Evaluation of the Possible Antioxidative Role of Bilirubin Protecting from Free Radical Related Illnesses in Neonates
There are disparate data regarding whether bilirubin is protective or toxic during free radical related illness among neonates. Seventy one infants with gestational age (GA) of <32 weeks and/or birth weight (BW) of <1500 g, who survived beyond 4 weeks and completed physical examinations were enrolled in this study. The infants were divided into two groups based on the presence or absence of advanced retinopathy of prematurity (ROP), grade III intraventricular hemorrhage (IVH), grade III necrotizing enterocolitis (NEC), respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), sepsis or severe fungal infection (SFI). The mean of total serum bilirubin (TSB) of the first 14 days of life were measured and compared between these two groups. A significant lower TSB were found in severe form of ROP (P<0.001), grade III NEC (P=0.008), grade III IVH (P=0.021), SFI (P=0.003) and sepsis (P=0.007) in comparison to mild or disease free status. Moreover, the cut-off point of 5.1 mg/dl for the mean of TSB had the sensitivity of 88.1% and specificity of 84.6% to detect severe grades of ROP. Also the cut-off point of 3.25 mg/dl had 97.2% sensitivity and 100% specificity in order to distinguish SFI. It is concluded that bilirubin may play an antioxidant role in vivo as in vitro; and protect preterm infant against these free radical related disorders. Our findings suggest that not only the upper limits of serum bilirubin, but also the lower limits must be taking into account in order to both preventing from neurotoxic effects and free radical based illnesses, respectively.
Frank L. Developmental aspects of experimental pulmonary oxygen toxicity. Free Radic Biol Med 1991;11(5):463-94.
Frank L, Sosenko IR. Failure of premature rabbits to increase antioxidant enzymes during hyperoxic exposure: increased susceptibility to pulmonary oxygen toxicity compared with term rabbits. Pediatr Res 1991;29(3):292-6.
Morton RL, Das KC, Guo XL, Iklé DN, White CW. Effect of oxygen on lung superoxide dismutase activities in premature baboons with bronchopulmonary dysplasia. Am J Physiol 1999;276(1 Pt 1):L64-74.
Saugstadt OD. Oxygen radical disease in neonatology. Semin. Neonatol 1998;3:239-44.
Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN. Bilirubin is an antioxidant of possible physiological importance. Science 1987;235(4792):1043-6.
Stocker R, Ames BN. Potential role of conjugated bilirubin and copper in the metabolism of lipid peroxides in bile. Proc Natl Acad Sci U S A 1987;84(22):8130-4.
Stocker R, Glazer AN, Ames BN. Antioxidant activity of albumin-bound bilirubin. Proc Natl Acad Sci U S A 1987;84(16):5918-22.
Dennery PA, McDonagh AF, Spitz DR, Rodgers PA, Stevenson DK. Hyperbilirubinemia results in reduced oxidative injury in neonatal Gunn rats exposed to hyperoxia. Free Radic Biol Med 1995;19(4):395-404.
Gopinathan V, Miller NJ, Milner AD, Rice-Evans CA. Bilirubin and ascorbate antioxidant activity in neonatal plasma. FEBS Lett 1994;349(2):197-200.
Romeo MG, Tina LG, Scuderi A, Di Pietro M, Caracciolo M, Distefano G. Variations of blood bilirubin levels in the newborn with and without retinopathy of prematurity (ROP). Pediatr Med Chir 1994;16(1):59-62.
Teng RJ, Wu TJ, Yau KI. Retinopathy of prematurity in very-low-birthweight neonates: epidemiology and risk factors. Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi 1997;38(5):370-4.
Milner JD, Aly HZ, Ward LB, El-Mohandes A. Does elevated peak bilirubin protect from retinopathy of prematurity in very low birthweight infants. J Perinatol 2003;23(3):208-11.
Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;163(7):1723-9.
Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin North Am 1986;33(1):179-201.
Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr 1978;92(4):529-34.
Section on Ophthalmology American Academy of Pediatrics; American Academy of Ophthalmology; American Association for Pediatric Ophthalmology and Strabismus. Screening examination of premature infants for retinopathy of prematurity. Pediatrics 2006;117(2):572-6.
International Committee for the Classification of Retinopathy of Prematurity. The International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol 2005;123(7):991-9.
Maines MD. The heme oxygenase system: a regulator of second messenger gases. Annu Rev Pharmacol Toxicol 1997;37:517-54.
Sedlak TW, Snyder SH. Bilirubin benefits: cellular protection by a biliverdin reductase antioxidant cycle. Pediatrics 2004;113(6):1776-82.
Benaron DA, Bowen FW. Variation of initial serum bilirubin rise in newborn infants with type of illness. Lancet 1991;338(8759):78-81.
Hegyi T, Goldie E, Hiatt M. The protective role of bilirubin in oxygen-radical diseases of the preterm infant. J Perinatol 1994;14(4):296-300.
Yeo KL, Perlman M, Hao Y, Mullaney P. Outcomes of extremely premature infants related to their peak serum bilirubin concentrations and exposure to phototherapy. Pediatrics 1998;102(6):1426-31.
Boynton BR, Boynton CA. Retinopathy of prematurity and bilirubin. N Engl J Med 1989;321(3):193-4.
Gaton DD, Gold J, Axer-Siegel R, Wielunsky E, Naor N, Nissenkorn I. Evaluation of bilirubin as possible protective factor in the prevention of retinopathy of prematurity. Br J Ophthalmol 1991;75:532-4.
Fauchère JC, Meier-Gibbons FE, Koerner F, Bossi E. Retinopathy of prematurity and bilirubin--no clinicalevidence for a beneficial role of bilirubin as a physiological anti-oxidant. Eur J Pediat 1994;153(5):358-62.
Hosono S, Ohno T, Kimoto H, Shimizu M, Nozawa M, Genkawa R, Yoshida T, Wada S, Harada K. No clinical correlation between bilirubin levels and severity of retinopathy of prematurity. J Pediatr Ophthalmol Strabismus 2002;39(3):151-6.
DeJonge MH, Khuntia A, Maisels MJ, Bandagi A. Bilirubin levels and severe retinopathy of prematurity in infants with estimated gestational ages of 23 to 26 weeks. J Pediatr 1999;135(1):102-4.
Hammerman C, Goldstein R, Kaplan M, Eran M, Goldschmidt D, Eidelman AI, Gartner LM. Bilirubin in the premature: toxic waste or natural defense? Clin Chem 1998;44(12):2551-3.
Bélanger S, Lavoie JC, Chessex P. Influence of bilirubin on the antioxidant capacity of plasma in newborn infants. Biol Neonate 1997;71(4):233-8.
Wayner DD, Burton GW, Ingold KU, Barclay LR, Locke SJ. The relative contributions of vitamin E, urate, ascorbate and proteins to the total peroxyl radical-trapping antioxidant activity of human blood plasma. Biochim Biophys Acta 1987;924(3):408-19.
Lee YK, Daito Y, Katayama Y, Minami H, Negishi H. The significance of measurement of serum unbound bilirubin concentrations in high-risk infants. Pediatr Int 2009;51(6):795-9.
Hammerman C, Goldschmidt D, Caplan MS, Kaplan M, Bromiker R, Eidelman AI, Gartner LM, Hochman A. Protective effect of bilirubin in ischemia-reperfusion injury in the rat intestine. J Pediatr Gastroenterol Nutr 2002;35(3):344-9.
Oh W, Tyson JE, Fanaroff AA, Vohr BR, Perritt R, Stoll BJ, Ehrenkranz RA, Carlo WA, Shankaran S, Poole K,Wright LL; National Institute of Child Health and Human Development Neonatal Research Network. Association between peak serum bilirubin and neurodevelopmental outcomes in extremely low birth weight infants. Pediatrics 2003;112(4):773-9.
Wang WW, Smith DL, Zucker SD. Bilirubin inhibits iNOS expression and NO production in response to endotoxin in rats. Hepatology 2004;40(2):424-33.
Lanone S, Bloc S, Foresti R, Almolki A, Taillé C, Callebert J, Conti M, Goven D, Aubier M, Dureuil B, El- Benna J, Motterlini R, Boczkowski J. Bilirubin decreases nos2 expression via inhibition of NAD(P)H oxidase: implications for protection against endotoxic shock in rats. FASEB J 2005;19(13):1890-2.
Otani K, Shimizu S, Chijiiwa K, Yamaguchi K, Kuroki S, Tanaka M. Increased urinary excretion of bilirubin oxidative metabolites in septic patients: a new marker for oxidative stress in vivo. J Surg Res 2001;96(1):44-9.
Yamaguchi T, Horio F, Hashizume T, Tanaka M, Ikeda S, Kakinuma A, Nakajima H. Bilirubin is oxidized in rats treated with endotoxin and acts as a physiological antioxidant synergistically with ascorbic acid in vivo. Biochem Biophys Res Commun 1995;214(1):11-9.
Frei B, Stocker R, Ames BN. Antioxidant defenses and lipid peroxidation in human blood plasma. Proc Natl Acad Sci USA 1988;85(24):9748-52.
Berger HM, Molicki JS, Moison RM, Van Zoeren-. Grobben D. Extracellular defence against oxidative stress in the newborn. Semin Neonatol 1998;3:183-90.
Lindeman JH, Lentjes EG, Berger HM. Diminished protection against copper-induced lipid peroxidation by cord blood plasma of preterm and term infants. JPEN J Parenter Enteral Nutr 1995;19(5):373-5.
Shukla SP, Sarkar A, Adhikari S, Joshi R, Ghanty TK, Mukherjee T. Experimental results and theoretical validation for the antioxidant mechanism of bilirubin. J Indian Chem Soc 2010;87:139-46.
Neimark E, LeLeiko NS. Antioxidant effect of bilirubin and pediatric nonalcoholic fatty liver disease. Pediatrics 2009;124(6):e1240-1.
Sedlak TW, Saleh M, Higginson DS, Paul BD, Juluri KR, Snyder SH. Bilirubin and glutathione have complementary antioxidant and cytoprotective roles. Proc Natl Acad Sci U S A 2009;106(13):5171-6.
Maghzal GJ, Leck MC, Collinson E, Li C, Stocker R. Limited role for the bilirubin-biliverdin redox amplification cycle in the cellular antioxidant protection by biliverdin reductase. J Biol Chem 2009;284(43):29251-9.
Florczyk UM, Jozkowicz A, Dulak J. Biliverdin reductase: new features of an old enzyme and its potential therapeutic significance. Pharmacol Rep 2008;60(1):38-48.
Dennery PA, Rodgers PA, Lum MA, Jennings BC, Shokoohi V. Hyperoxic regulation of lung heme oxygenase in neonatal rats. Pediatr Res 1996;40(6):815-21.
Doré S, Takahashi M, Ferris CD, Zakhary R, Hester LD, Guastella D, Snyder SH. Bilirubin, formed by activation of heme oxygenase-2, protects neurons against oxidativestress injury. Proc Natl Acad Sci U S A 1999;96(5):2445-50.
Aycicek A, Erel O. Total oxidant/antioxidant status in jaundiced newborns before and after phototherapy. J Pediatr (Rio J) 2007;83(4):319-22.
Aycicek A, Kocyigit A, Erel O, Senturk H. Phototherapy causes DNA damage in peripheral mononuclear leukocytesin term infants. J Pediatr (Rio J) 2008;84(2):141-6.
Wiedemann M, Kontush A, Finckh B, Hellwege HH, Kohlschütter A. Neonatal blood plasma is less susceptible to oxidation than adult plasma owing to its higher content of bilirubin and lower content of oxidizable Fatty acids. Pediatr Res 2003;53(5):843-9.
Shekeeb Shahab M, Kumar P, Sharma N, Narang A, Prasad R. Evaluation of oxidant and antioxidant status in term neonates: a plausible protective role of bilirubin. Mol Cell Biochem 2008;317(1-2):51-9.
Dani C, Martelli E, Bertini G, Pezzati M, Filippi L, Rossetti M, Rizzuti G, Rubaltelli FF. Plasma bilirubin level and oxidative stress in preterm infants. Arch Dis Child Fetal Neonatal Ed 2003;88(2):F119-23.
Arai T, Yoshikai Y, Kamiya J, Nagino M, Uesaka K, Yuasa N, Oda K, Sano T, Nimura Y. Bilirubin impairs bactericidal activity of neutrophils through an antioxidant mechanism in vitro. J Surg Res 2001;96(1):107-13.
|Issue||Vol 50, No 3 (2012)|
|Bilirubin Free radical Preterm Antioxidant Retinopathy of prematurity (ROP)|
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