Antioxidants and Biomarkers of Oxidative Stress in Preterm Infants with Symptomatic Patent Ductus Arteriosus

Abstract

Objective Immature antioxidant and oxygen-sensing mechanisms are involved in the pathogenesis of the patent ductus arteriosus (PDA). We conducted a prospective, observational, pilot study to test the hypothesis that antioxidant activity is low at birth in preterm infants at risk for symptomatic PDA.

Study Design Blood and urine samples were collected within 24 to 48 hours of life in 53 preterm infants (≤32 weeks' gestation) who developed early PDA symptoms and in 30 term (≥37 weeks' gestation) control infants. Thirty preterm infants developed hemodynamically significant PDA (hsPDA) and required pharmacologic treatment and/or PDA ligation. For these infants, blood and urine samples were also collected at 24 hours posttreatment. Samples were analyzed for biomarkers of antioxidant activity, oxidative stress, and lipid peroxidation.

Results At 24 to 48 hours after birth, plasma superoxide dismutase (SOD), urinary catalase, and plasma and urinary 8-isoPGF_2α were significantly lower in preterm infants who developed hsPDA. Plasma 8-isoPGF_2α levels rebounded post–PDA treatment, while urinary prostaglandin E₂, plasma and urinary thromboxane B₂, and plasma SOD declined.

Conclusion The antioxidant status is low in preterm infants at risk for developing hsPDA. SOD may be a key antioxidant regulating functional ductus arteriosus closure. Therefore, low levels may result in persistence of a hsPDA.

Keywords

antioxidant - oxidative stress - patent ductus arteriosus - premature infants

• References

• 1 Capozzi G, Santoro G. Patent ductus arteriosus: patho-physiology, hemodynamic effects and clinical complications. J Matern Fetal Neonatal Med 2011; 24 (Suppl. 01) 15-16
• 2 Watterberg KL, Scott SM, Backstrom C, Gifford KL, Cook KL. Links between early adrenal function and respiratory outcome in preterm infants: airway inflammation and patent ductus arteriosus. Pediatrics 2000; 105 (2) 320-324
• 3 Shimada S, Kasai T, Konishi M, Fujiwara T. Effects of patent ductus arteriosus on left ventricular output and organ blood flows in preterm infants with respiratory distress syndrome treated with surfactant. J Pediatr 1994; 125 (2) 270-277
• 4 Fowlie PW. Managing the baby with a patent ductus arteriosus. More questions than answers?. Arch Dis Child Fetal Neonatal Ed 2005; 90 (3) F190
• 5 Van Overmeire B, Chemtob S. The pharmacologic closure of the patent ductus arteriosus. Semin Fetal Neonatal Med 2005; 10 (2) 177-184
• 6 Reyes JL, Aldana I, Barbier O, Parrales AA, Melendez E. Indomethacin decreases furosemide-induced natriuresis and diuresis on the neonatal kidney. Pediatr Nephrol 2006; 21 (11) 1690-1697
• 7 Ohlsson A, Walia R, Shah S. Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2008; 23 (1) CD003481
• 8 Mosalli R, Alfaleh K. Prophylactic surgical ligation of patent ductus arteriosus for prevention of mortality and morbidity in extremely low birth weight infants. (Review) Cochrane Database Syst Rev 2008; 1 (1) CD006181
• 9 Malviya M, Ohlsson A, Shah S. Surgical versus medical treatment with cyclooxygenase inhibitors for symptomatic patent ductus arteriosus in preterm infants. (Review) Cochrane Database Syst Rev 2008; 23 (1) CD003951
• 10 Benitz WE. Treatment of persistent patent ductus arteriosus in preterm infants: time to accept the null hypothesis?. J Perinatol 2010; 30 (4) 241-252
• 11 Clyman RI, Couto J, Murphy GM. Patent ductus arteriosus: are current neonatal treatment options better or worse than no treatment at all?. Semin Perinatol 2012; 36 (2) 123-129
• 12 Fay FS. Guinea pig ductus arteriosus. I. Cellular and metabolic basis for oxygen sensitivity. Am J Physiol 1971; 221 (2) 470-479
• 13 Reeve HL, Tolarova S, Nelson DP, Archer S, Weir EK. Redox control of oxygen sensing in the rabbit ductus arteriosus. J Physiol 2001; 533 (Pt 1): 253-261
• 14 Olschewski A, Hong Z, Peterson DA, Nelson DP, Porter VA, Weir EK. Opposite effects of redox status on membrane potential, cytosolic calcium, and tone in pulmonary arteries and ductus arteriosus. Am J Physiol Lung Cell Mol Physiol 2004; 286 (1) L15-L22
• 15 Weir EK, Obreztchikova M, Vargese A, Cabrera JA, Peterson DA, Hong Z. Mechanisms of oxygen sensing: a key to therapy of pulmonary hypertension and patent ductus arteriosus. Br J Pharmacol 2008; 155 (3) 300-307
• 16 Greyner H, Dzialowski EM. Mechanisms mediating the oxygen-induced vasoreactivity of the ductus arteriosus in the chicken embryo. Am J Physiol Regul Integr Comp Physiol 2008; 295 (5) R1647-R1659
• 17 Cogolludo AL, Moral-Sanz J, van der Sterren S , et al. Maturation of O2 sensing and signaling in the chicken ductus arteriosus. Am J Physiol Lung Cell Mol Physiol 2009; 297 (4) L619-L630
• 18 Auten RL, Davis JM. Oxygen toxicity and reactive oxygen species: the devil is in the details. Pediatr Res 2009; 66 (2) 121-127
• 19 Michelakis ED, Rebeyka I, Wu X , et al. O2 sensing in the human ductus arteriosus: regulation of voltage-gated K+ channels in smooth muscle cells by a mitochondrial redox sensor. Circ Res 2002; 91 (6) 478-486
• 20 Andriantsitohaina R, Duluc L, García-Rodríguez JC , et al. Systems biology of antioxidants. Clin Sci (Lond) 2012; 123 (3) 173-192
• 21 Hsu J-H, Oishi P, Wiseman DA , et al. Nitric oxide alterations following acute ductal constriction in the fetal lamb: a role for superoxide. Am J Physiol Lung Cell Mol Physiol 2010; 298 (6) L880-L887
• 22 Georgeson GD, Szony BJ, Streitman K , et al. Antioxidant enzyme activities are decreased in preterm infants and in neonates born via caesarean section. Eur J Obstet Gynecol Reprod Biol 2002; 103 (2) 136-139
• 23 Nassi N, Ponziani V, Becatti M, Galvan P, Donzelli G. Anti-oxidant enzymes and related elements in term and preterm newborns. Pediatr Int 2009; 51 (2) 183-187
• 24 Perrone S, Negro S, Tataranno ML, Buonocore G. Oxidative stress and antioxidant strategies in newborns. J Matern Fetal Neonatal Med 2010; 23 (Suppl. 03) 63-65
• 25 Ballard JL, Khoury JC, Wedig K, Wang L, Eilers-Walsman BL, Lipp R. New Ballard Score, expanded to include extremely premature infants. J Pediatr 1991; 119 (3) 417-423
• 26 Clerch LB, Massaro D. Rat lung antioxidant enzymes: differences in perinatal gene expression and regulation. Am J Physiol 1992; 263 (4, Pt 1) L466-L470
• 27 Clyman R, Cassady G, Kirklin JK, Collins M, Philips III JB. The role of patent ductus arteriosus ligation in bronchopulmonary dysplasia: reexamining a randomized controlled trial. J Pediatr 2009; 154 (6) 873-876
• 28 Chorne N, Leonard C, Piecuch R, Clyman RI. Patent ductus arteriosus and its treatment as risk factors for neonatal and neurodevelopmental morbidity. Pediatrics 2007; 119 (6) 1165-1174
• 29 Frank L, Groseclose EE. Preparation for birth into an O2-rich environment: the antioxidant enzymes in the developing rabbit lung. Pediatr Res 1984; 18 (3) 240-244
• 30 Fukai T, Ushio-Fukai M. Superoxide dismutases: role in redox signaling, vascular function, and diseases. Antioxid Redox Signal 2011; 15 (6) 1583-1606
• 31 Hamrick SEG, Hansmann G. Patent ductus arteriosus of the preterm infant. Pediatrics 2010; 125 (5) 1020-1030
• 32 Weir EK, López-Barneo J, Buckler KJ, Archer SL. Acute oxygen-sensing mechanisms. N Engl J Med 2005; 353 (19) 2042-2055
• 33 Weir EK, Hong Z, Porter VA, Reeve HL. Redox signaling in oxygen sensing by vessels. Respir Physiol Neurobiol 2002; 132 (1) 121-130
• 34 Weir EK, Archer SL. The role of redox changes in oxygen sensing. Respir Physiol Neurobiol 2010; 174 (3) 182-191
• 35 Thébaud B, Michelakis ED, Wu XC , et al. Oxygen-sensitive Kv channel gene transfer confers oxygen responsiveness to preterm rabbit and remodeled human ductus arteriosus: implications for infants with patent ductus arteriosus. Circulation 2004; 110 (11) 1372-1379
• 36 Kajimoto H, Hashimoto K, Bonnet SN , et al. Oxygen activates the Rho/Rho-kinase pathway and induces RhoB and ROCK-1 expression in human and rabbit ductus arteriosus by increasing mitochondria-derived reactive oxygen species: a newly recognized mechanism for sustaining ductal constriction. Circulation 2007; 115 (13) 1777-1788
• 37 Basu S. Isoprostanes: novel bioactive products of lipid peroxidation. Free Radic Res 2004; 38 (2) 105-122
• 38 Praticò D. F(2)-isoprostanes: sensitive and specific non-invasive indices of lipid peroxidation in vivo. Atherosclerosis 1999; 147 (1) 1-10
• 39 Longini M, Perrone S, Vezzosi P , et al. Isoprostane levels in urine of preterm newborns treated with ibuprofen for patent ductus arteriosus closure. Pediatr Nephrol 2011; 26 (1) 105-109
• 40 Clyman RI, Waleh N, Black SM, Riemer RK, Mauray F, Chen YQ. Regulation of ductus arteriosus patency by nitric oxide in fetal lambs: the role of gestation, oxygen tension, and vasa vasorum. Pediatr Res 1998; 43 (5) 633-644
• 41 Coceani F, Kelsey L, Seidlitz E. Occurrence of endothelium-derived relaxing factor—nitric oxide in the lamb ductus arteriosus. Can J Physiol Pharmacol 1994; 72 (1) 82-88
• 42 Coceani F, Huhtanen D, Hamilton NC, Bishai I, Olley PM. Involvement of intramural prostaglandin E2 in prenatal patency of the lamb ductus arteriosus. Can J Physiol Pharmacol 1986; 64 (6) 737-744
• 43 Mitchell JA, Akarasereenont P, Thiemermann C, Flower RJ, Vane JR. Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proc Natl Acad Sci U S A 1993; 90 (24) 11693-11697
• 44 Mueed I, Tazzeo T, Liu C , et al. Isoprostanes constrict human radial artery by stimulation of thromboxane receptors, Ca2+ release, and RhoA activation. J Thorac Cardiovasc Surg 2008; 135 (1) 131-138
• 45 Habib A, Badr KF. Molecular pharmacology of isoprostanes in vascular smooth muscle. Chem Phys Lipids 2004; 128 (1–2) 69-73
• 46 Fox JJ, Ziegler JW, Ivy DD, Halbower AC, Kinsella JP, Abman SH. Role of nitric oxide and cGMP system in regulation of ductus arteriosus tone in ovine fetus. Am J Physiol 1996; 271 (6, Pt 2): H2638-H2645
• 47 Momma K, Toyono M. The role of nitric oxide in dilating the fetal ductus arteriosus in rats. Pediatr Res 1999; 46 (3) 311-315
• 48 Kajino H, Chen YQ, Chemtob S, Waleh N, Koch CJ, Clyman RI. Tissue hypoxia inhibits prostaglandin and nitric oxide production and prevents ductus arteriosus reopening. Am J Physiol Regul Integr Comp Physiol 2000; 279 (1) R278-R286
• 49 Takizawa T, Kihara T, Kamata A, Yamamoto M, Arishima K. Role of nitric oxide in regulating the ductus arteriosus caliber in fetal rats. J Vet Med Sci 2000; 62 (7) 707-710
• 50 Seyberth HW, Müller H, Ulmer HE, Wille L. Urinary excretion rates of 6-keto-PGF1 alpha in preterm infants recovering from respiratory distress with and without patent ductus arteriosus. Pediatr Res 1984; 18 (6) 520-524