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:

Activation of Toll-like receptors in meconium aspiration syndrome

Journal of Perinatology volume 38, pages 137–141 (2018)Cite this article

Subjects

Abstract

Objective:

Meconium aspiration syndrome (MAS) is a common cause of neonatal morbidity and mortality. Incomplete understanding of the pathogenesis of MAS has hindered the development of specific therapies. We hypothesized that activation of Toll-like receptors (TLRs) might play a role in the pathogenesis of MAS. The present study evaluated the expression of TLR 1, 4, 7, 8 and 9 in neonates with MAS.

Study Design:

The study included 39 neonates with MAS and 17 healthy gestational age-matched neonates as controls. Neonates with maternal chorioamnionitis, perinatal asphyxia, sepsis and congenital malformations were excluded. Good-quality total RNA from umbilical cord blood was reverse transcribed to prepare cDNA using Bio-Rad reverse transcription kit. This cDNA was used to study the expression status of TLR 1, 4, 7, 8 and 9 by real-time quantitative polymerase chain reaction.

Results:

Compared with controls, TLR1 and TLR4 were highly expressed, TLR9 was moderately expressed, TLR7 was weakly expressed and TLR8 expression was neutral in neonates with MAS. Within the MAS group, no difference in TLR expression was observed with respect to consistency of meconium, severity of the disease, oxygenation index and outcome.

Conclusion:

There is activation of TLRs in neonates with MAS. We speculate that these TLRs probably act as endogenous ligands for various components of meconium that initiate the inflammatory cascade of MAS and contribute to its pathogenesis.

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
Figure 4
Figure 5

Similar content being viewed by others

Article 16 February 2023

Evdokia Dimitriadis, Daniel L. Rolnik, … Ellen Menkhorst

References

  1. Wiswell TE, Tuggle JM, Turner BS . Meconium aspiration syndrome: have we made a difference? Pediatrics 1990; 85: 715–721.

    CAS  PubMed  Google Scholar 

  2. Nangia S, Pal MM, Saili A, Gupta U . Effect of intrapartum oropharyngeal (IP-OP) suction on meconium aspiration syndrome (MAS) in developing country: A RCT. Resuscitation 2015; 97: 83–87.

    Article  Google Scholar 

  3. Wiswell TE, Gannon CM, Jacob J . Delivery room management of the apparently vigorous meconium stained neonate: results of multicentres, international collaborative trial. Pediatrics 2000; 105: 1–7.

    Article  CAS  Google Scholar 

  4. Vain NE, Sozyld EG, Wiswell TE . Oropharayngeal and nasopharyngeal suctioning of the meconium stained neonates before delivery of their shoulders: multicentre, randomized controlled trial. Lancet 2004; 364: 597–602. Comments in Lancet 2004; 364:560.

    Article  Google Scholar 

  5. Fischer C, Rybakowski C, Ferdynus C, Sagot P, Gouyon JB . A population-based study of meconium aspiration syndrome in neonates born between 37 and 43 weeks of gestation. Int J Pediatr 2012; 2012: 321545.

    Article  CAS  Google Scholar 

  6. van Ierland Y, de Beaufort AJ . Why does meconium cause meconium aspiration syndrome? Current concepts of MAS pathophysiology. Early Hum Dev 2009; 85: 617–620.

    Article  CAS  Google Scholar 

  7. Vidyasagar D, Zagariya A . Studies of meconium-induced lung injury: inflammatory cytokine expression and apoptosis. J Perinatol 2008; 28: S102–S107.

    Article  CAS  Google Scholar 

  8. Mollnes TE, Castellheim A, Lindenskov PH, Salvesen B, Saugstad OD . The role of complement in meconium aspiration syndrome. J Perinatol 2008; 28: S116–S119.

    Article  CAS  Google Scholar 

  9. Zagariya A, Bhat R, Uhal B, Navale S, Freidine M, Vidyasagar D . Cell death and lung cell histology in meconium aspirated newborn rabbit lung. Eur J Pediatr 2000; 159: 819–826.

    Article  CAS  Google Scholar 

  10. Usta IM, Sibai BM, Mercer BM . Use of maternal plasma level of zinc-coproporphyrin in the prediction of intrauterine passage of meconium: a pilot study. J Matern Fetal Med 2000; 9: 201–203.

    CAS  PubMed  Google Scholar 

  11. Mazor M, Furman B, Wiznitzer A, Shoham-Vardi I, Cohen J, Ghezzi F . Maternal and perinatal outcome of patients with preterm labor and meconium-stained amniotic fluid. Obstet Gynecol 1995; 86: 830–833.

    Article  CAS  Google Scholar 

  12. Wiswell TE, Henley MA . Intratracheal suctioning, systemic infection, and the meconium aspiration syndrome. Pediatrics 1992; 89: 203–206.

    CAS  PubMed  Google Scholar 

  13. Lin HC, Su BH, Tsai CH, Lin TW, Yeh TF . Role of antibiotics in management of non-ventilated cases of meconium aspiration syndrome without risk factors for infection. Biol Neonate 2005; 87: 51–55.

    Article  Google Scholar 

  14. Salvesen B, Fung M, Saugstad OD, Mollnes TE . Role of complement and CD14 in meconium-induced cytokine formation. Pediatrics 2008; 121: e496–e505.

    Article  Google Scholar 

  15. Salvesen B, Stenvik J, Rossetti C, Saugstad OD, Espevik T, Mollnes TE . Meconium-induced release of cytokines is mediated by the TRL4/MD-2 complex in a CD14-dependent manner. Mol Immunol 2010; 47: 1226–1234.

    Article  CAS  Google Scholar 

  16. Lindenskov PH, Castellheim A, Saugstad OD, Mollnes TE . Meconium aspiration syndrome: possible pathophysiological mechanisms and future potential therapies. Neonatology 2015; 107: 225–230.

    Article  Google Scholar 

  17. Kopincova J, Calkovska A . Meconium-induced inflammation and surfactant inactivation: specifics of molecular mechanisms. Pediatr Res 2016; 79: 514–521.

    Article  CAS  Google Scholar 

  18. Koga K, Mor G . Expression and function of toll-like receptors at the maternal-fetal interface. Reprod Sci 2008; 15: 231–242.

    Article  CAS  Google Scholar 

  19. Takeda K, Kaisho T, Akira S . Toll-like receptors. Annu Rev Immunol 2003; 21: 335–376.

    Article  CAS  Google Scholar 

  20. Seong SY, Matzinger P . Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses. Nat Rev Immunol 2004; 4: 469–478.

    Article  CAS  Google Scholar 

  21. Sandor F, Buc M . Toll-like receptors. I. Structure, function and their ligands. Folia Biol (Praha) 2005; 51: 148–156.

    CAS  Google Scholar 

  22. Kumar H, Kawai T, Akira S . Pathogen recognition in the innate immune response. Biochem J 2009; 420: 1–16.

    Article  CAS  Google Scholar 

  23. Swarnam K, Soraisham AS, Sivanandan S . Advances in the management of meconium aspiration syndrome. Int J Pediatr 2012; 2012: 359571.

    Article  Google Scholar 

  24. Cleary GM, Wiswell TE . Meconium-stained amniotic fluid and the meconium aspiration syndrome. An update. Pediatr Clin North Am 1998; 45: 511–529.

    Article  CAS  Google Scholar 

  25. Kattwinkel J, Perlman JM, Aziz K, Colby C, Fairchild K, Gallagher J et al. American Heart Association. Neonatal resuscitation: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Pediatrics 2010; 126: e1400–e1413.

    Article  Google Scholar 

  26. Ahanya SN, Lakshmanan J, Morgan BL, Ross MG . Meconium passage in utero: mechanisms, consequences, and management. Obstet Gynecol Surv 2005; 60: 45–56.

    Article  Google Scholar 

  27. Righetti C, Peroni DG, Pietrobelli A, Zancanaro C . Proton nuclear magnetic resonance analysis of meconium composition in newborns. J Pediatr Gastroenterol Nutr 2003; 36: 498–501.

    Article  CAS  Google Scholar 

  28. Ran-Ressler RR, Devapatla S, Lawrence P, Brenna JT . Branched chain fatty acids are constituents of the normal healthy newborn gastrointestinal tract. Pediatr Res 2008; 64: 605–609.

    Article  CAS  Google Scholar 

  29. Zagariya A, Bhat R, Chari G, Uhal B, Navale S, Vidyasagar D . Apoptosis of airway epithelial cells in response to meconium. Life Sci 2005; 76: 1849–1858.

    Article  CAS  Google Scholar 

  30. Castellheim A, Lindenskov PH, Pharo A, Fung M, Saugstad OD, Mollnes TE . Meconium is a potent activator of complement in human serum and in piglets. Pediatr Res 2004; 55: 310–318.

    Article  CAS  Google Scholar 

  31. Medzhitov R, Janeway C Jr . The Toll receptor family and microbial recognition. Trends Microbiol 2000; 8: 452–456.

    Article  CAS  Google Scholar 

  32. Beutler B, Rietschel ET . Innate immune sensing and its roots, the story of endotoxin. Nat Rev Immunol 2003; 3: 169–176.

    Article  CAS  Google Scholar 

  33. Smiley ST, King JA, Hancock WW . Fibrinogen stimulates macrophage chemokine secretion through toll like receptor 4. J Immunol 2001; 167: 2887–2894.

    Article  CAS  Google Scholar 

  34. Zhang X, Mosser DM . Macrophage activation by endogenous danger signals. J Pathol 2008; 214: 161–178.

    Article  CAS  Google Scholar 

  35. Lotze MT, Zeh HJ, Rubartelli A, Sparvero LJ, Amoscato AA, Washburn NR et al. The grateful dead: damage associated molecular pattern molecules and reduction/oxidation regulate immunity. Immunol Rev 2007; 220: 60–81.

    Article  CAS  Google Scholar 

  36. Levy RM, Prince JM, Yang R, Mollen KP, Liao H, Watson GA et al. Systemic inflammation and remote organ damage following bilateral femur fracture requires Toll-like receptor 4. Am J Physiol Regul Integr Comp Physiol 2006; 291: R970–R976.

    Article  CAS  Google Scholar 

  37. Gay NJ, Gangloff M . Structure and function of Toll receptors and their ligands. Annu Rev Biochem 2007; 76: 141–165.

    Article  CAS  Google Scholar 

  38. Salvesen B, Nielsen EW, Harboe M, Saugstad OD, Mollnes TE . Mechanisms of complement activation and effects of C1-inhibitor on the meconium-induced inflammatory reaction in human cord blood. Mol Immunol 2009; 46: 688–694.

    Article  CAS  Google Scholar 

  39. Mollnes TE, Saugstad OD. Methods and compositions for the treatment of meconium aspiration syndrome. US 20070065433 A1. Available at https://www.google.tl/patents/US20070065433 (accessed on 22 August 2017).

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics, Neonatal Unit, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India

    V Anand, S Basu, B D Bhatia & A Kumar

  2. Department of Molecular and Human Genetics, Institute of Science, Banaras Hindu University, Varanasi, India

    S S Yadav & G Narayan

Authors
  1. V Anand
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Basu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S S Yadav
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G Narayan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B D Bhatia
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A Kumar.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Journal of Perinatology website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Anand, V., Basu, S., Yadav, S. et al. Activation of Toll-like receptors in meconium aspiration syndrome. J Perinatol 38, 137–141 (2018). https://doi.org/10.1038/jp.2017.169

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/jp.2017.169

This article is cited by

Search

Advanced search

Quick links