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Perrone, S.; Manti, S.; Petrolini, C.; Dell’orto, V.G.; Boscarino, G.; Ceccotti, C.; Bertini, M.; Buonocore, G.; Esposito, S.M.R.; Gitto, E. Free Radical Disease in Newborn. Encyclopedia. Available online: https://encyclopedia.pub/entry/42518 (accessed on 16 July 2025).
Perrone S, Manti S, Petrolini C, Dell’orto VG, Boscarino G, Ceccotti C, et al. Free Radical Disease in Newborn. Encyclopedia. Available at: https://encyclopedia.pub/entry/42518. Accessed July 16, 2025.
Perrone, Serafina, Sara Manti, Chiara Petrolini, Valentina Giovanna Dell’orto, Giovanni Boscarino, Chiara Ceccotti, Mattia Bertini, Giuseppe Buonocore, Susanna Maria Roberta Esposito, Eloisa Gitto. "Free Radical Disease in Newborn" Encyclopedia, https://encyclopedia.pub/entry/42518 (accessed July 16, 2025).
Perrone, S., Manti, S., Petrolini, C., Dell’orto, V.G., Boscarino, G., Ceccotti, C., Bertini, M., Buonocore, G., Esposito, S.M.R., & Gitto, E. (2023, March 24). Free Radical Disease in Newborn. In Encyclopedia. https://encyclopedia.pub/entry/42518
Perrone, Serafina, et al. "Free Radical Disease in Newborn." Encyclopedia. Web. 24 March, 2023.
Free Radical Disease in Newborn
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This entry is adapted from the peer-reviewed paper 10.3390/children10030579

Oxygen toxicity is mainly due to the production of oxygen radicals, molecules normally produced in humans and involved in a myriad of physiological reactions. In the neonatal period, an imbalance between oxidants and antioxidant defenses, the so-called oxidative stress, might occur, causing severe pathological consequences.

preterm reactive oxygen species reactive nitrogen species free radicals newborn infants prematurity

1. Introduction

Oxidative stress is now considered the common denominator of several pathologies able to present itself with different manifestations according to the organ mostly affected. Among these, grouped together as “oxygen radical disease of neonatology”, are counted retinopathy of prematurity (ROP), periventricular leukomalacia (PVL), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC) and patent ductus arteriosus (PDA) [1]. Table 1 shows clinical studies investigation the association between oxidative stress biomarkers and free radical-mediated diseases of newborns.
Table 1. List of the included papers. Table legend: OS (oxidative stress); ROP (retinopathy of prematurity); VEGF (endothelial growth factor); TOS (Total oxidative status); TAS (total antioxidant status); MDA (malondialdehyde); PON1 (paraoxonase 1); PVL (periventricular leukomalacia); IPs (isoprostane); BPD (bronchopulmonary dysplasia); NOX (NADPH oxidase); ROS (reactive oxygen species); AEC (alveolar epithelial cell); SP (surfactant protein); NEC (necrotizing enterocolitis); NPBI (non-protein bound iron); AOPP (advanced oxidation protein products); TH (total hydroperoxides; PDA (patent ductus arteriosus).
Disease Reference Population OS Biomarker Results
ROP Pierce 1996 [2] Neonatal mice exposed to
hyperoxia		 VEGF The expression of VEGF in the peripheral retina was down-regulated by hyperoxia in conjunction with the arrest of growth and the loss of some of the developing vasculature.
Banjac 2018 [3] Preterm newborns TOS, TAS, MDA and PON1 TOS and MDA were significantly higher in infants with ROP as compared to infants
without ROP
WMI Coviello 2021 [4] Preterm newborns Cord blood and plasma IPs Cord blood IPs were not correlated with white matter injury score, whereas higher plasma IPs and lower gestational age predicted higher white matter injury score
Coviello 2022 [1] Preterm newborns IPs Higher plasma IPs levels are associated with decreased functional brain activity.
BPD Carnesecchi 2009 [5] Wild-type and NOX1- and NOX2-deficient mice ROS ROS production was reduced in lung from NOX1-deficient mice.
Hou 2015 [6] Newborn rats AEC I (aquaporin 5, T1α) and AEC II markers (SP-C, SP-B) Authors found an increase in AEC II-to-AEC I transdifferentiation in a hyperoxia-induced, BPD-like model at both the tissue and cellular levels.
NEC Baregamian 2011 [7] Rat and human fetal intestinal epithelial cells ROS OS leads to increased intracellular ROS production by mitochondria and activation of mitochondrial apoptotic signaling pathways in both human fetal and rat intestinal epithelial cells.
Perrone 2012 [8] Preterm newborns NPBI, AOPP and TH AOPP, TH and NPBI cord blood levels were significantly higher in babies with NEC
PDA Longini 2010 [9] Preterm newborns (<33 weeks of gestational age) urinary IPs Ibuprofen therapy for PDA closure reduces the
risk of OS, inducing a decrease of urinary IPs.
Chen 2012 [10] Newborn mouse IPs IPs levels are increased shortly after birth in response to increased oxygen tension and this may serve as a novel physiological signal to stimulate postnatal PDA closure. Authors found that IPs have both vasoconstrictive and vasodilatory effects.

2. Retinopathy of Prematurity

Despite improvements in neonatal care, ROP represents one of the main causes of visual impairment and blindness in premature babies. Several perinatal and postnatal factors contribute to its genesis with a higher incidence of decreasing birth weight and gestational age [11].
ROP is a multiphasic pathologic process linked to the incomplete maturation of retinal vascularization in premature newborns. It occurs in two phases, the vascular attenuation phase and the fibrovascular proliferative one in which suppression and production of vascular-endothelial growth factor (VEGF), respectively, plays an important role [2].
The vascular attenuation phase is the first phase of ROP. It starts after preterm birth when supplemental oxygen, required during resuscitation/stabilization in the delivery room, causes cessation of normal retinal vascularization. The enhanced production of ROS, due to supplemental oxygen, determines structural and functional changes in several retinal molecules leading to the arrest of neurovascular development and the obliteration of existing vascular beds [12].
The fibrovascular proliferative phase is the second phase in which hypoxia, due to the arrest of the growth of retinal blood vessels, induces retinal vasoproliferation increasing VEGF production to improve retinal perfusion. Hypoxia itself increases ROS slowing upstream events in the electron transport chain, raising the concentration of oxygen donors and promoting oxidative stress [13].
The retina is highly sensitive to lipid peroxidation as it is composed of lipids with high levels of polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA), cis-arachidonic acid, and choline phosphoglyceride [14].
Among a panel of biomarkers currently investigated, MDA, GSH/GSSG, 8-Hdhg, and PUFAs appear to be the most promising for the diagnosis and treatment monitoring of ROP [6][15]. All these biomarkers are involved in the cascade of events leading to oxidative stress damage. Thus, their potential role in the prevention of retinal damage and irreversible vision disorders is justified.

3. Periventricular Leukomalacia

PVL is the main substrate for cerebral palsy and is a form of cerebral white matter damaged characterized by focal necrosis of white matter near the lateral ventricles, with subsequent cystic formation, and more diffuse injury of deep cerebral white matter. The classic neuropathology of PVL has given rise to several hypotheses about the pathogenesis, largely relating to ischemia-reperfusion damage in the premature infant [16].
Oligodendroglia (OL) precursor cells, the main target in PVL, are exquisitely vulnerable to attack by free radicals [7]. This vulnerability is maturation-dependent, decreasing in OL mature cells, and appears to relate to a developmental window characterized by a combination of deficient antioxidant defenses and active acquisition of iron during OL differentiation [16]. The high concentration of unsaturated fatty acids in the neonatal brain and the high metabolic rate, almost exclusively supported by oxidative metabolism of the developing neural tissues, predispose to the propagation of oxidative stress [7].
Coviello et al. [8] demonstrated that measurement of plasma-isoprostanes in the first days of life in very low birth weight infants may help discriminate patients showing abnormal white matter injury score at the term of gestational age, thus showing the potential to early identify newborns at risk for brain injury.
Plasma-isoprostanes may also represent a useful biomarker of brain vulnerability in high-risk infants [17].

4. Bronchopulmonary Dysplasia

BPD is the major cause of chronic lung disease and morbidity in preterm infants. As opposed to “old BPD”, expression of lung injury caused by high airway pressures and oxygen toxicity, the “new BPD” is the result of complex interactions between altered alveolar and vascular development, injury by ante-/post-natal pathogenic factors and lung reparative processes [10][18]. One of the main causes of BPD is oxidative stress continuously sustained by the lung inflammatory process due to hyperoxia exposure. Inadequate nutrition and type of ventilation contribute to increased oxidative stress which may trigger changes leading to permanent lung damage [19][20]. Hyperoxia-induced acute oxidative stress is mediated by the increased number and over-activation of NOX1 during hyperoxia with subsequent excessive ROS production and destruction of the alveolar capillary barrier [5].
Oxidative stress can lead to BPD in various ways. Fibrotic process described in BPD is due to the balance between matrix metalloproteins (MMPs) and their inhibitors. Oxidative stress increases both MMPs and their inhibitors, so it may lead to lung damage by increasing collagenase activity causing disruption of the extracellular matrix [9].
Oxidative stress also interferes with the production of surfactant. As a result of inflammation and edema, transudate plasma proteins and inflammatory cells impair extracellular surfactant. Hyperoxia reduces also surfactant phospholipid production [21].
Furthermore, alveolar epithelial type-II cells (AEC II) are the most important stem cells in lung tissue playing a crucial role in the regulation of lung tissue growth, maturation, wound-repair process, and lung fluid homeostasis. The proliferation and differentiation of AECIIs are the major factors that regulate the post-injury repair of alveolar epithelial structure and functions. Additionally during lung injury, as a stem cell, AECII can be converted to AECI, and can secrete a variety of bioactive substances to restore alveolar capillary barrier integrity and maintain alveolar function. Oxidative stress due to hyperoxia exposure interferes with all these important functions of AECII inducing excessive apoptosis of AECII and inhibiting their proliferation, promoting further lung damage [22].
The involvement of harmful effects of oxygen supplementation and oxidative stress has been demonstrated in experimental and clinical studies in the neonatal population [23].

5. Necrotizing Enterocolitis

NEC is a disorder of premature newborns that results in inflammation and bacterial invasion of the bowel wall [24]. Many etiologic factors including immaturity, hypoxia/ischemia, hyperosmolar feedings, bacterial colonization, and oxidative stress have been identified [24]. Some authors recently proposed that the underlying initial condition is the reduced ability of the neonatal gut epithelial cells to reduce oxidative stress so that, after bowel exposition to enteral feeding, the increased oxidative stress tips the epithelial gut cells toward apoptosis, inflammation, bacterial activation, and eventual necrosis [25].
Confirming the role played by oxidative stress in determining NEC, levels of non-protein bound iron and total hydroperoxides, measured in cord blood, showed a clear correlation between intrauterine stress oxidative events and the risk of developing NEC [26].

6. Patent Ductus Arteriosus

PDA consists of a persistence of the fetal communication between the descending aorta and the left pulmonary artery. After birth ductus arteriosus usually closes in the first days of life and closure is due both to a decrease of circulating prostaglandin E2, a vasodilator synthetized by the placenta during fetal life, and an increase of circulating oxygen after breathing [27]. Ductus arteriosus (DA) is therefore affected by changes in pO2 as intrauterine hypoxia maintains the patency of the ductus and hyperoxia at birth facilitates its closure.
PDA is more frequently seen in preterm infants, particularly those born at <30 weeks’ gestation [27], probably due to the different role played by isoprostanes (IsoPs), a biomarker of oxidative stress, in preterm or term newborns [28]. Oxygen exposure increases IsoPs levels in newborn mouse lungs causing constriction of the isolated DA by activating the thromboxane (TxA2) receptor, however, IsoPs induce vasodilation of preterm isolated DA following the interaction with prostaglandin E2 receptor 4 (EP4). IsoPs can therefore mediate constrictive or dilatory effects on the DA according to the relative concentration of TxA2 and EP4 receptors which modify their levels in consideration of gestational age. In fact, as gestational age increases, EP4 receptors are reduced and TxA2 receptors increase. In consideration of these studies, it can be hypothesized that oxidative stress associated with delivery could favor DA closure in term infants by activating the TxA2 receptors or DA dilation and PDA in preterm infants by activating EP4 receptors [29].
In addition, hemodynamically significant PDA may cause hypoperfusion of organs which can contribute to the genesis of other free radical diseases [30][31]. In line with these findings, Longini et al. [32] reported increased urinary IsoPs levels in forty-three preterm babies (GA: <33 weeks) with PDA. Moreover, seven days after treatment with ibuprofen, a significant decrease in IsoPs was detected, confirming the role of inflammation in the PDA and the benefit of ibuprofen treatment in reducing the risk of OS related to free-radical (FR) generation.

References

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Subjects: Pediatrics
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Serafina Perrone
,
Sara Manti
,
Chiara Petrolini
,
Valentina Giovanna Dell’Orto
,
Giovanni Boscarino
,
Chiara Ceccotti
,
Mattia Bertini
,
Giuseppe Buonocore
,
Susanna Maria Roberta Esposito
,
Eloisa Gitto
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Update Date: 27 Mar 2023
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