Free radicals (FRs) generation is an unavoidable consequence of the life in an oxygen-rich atmosphere. FRs can be considered a double-edged sword. Beneficial effects of FRs occur at moderate concentrations and involve physiological roles in cellular responses to noxia, as in defense against infectious agents, in the function of a number of cellular signaling pathways and the induction of a mitogenic response. The over-production of FRs and the insufficiency of an antioxidant mechanism result in oxidative stress (OS), a deleterious process and important mediator of damage to cell structures and tissues. It occurs at birth in all newborns as a consequence of the hyperoxic challenge after the transition from the hypoxic intrauterine environment to extrauterine life. During the perinatal period, OS can be magnified by others predisposing conditions such as hyperoxia, hypoxia, ischemia, hypoxia-reperfusion, inflammation and high levels of non-protein bound iron. Epidemiological studies linked OS occurring during fetal stages and early infancy with adverse health outcomes later in life, indicating that OS is an early event in the etiology of these chronic diseases. Newborns, especially if preterm, are particularly susceptible to OS and damage due to the increased generation of FRs, the lack of adequate antioxidant protection, and the inability to induce antioxidant defenses during the hyperoxic challenge at birth. This impairment of the oxidative balance has been thought to be the common factor of pathologies grouped together as “free radical disease in the neonate” that include retinopathy of prematurity (which may lead to blindness in severe cases), bronchopulmonary dysplasia (a particularly debilitating pulmonary lesion of the preterm infant), periventricular leukomalacia (an important cause of severe neurodisability) and necrotizing enterocolitis. In this review we discuss in detail these perinatal diseases. Particularly, we analyze the current knowledge about the role of OS in their pathogenesis.
Buonocore, G. and Groenendaal, F. (2007) Anti-oxidant strategies. Seminars in Fetal and Neonatal Medicine, 12, 287-295. doi:10.1016/j.siny.2007.01.020
Buonocore, G., Perrone, S. And Tataranno, M.L. (2010) Oxygen toxicity: Chemistry and biology of reactive oxygen species. Seminars in Fetal and Neonatal Medicine, 15, 186-190. doi:10.1016/j.siny.2010.04.003
Lee, J., Giordano, S. and Zhang, J. (2012) Autophagy, mitochondria and oxidative stress: Crosstalk and redox signalling. Biochemical Journal, 441, 523-540. doi:10.1042/BJ20111451
Perrone, S., Tataranno, M.L., Negro, S., Longini, M., Marzocchi, B., Proietti, F., Iacoponi, F., Capitani, S. and Buonocore, G. (2010) Early identification of the risk for free radical-related diseases in preterm newborns. Early Human Development, 86, 241-244. doi:10.1016/j.earlhumdev.2010.03.008
Alderton, W.K., Cooper, C.E. and Knowles, R.G. (2001) Nitric oxide synthases: Structure, function and inhibition. Biochemical Journal, 357, 593-615. doi:10.1042/0264-6021:3570593
Auten, R.L. and Davis, J.M. (2009) Oxygen toxicity and reactive oxygen species: The devil is in the details. Pediatric Research, 66, 121-127. doi:10.1203/PDR.0b013e3181a9eafb
McCarthy, S.M., Bove, P.F., Matthews, D.E., Akaike, T. and van der Vliet, A. (2008) Nitric oxide regulation of MMP-9 activation and its relationship to modifications of the cysteine switch. Biochemistry, 47, 5832-5840. doi:10.1021/bi702496v
Gutteridge, J.M. (1982) The role of superoxide and hydroxyl radicals in phospholipid peroxidation catalysed by iron salts. FEBS Letters, 150, 454-458. doi:10.1016/0014-5793(82)80788-6
Conner, E.M. and Grisham, M.B. (1996) Inflammation, free radicals, and antioxidants. Nutrition, 12, 274-277. doi:10.1016/S0899-9007(96)00000-8
Bachowski, S., Kolaja, K.L., Xu, Y., Ketcham, C.A., Stevenson, D.E., Walborg, E.F. and Klaunig, J.E. (1997) Role of oxidative stress in the mechanism of dieldrin’s hepatotoxicity. Annals of Clinical & Laboratory Science, 27, 196-209.
Davies, K.J. (2000) Oxidative stress, antioxidant defenses, and damage removal, repair, and replacement systems. IUBMB Life, 50, 279-289. doi:10.1080/15216540051081010
Saugstad, O.D. (1989) The oxygen radical disease in neonatology. Indian Journal of Pediatrics, 56, 585-593. doi:10.1007/BF02722373
Volpe, J.J. (2001) Perinatal brain injury: From pathogenesis to neuroprotection. Mental Retardation and Developmental Disabilities Research Reviews, 7, 56-64. doi:10.1002/1098-2779(200102)7:1 3.0.CO;2-A
McCrea, H.J. and Ment, L.R. (2008) The diagnosis, management, and postnatal prevention of intraventricular hemorrhage in the preterm neonate. Clinics in Perinatology, 35, 777-792. doi:10.1016/j.clp.2008.07.014
Ackerman, W.E. 4th, Rovin, B.H. and Kniss, D.A. (2004) Epidermal growth factor and interleukin-1beta utilize divergent signaling pathways to synergistically upregulate cyclooxygenase-2 gene expression in human amnion-derived WISH cells. Biology of Reproduction, 71, 2079-2086. doi:10.1095/biolreprod.104.030841
Kuwano, T., Nakao, S., Yamamoto, H., Tsuneyoshi, M., Kuwano, M. and Ono, M. (2004) Cyclooxygenase 2 is a key enzyme for inflammatory cytokine-induced angiogenesis. FASEB Journal, 18, 300-310. doi:10.1096/fj.03-0473com
Ulfig, N., Bohl, J., Neud?rfer, F. and Rezaie, P. (2004) Brain macrophages and microglia in human fetal hydrocephalus. Brain & Development, 26, 307-315. doi:10.1016/S0387-7604(03)00172-4
Folkerth, R.D., Keefe, R.J., Haynes, R.L., Trachtenberg, F.L., Volpe, J.J. and Kinney, H.C. (2004) Interferongamma expression in periventricular leukomalacia in the human brain. Brain Pathology, 14, 265-274. doi:10.1111/j.1750-3639.2004.tb00063.x
Back, S.A., Luo, N.L., Mallinson, R.A., O’Malley, J.P., Wallen, L.D., Frei, B., Morrow, J.D., Petito, C.K., Roberts, C.T. Jr., Murdoch, G.H. and Montine, T.J. (2005) Selective vulnerability of preterm white matter to oxidative damage defined by F2-isoprostanes. Annals of Neurology, 58, 108-120. doi:10.1002/ana.20530
Inder, T., Mocatta, T., Darlow, B., Spencer, C., Volpe, J.J. and Winterbourn, C. (2002) Elevated free radical products in the cerebrospinal fluid of VLBW infants with cerebral white matter injury. Pediatric Research, 52, 213-218. doi:10.1203/00006450-200208000-00013
Perrone, S., Bracci, R. and Buonocore G. (2002) New biomarkers of fetal-neonatal hypoxic stress. Acta Paediatrica, 91, 135-138. doi:10.1111/j.1651-2227.2002.tb02919.x
McQuillen, P.S. and Ferriero, D.M. (2004) Selective vulnerability in the developing central nervous system. Pediatric Neurology, 30, 227-235. doi:10.1016/j.pediatrneurol.2003.10.001
Gazzolo, D., Perrone, S., Paffetti, P., Longini, M., Vezzosi, P., Bruschettini, M., Lituania, M. and Buonocore, G. (2005) Non protein bound iron concentrations in amniotic fluid. Clinical Biochemistry, 38, 674-677. doi:10.1016/j.clinbiochem.2005.03.010
Gaasch, J.A., Lockman, P.R., Geldenhuys, W.J., Allen, D.D. and Van der Schyf, C.J. (2007) Brain iron toxicity: Differential responses of astrocytes, neurons, and endothelial cells. Neurochemical Research, 32, 1196-1208. doi:10.1007/s11064-007-9290-4
Won, S.M., Lee, J.H., Park, U.J., Gwag, J., Gwag, B.J. and Lee, Y.B. (2011) Iron mediates endothelial cell damage and blood-brain barrier opening in the hippocampus after transient forebrain ischemia in rats. Experimental and Molecular Medicine, 43, 121-128. doi:10.3858/emm.2011.43.2.020
Yang, Y. and Loscalzo, J. (2000) Regulation of tissue factor expression in human microvascular endothelial cells by nitric oxide. Circulation, 101, 2144-2148. doi:10.1161/01.CIR.101.18.2144
Van Buren, P., Velez, R.L., Vaziri, N.D. and Zhou, X.J. (2012) Iron overdose: a contributor to adverse outcomes in randomized trials of anemia correction in CKD. International Urology and Nephrology, 44, 499-507. doi:10.1007/s11255-011-0028-5
Pomfy, M. and Húska, J. (1992) The state of the microcirculatory bed after total ischaemia of the brain. An experimental ultrastructural study. Functional and Developmental Morphology, 2, 253-258.
Rivera, J.C., Sapieha, P., Joyal, J.S., Duhamel, F., Shao, Z., Sitaras, N., Picard, E., Zhou, E., Lachapelle, P. and Chemtob, S. (2011) Understanding retinopathy of prematurity: Update on pathogenesis. Neonatology, 100, 343-353. doi:10.1159/000330174
Shastry, B.S. (2010) Genetic susceptibility to advanced retinopathy of prematurity (ROP). Journal of Biomedical Science, 17, 69. doi:10.1186/1423-0127-17-69
Pierce, E.A., Foley, E.D. and Smith, L.E. (1996) Regulation of vascular endothelial growth factor by oxygen in a model of retinopathy of prematurity. Archives of Ophthalmology, 114, 1219-1228. doi:10.1001/archopht.1996.01100140419009
Saugstad, O.D. (2006) Oxygen and retinopathy of prematurity. Journal of Perinatology, 26, S46-S50.
Penn, J.S., Henry, M.M. and Tolman, B.L. (1994) Exposure to alternating hypoxia and hyperoxia causes severe proliferative retinopathy in the newborn rat. Pediatric Research, 36, 724-731. doi:10.1203/00006450-199412000-00007
Saugstad, O.D. and Rognum, T.O. (1988) High postmortem levels of hypoxanthine in the vitreous humor of pre-mature babies with respiratory distress syndrome. Pediatrics, 81, 395-398.
Perrone, S., Vezzosi, P., Longini, M., Marzocchi, B., Paffetti, P., Bellieni, C.V., Martinelli, S. and Buonocore, G. (2009) Biomarkers of oxidative stress in babies at high risk for retinopathy of prematurity. Frontiers in Bioscience, 1, 547-552.
Chen, W., Hunt, D.M., Lu, H. and Hunt, R.C. (1999) Expression of antioxidant protective proteins in the rat retina during prenatal and postnatal development. Investigative Ophthalmology & Visual Science, 40, 744-751.
Raju, T.N., Langenberg, P., Bhutani, V. and Quinn, G.E. (1997) Vitamin E prophylaxis to reduce retinopathy of prematurity: A reappraisal of published trials. Journal of Pediatrics, 131, 844-850. doi:10.1016/S0022-3476(97)70031-3
Lineham, J.D., Smith, R.M., Dahlenburg, G.W., King, R.A., Haslam, R.R., Stuart, M.C. and Faull, L. (1986) Circulating insulin-like growth factor I levels in newborn premature and full-term infants followed longitudinally. Early Human Development, 13, 37-46. doi:10.1016/0378-3782(86)90096-4
Joung, K.E., Kim, H.S., Lee ,J., Shim, G.H., Choi, C.W., Kim, E.K., Kim, B.I. and Choi, J.H. (2011) Correlation of urinary inflammatory and oxidative stress markers in very low birth weight infants with subsequent development of bronchopulmonary dysplasia. Free Radical Research, 45, 1024-1032. doi:10.3109/10715762.2011.588229
Saugstad, O.D. (2003) Bronchopulmonary dysplasia-oxidative stress and antioxidants. Seminars in Neonatology, 8, 39-49. doi:10.1016/S1084-2756(02)00194-X
Fellman, V. (1997) Respiratory distress syndrome of neonates today. Duodecim, 113, 1024-1031.
Groneck, P. and Speer, C.P. (1993) Interleukin-8 in pulmonary effluent fluid of preterm infants. Journal of Pediatrics, 123, 839-840. doi:10.1016/S0022-3476(05)80884-4
Haagsman, H.P. (1998) Interactions of surfactant protein A with pathogens. Biochimica et Biophysica Acta, 1408, 264-277. doi:10.1016/S0925-4439(98)00072-6
Varsila, E., Hallman, M. and Andersson, S. (1994) Free-radical-induced lipid peroxidation during the early neonatal period. Acta Paediatrica, 83, 692-695. doi:10.1111/j.1651-2227.1994.tb13120.x
Inder, T.E., Graham, P., Sanderson, K. and Taylor, B.J. (1994) Lipid peroxidation as a measure of oxygen free radical damage in the very low birthweight infant. Archives of Disease in Childhood Fetal Neonatal Edition, 70, F107-F111. doi:10.1136/fn.70.2.F107
Gladstone, I.M. Jr. and Levine, R.L. (1994) Oxidation of proteins in neonatal lungs. Pediatrics, 93, 764-768.
Varsila, E., Pesonen, E. and Andersson, S. (1995) Early protein oxidation in the neonatal lung is related to development of chronic lung disease. Acta Paediatrica, 84, 1296-1299. doi:10.1111/j.1651-2227.1995.tb13552.x
Baregamian, N., Song, J., Bailey, C.E., Papaconstantinou, J., Evers, B.M. and Chung, D.H. (2009) Tumor necrosis factor-alpha and apoptosis signal-regulating kinase 1 control reactive oxygen species release, mitochondrial autophagy, and c-Jun N-terminal kinase/p38 phosphorylation during necrotizing enterocolitis. Oxidative Medicine and Cellular Longevity, 2, 297-306. doi:10.4161/oxim.2.5.9541
Buonocore, G., Bracci, R. and Weindling, M. (2011) Neonatology. A pratical approach to neonatal management. Springer Verlag Italia, Milano.
Aydemir, C., Dilli, D., Uras, N., Ulu, H.O., Oguz, S.S., Erdeve, O. and Dilmen, U. (2011) Total oxidant status and oxidative stress are increased in infants with necrotizing enterocolitis. Journal of Pediatric Surgery, 46, 2096-2100. doi:10.1016/j.jpedsurg.2011.06.032
Kim, M., Christley, S., Alverdy, J.C., Liu, D. and An, G. (2012) Immature Oxidative Stress Management as a Unifying Principle in the Pathogenesis of Necrotizing Enterocolitis: Insights from an Agent-Based Model. Surgical Infections, 13, 18-32. doi:10.1089/sur.2011.057
Baregamian, N., Song, J., Papaconstantinou, J., Hawkins, H.K., Evers, B.M. and Chung, D.H. (2011) Intestinal mitochondrial apoptotic signaling is activated during oxidative stress. Pediatric Surgery International, 27, 871-877. doi:10.1007/s00383-011-2880-x
Perrone, S., Tataranno, M.L., Negro, S., Cornacchione, S., Longini, M., Proietti, F., Soubasi, V., Benders, M.J., Van Bel, F. and Buonocore, G. (2012) May oxidative stress biomarkers in cord blood predict the occurrence of necrotizing enterocolitis in preterm infants? Journal of Maternal-Fetal and Neonatal Medicine, 1, 128-131 doi:10.3109/14767058.2012.663197
Lee, J.H. (2011) An update on necrotizing enterocolitis: Pathogenesis and preventive strategies. Korean Journal of Pediatrics, 54, 368-372. doi:10.3345/kjp.2011.54.9.368
Claud, E.C., Zhang, X., Petrof, E.O. and Sun, J. (2007) Developmentally regulated tumor necrosis factor-alpha induced nuclear factor-kappaB activation in intestinal epithelium. American Journal of Physiology Gastrointestinal and Liver Physiology, 292, G1411-G1419. doi:10.1152/ajpgi.00557.2006
Alexander, V.N., Northrup, V. and Bizzarro, M.J. (2011) Antibiotic exposure in the newborn intensive care unit and the risk of necrotizing enterocolitis. Journal of Pediatrics, 159, 392-397. doi:10.1016/j.jpeds.2011.02.035
Nankervis, C.A., Giannone, P.J. and Reber, K.M. (2008) The neonatal intestinal vasculature: Contributing factors to necrotizing enterocolitis. Seminars in Perinatology, 32, 83-91. doi:10.1053/j.semperi.2008.01.003
Abdelhamid, A.E., Chuang, S.L., Hayes, P. and Fell, J.M. (2011) In vitro cow’s milk protein-specific inflammatory and regulatory cytokine responses in preterm infants with necrotizing enterocolitis and sepsis. Pediatric Research, 69, 165-169. doi:10.1203/PDR.0b013e31820263e7
Moonen, R.M., Paulussen, A.D., Souren, N.Y., Kessels, A.G., Rubio-Gozalbo, M.E. and Villamor, E. (2007) Carbamoyl phosphate synthetase polymorphisms as a risk factor for necrotizing enterocolitis. Pediatric Research, 62, 188-190. doi:10.1203/PDR.0b013e3180a0324e
Bányász, I., Bokodi, G., Vásárhelyi, B., Treszl, A., Derzbach, L., Szabó, A., Tulassay, T. and Vannay, A. (2006) Genetic polymorphisms for vascular endothelial growth factor in perinatal complications. European Cytokine Network, 17, 266-270.
Treszl, A., Kaposi, A., Hajdú, J., Szabó, M., Tulassay, T. and Vásárhelyi, B. (2007) The extent to which genotype information may add to the prediction of disturbed perinatal adaptation: None, minor, or major? Pediatric Research, 62, 610-614. Malik, A.S., Boyko, O., Atkar, N. and Young, W.F. (2001) A comparative study of MR imaging profile of titanium pedicle screws. Acta Radiologica, 42, 291-293.