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Mechanisms of bilirubin toxicity

  • Living Pediatrics Symposium in Honour of the 80th Birthday of Professor E. Rossi, Berne, Switzerland
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Abstract

Possible mechanisms of bilirubin toxicity on the brain and lung were studied in animal experiments and in vitro. The uptake of tyrosine as precursor of dopamine in rat synaptosomes was evaluated to study the role of different bilirubin concentrations on synaptic neurotransmission. The results of this study show a statistically significant correlation between bilirubin levels and tyrosine uptake, supporting the hypothesis that the effect of bilirubin on neuronal excitability is dose-dependent. Concerning bilirubin toxicity on the lung, we studied the effect of different bilirubin concentrations on surface activity of modified natural surfactant (Curosurf) and synthetic surfactant (Exosurf), both in current clinical use for treatment of neonatal respiratory distress syndrome. Surface activity of Curosurf and Exosurf was investigated with the captive bubble surfactometer. The results of this study show that bilirubin impairs, in vitro, the surface tension activity of natural surfactant in a dose dependent manner and has no effect on surface tension activity of artificial surfactant. These data suggest that bilirubin interferes with surfactant proteins SP-B and/or SP-C, thus impairing surfactant activity at the air-liquid interface. We conclude that bilirubin shows its toxic effect reacting with different biological systems in a dose-dependent fashion.

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Abbreviations

CBS :

captive bubble surfactometer

HRP :

horseradish peroxidase

RDS :

respiratory distress syndrome

UCBC :

unconjugated bilirubin

References

  1. Leonard M, Zakim D (1989) The interactions of bilirubin with model and biological membranes. J Biol Chem 264: 5648–5652

    PubMed  Google Scholar 

  2. Kawai K, Cowger ML (1981) Effect of bilirubin on ATPase activity of human erythrocyte membranes. Res Commun Chem Pathol Pharmacol 32: 123–135

    PubMed  Google Scholar 

  3. Brodersen B (1979) Bilirubin: solubility and interaction with albumin and phospholipid. J Biol Chem 254: 2364–2369

    PubMed  Google Scholar 

  4. Cashore WJ (1990) The neurotoxicity of bilirubin. Clin Perinatol 17: 437–447

    PubMed  Google Scholar 

  5. Macgregor D, Whitfield MF, Delcati D, Roland E (1989) Bilirubin and kernicterus in infants < 1000 grams birth weight: a follow-up study. Pediatr Res 25: 257A

    Google Scholar 

  6. Connolly AM, Volpe JJ (1990) Clinical features of bilirubin encephalopathy. Clin Perinatol 17: 371–379

    PubMed  Google Scholar 

  7. Vazquez J, Garcia-Calvo M, Valdivieaso F, Mayor F (1989) Interaction of bilirubin with the synaptosomal plasma membrane. J Biol Chem 263: 1255–1265

    Google Scholar 

  8. Hansen TWR, Bratlid D (1986) Bilirubin and brain toxicity. Acta Paediatr Scand 75: 513–522

    PubMed  Google Scholar 

  9. Gartner LM, Snyder RN, Chabon RS, Bernstein J (1970) Kernicterus: high incidence in premature infants with low serum bilirubin concentrations. Pediatrics 45: 906–917

    PubMed  Google Scholar 

  10. Cashore WJ, Oh W (1982) Unbound bilirubin and kernicterus in low birth weight infants. Pediatrics 69: 481–485

    PubMed  Google Scholar 

  11. Valdöes-Dapena MA, Nissim JE, Arey JB, Godleski J, Schaaf HD, Haust MD (1976) Yellow pulmonary hyaline membranes. J Pediatr 89 (1): 128–132

    PubMed  Google Scholar 

  12. Notter RH, Shapiro DL, Taubold R, Chen J (1982) Bilirubin interactions with phospholipid components of lung surfactant. Pediatr Res 16: 130–136

    PubMed  Google Scholar 

  13. Schürch S, Bachofen H, Goerke J, Green F (1992) Surface properties of rat pulmonary surfactant studied with the captive bubble method: adsorption, hysteresis, stability. Biochim Biophys Acta 1103: 127–136

    PubMed  Google Scholar 

  14. Collaborative European Multicenter Study Group (Robertson B) (1988) Surfactant replacement therapy for severe neonatal respiratory distress syndrome: an international randomized clinical trial. Pediatrics 82: 683–691

    Google Scholar 

  15. Collaborative European Multicenter Study Group (1991) Factors influencing the clinical response to surfactant replacement therapy in babies with severe respiratory distress syndrome. Eur J Pediatr 150: 433–439

    Google Scholar 

  16. Sun B, Curstedt T, Robertson B (1995) Long-term cycling of surfactant films in Wilhelmy balance. J Dev Physiol (in press)

  17. Schürch S, Bachofen H, Goerke J, Possmayer F (1989) A captive bubble method reproduces the in situ behavior of lung surfactant monolayers. J Appl Physiol 67: 2389–2396

    PubMed  Google Scholar 

  18. Schoel WM, Schürch S, Goerke J (1994) Thr captive bubble method for the evaluation of pulmonary surfactant: surface tension, area and volume calculations. Biochim Biophys Acta 1200: 281–290

    PubMed  Google Scholar 

  19. Rotenberg Y, Boruvka L, Neumann AW (1983) Determination of surface tension and contact angle from the shapes of axisymmetric fluid interfaces. J Colloid Interface Sci 93: 169–183

    Google Scholar 

  20. Malcolm JD, Elliot CD (1980) Interfacial tension from height and diameter of a single profile drop or captive bubble. Can J Chem Eng 58: 151–153

    Google Scholar 

  21. Watchko JF, Oski FA (1992) Kernicterus in preterm newborns: past, present and future. Pediatrics 90: 707–715

    PubMed  Google Scholar 

  22. Ostrow JD, Mukerjee P, Tiribelli C (1994) Structure and binding of unconjugated bilirubin: relevance for physiological and pathophysiological function. J Lipid Res 35: 1715–1737

    PubMed  Google Scholar 

  23. Bratlid D, Cashore WJ, Oh W (1994) Effect of acidosis on bilirubin deposition in rat brain. Pediatrics 73: 431–434

    Google Scholar 

  24. Brann BS, Cashore WJ, Patrick R, Oh W (1995) In vitro effect of bilirubin on dopamine synthesis in adult rat brain synaptosomes. Pediatr Res 19: 335A

    Google Scholar 

  25. Amato MM, Kilguss NV, Gelardi NL, Cashore WJ (1994) Dose-effect relationship of bilirubin on striatal synaptosomes in rats. Biol Neonate 66: 288–293

    PubMed  Google Scholar 

  26. Amato M, Hüppi P, Markus D (1990) Assessment of neonatal jaundice in low birth weight infants comparing transcutaneous, capillary and arterial bilirubin levels. Eur J Pediatr 150: 59–61

    PubMed  Google Scholar 

  27. Holm BA, Enhorning G, Notter RH (1988) A biophysical mechanism by which plasma proteins inhibit lung surfactant activity. Chem Phys Lipids 49: 49–55

    PubMed  Google Scholar 

  28. Kobayashi T, Nitta K, Ganzuka M, et al (1991) Inactivation of exogenous surfactant by pulmonary edema fluid. Pediatr Res 29: 353–356

    PubMed  Google Scholar 

  29. Fuchimukai T, Fujiwara T, Takahashi A, Enhorning G (1987) Artificial pulmonary surfactant inhibited by proteins. J Appl Physiol 62: 429–437

    PubMed  Google Scholar 

  30. Jobe A (1989) Protein leaks and surfactant dysfunction in the pathogenesis of respiratory distress syndrome. Eur Respir J 2 (3): 27–32

    Google Scholar 

  31. Seeger W, St_hr G, Wolf HR, Neuhof H (1985) Alteration of surfactant function due to protein leakage: special interaction with fibrin monomer. J Appl Physiol 58(2): 326–338

    PubMed  Google Scholar 

  32. Amato M, Bo Sun, Robertson B (1994) Ethamsylate and lung permeability in ventilated immature newborn rabbits. Biol Neonate 65: 103–107

    PubMed  Google Scholar 

  33. Jobe A, Ikegami M (1987) Surfactant for the treatment of respiratory distress syndrome. Am Rev Respir Dis 136: 1256–1275

    PubMed  Google Scholar 

  34. Clements JA (1957) Surface tension of lung extracts. Proc Soc Exp Biol Med 95: 170–172

    PubMed  Google Scholar 

  35. Enhorning G (1977) Pulsating bubble technique for evaluating pulmonary surfactant. J Appl Physiol 43(2): 198–203

    PubMed  Google Scholar 

  36. Schürch S, Schürch D, Curstedt T, Robertson B (1994) Surface activity of lipid extract surfactant in relation to film area compression and collapse. J Appl Physiol 77(2): 974–986

    PubMed  Google Scholar 

  37. Bachofen H, Schürch S, Urbinelli M, Weibel ER (1987) Relations among alveolar surface tension, surface area, volume and recoil pressure. J Appl Physiol 62(5): 1878–1887

    PubMed  Google Scholar 

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Amato, M. Mechanisms of bilirubin toxicity. Eur J Pediatr 154 (Suppl 4), S54–S59 (1995). https://doi.org/10.1007/BF02191507

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  • DOI: https://doi.org/10.1007/BF02191507

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