammation in ventilated preterm lambs. Am J Respir Crit Care Med 2002; 165: 463–469.

    Article  Google Scholar 

  71. Gille C, Spring B, Tewes LJ, Loffler J, Dannecker GE, Hoffmann MK et al. Diminished response to interleukin-10 and reduced antibody-dependent cellular cytotoxicity of cord blood monocyte-derived macrophages. Pediatr Res 2006; 60: 152–157.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics, Academisch ziekenhuis Maastricht, Maastricht, The Netherlands

    B W Kramer

Authors
  1. B W Kramer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B W Kramer.

Additional information

Disclosure

Nothing to declare.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kramer, B. Antenatal inflammation and lung injury: prenatal origin of neonatal disease. J Perinatol 28 (Suppl 1), S21–S27 (2008). https://doi.org/10.1038/jp.2008.46

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/jp.2008.46

Keywords

This article is cited by

Search

Advanced search

Quick links