Advertisement

Antiinflammatory Effect of N-Acetylcysteine Combined with Exogenous Surfactant in Meconium-Induced Lung Injury

  • P. Mikolka
  • J. Kopincova
  • L. Tomcikova Mikusiakova
  • P. Kosutova
  • A. Calkovska
  • D. MokraEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 934)

Abstract

Neonatal meconium aspiration syndrome (MAS) can be treated by exogenous surfactant (S). However, aspirated meconium initiates local inflammation and oxidation which may inactivate surfactant and reduce its action. This experimental study estimated whether combined use of surfactant and the antioxidant N-acetylcysteine (NAC) can enhance effectiveness of therapy. Meconium-instilled rabbits were non-treated (M), treated with monotherapies (M + S, M + NAC), combined therapy (M + S + NAC), or received saline instead of meconium (controls, C). Surfactant therapy consisted of two lung lavages (BAL) with diluted Curosurf (5 mg phospholipids/ml, 10 ml/kg) followed by undiluted Curosurf (100 mg phospholipids/kg). N-acetylcysteine (Acc Injekt, 10 mg/kg) was given intravenously in M + S + NAC group 10 min after surfactant therapy. Animals were oxygen-ventilated for additional 5 h. Then, differential white cell count in the blood (WBC) was determined. Left lung was saline-lavaged and differential cell count in BAL was determined. In right lung tissue, wet/dry weight ratio, oxidation markers (TBARS, 3NT) and interleukines (IL-2, IL-6, IL-13, and TNFα) using ELISA and RT-PCR were estimated. Combined S + NAC therapy significantly decreased W/D ratio, TBARS, 3NT, and IL, whereas the effect of monotherapies (either S or NAC) was less obvious. In conclusion, addition of NAC to surfactant treatment may enhance the therapeutic outcome in MAS.

Keywords

Antioxidant Inflammation Meconium aspiration syndrome N-Acetylcysteine Oxidative damage Surfactant 

Notes

Acknowledgements

Authors thank Chiesi Farmaceutici for a kind donation of Curosurf and D. Kuliskova, Z. Remisova, M. Petraskova, and M. Hutko for technical assistance. This study was supported by projects APVV-0435-11, APVV-15-0075, VEGA 1/0291/12, VEGA 1/0305/14, and also by the project ‘Biomedical Center Martin’ – ITMS code: 26220220187, co-financed from EU sources.

Conflicts of Interest

The authors declare no conflict of interest in association with this study.

References

  1. Anderson P (2008) Post-transcriptional control of cytokine production. Nat Immunol 9:353–359CrossRefPubMedGoogle Scholar
  2. Bhatia M, Moochhala S (2004) Role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome. J Pathol 202:145–156CrossRefPubMedGoogle Scholar
  3. Castellheim A, Pharo A, Fung M, Saugstad OD, Mollnes TE (2005) Complement C5a is a key mediator of meconium-induced neutrophil activation. Pediatr Res 57:242–247CrossRefPubMedGoogle Scholar
  4. Craig S, Lopez A, Hoskin D, Markham F (2005) Meconium inhibits phagocytosis and stimulates respiratory burst in alveolar macrophages. Pediatr Res 57:813–818CrossRefPubMedGoogle Scholar
  5. Cuzzocrea S, Mazzon E, Dugo L, Serraino I, Ciccolo A, Centorrino T, De Sarro A, Caputi AP (2001) Protective effects of n-acetylcysteine on lung injury and red blood cell modification induced by carrageenan in the rat. FASEB J 15:1187–1200CrossRefPubMedGoogle Scholar
  6. Dani C, Pratesi S (2013) Nitric oxide for the treatment of preterm infants with respiratory distress syndrome. Expert Opin Pharmacother 14:97–103CrossRefPubMedGoogle Scholar
  7. Dargaville PA, Mills JF, HeadleyBM CY, Coleman L, Loughnan PM, Morley CJ (2003) Therapeutic lung lavage in the piglet model of meconium aspiration syndrome. Am J Respir Crit Care Med 168:456–463CrossRefPubMedGoogle Scholar
  8. De Beaufort AJ, Bakker AC, van Tol MJ, Poorthuis BJ, Schrama AJ, Berger HM (2003) Meconium is a source of pro-inflammatory substances and can induce cytokine production in cultured A549 epithelial cells. Pediatr Res 54:491–495CrossRefPubMedGoogle Scholar
  9. Dodd S, Dean O, Copolov DL, Malhi GS, Berk M (2008) N-acetylcysteine for antioxidant therapy: pharmacology and clinical utility. Expert Opin Biol Ther 8:1955–1962CrossRefPubMedGoogle Scholar
  10. Grommes J, Soehnlein O (2011) Contribution of neutrophils to acute lung injury. Mol Med 17:293–307CrossRefPubMedGoogle Scholar
  11. Kääpä P, Soukka H (2008) Phospholipase A2 in meconium-induced lung injury. J Perinatol 28:120–122CrossRefGoogle Scholar
  12. Kattan J, González A, Becker P, Faunes M, Estay A, Toso P, Urzúa S, Castillo A, Fabres J (2013) Survival of newborn infants with severe respiratory failure before and after establishing an extracorporeal membrane oxygenation program. Pediatr Crit Care Med 14:876–883CrossRefPubMedGoogle Scholar
  13. Langley SC, Kelly FJ (1993) N-acetylcysteine ameliorates hyperoxic lung injury in the preterm guinea pig. Biochem Pharmacol 45:841–846CrossRefPubMedGoogle Scholar
  14. Mikolka P, Mokra D, Kopincova J, Tomciková-Mikusiakova L, Calkovska A (2013) Budesonide added to modified porcine surfactant Curosurf may additionally improve the lung functions in meconium aspiration syndrome. Physiol Res 12:191–200Google Scholar
  15. Nkadi PO, Merritt TA, Pillers DA (2009) An overview of pulmonary surfactant in the neonate: genetics, metabolism, and the role of surfactant in health and disease. Mol Genet Metab 97:95–101CrossRefPubMedPubMedCentralGoogle Scholar
  16. Østerholt HC, Dannevig I, Wyckoff MH, Liao J, Akgul Y, Ramgopal M, Mija DS, Cheong N, Longoria C, Mahendroo M, Nakstad B, Saugstad OD, Savani RC (2012) Antioxidant protects against increases in low molecular weight hyaluronan and inflammation in asphyxiated newborn pigs resuscitated with 100 % oxygen. PLoS ONE 7:e38839CrossRefPubMedPubMedCentralGoogle Scholar
  17. Paterson RL, Galley HF, Webster NR (2003) The effect of N-acetylcysteine on nuclear factor-kappa B activation, interleukin-6, interleukin-8, and intercellular adhesion molecule-1 expression in patients with sepsis. Crit Care Med 31:2574–2578CrossRefPubMedGoogle Scholar
  18. Roper JM, Mazzatti DJ, Watkins RH, Maniscalco WM, Keng PC, O’Reilly MA (2004) In vivo exposure to hyperoxia induces DNA damage in a population of alveolar type II epithelial cells. Am J Physiol Lung Cell Mol Physiol 286:1045–1054CrossRefGoogle Scholar
  19. Rushworth GF, Megson IL (2014) Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits. Pharmacol Ther 141:150–159CrossRefPubMedGoogle Scholar
  20. Salvesen B, Stenvik J, Rossetti C, Saugstad OD, Espevik T, Mollnes TE (2010) Meconium-induced release of cytokines is mediated by the TRL4/MD-2 complex in a CD14-dependent manner. Mol Immunol 47:1226–1234CrossRefPubMedGoogle Scholar
  21. Soltan-Sharifi MS, Mojtahedzadeh M, Najafi A, Reza Khajavi M, Reza Rouini M, Moradi M, Mohammadirad A, Abdollahi M (2007) Improvement by N-acetylcysteine of acute respiratory distress syndrome through increasing intracellular glutathione, and extracellular thiol molecules and anti-oxidant power: evidence for underlying toxicological mechanisms. Hum Exp Toxicol 26:697–703CrossRefPubMedGoogle Scholar
  22. Soukka HR, Ahotupa M, Ruutu M, Kääpä PO (2002) Meconium stimulates neutrophil oxidative burst. Am J Perinatol 19:279–284CrossRefPubMedGoogle Scholar
  23. Wiswell TE, Knight GR, Finer NN et al (2002) A multicenter, randomized, controlled trial comparing surfaxin (Lucinactant) lavage with standard care for treatment of meconium aspiration syndrome. Pediatrics 109:1081–1087CrossRefPubMedGoogle Scholar
  24. Zafarullah M, Li WQ, Sylvester J, Ahmad M (2003) Molecular mechanisms of N-acetylcysteine actions. Cell Mol Life Sci 60:6–20CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • P. Mikolka
    • 1
  • J. Kopincova
    • 1
  • L. Tomcikova Mikusiakova
    • 1
  • P. Kosutova
    • 1
  • A. Calkovska
    • 1
  • D. Mokra
    • 1
    Email author
  1. 1.Biomedical Center Martin, Division of Respirology and Department of Physiology, Jessenius School of Medicine in MartinComenius University in BratislavaMartinSlovakia

Personalised recommendations