Non-invasive assessment of oxidative stress in preterm infants

https://doi.org/10.1016/j.freeradbiomed.2019.02.019Get rights and content

Highlights

  • Reducing invasive and painful techniques in preterm infants studies.

  • Non-invasive samples to determine oxidative stress biomarkers.

  • New biomarkers for a close monitoring.

Abstract

Preterm newborns have an immature antioxidant defense system and are especially susceptible to oxidative stress. Resuscitation, mechanical ventilation, intermittent hypoxia and apneic episodes require frequently oxygen supplementation which leads to oxidative stress in preterm newborns. The consequences of oxidative damage are increased short and long-term morbidities, neurodevelopmental impairment and increased mortality.

Oxidative stress biomarkers are determined in blood samples from preterm children during their stay in neonatal intensive care units especially for research purposes. However, there is a tendency towards reducing invasive and painful techniques in the NICU (Neonatal Intensive Care Unit) and avoiding excessive blood extractions procedures.

In this paper, it has been described some studies that employed non-invasive samples to determine oxidative stress biomarkers form preterm infants in order to perform a close monitoring biomarker with a significant greater predictive value. Among these methods we describe a previously developed and validated high-performance liquid chromatography tandem mass spectrometry method that allow to accurately determine the most reliable biomarkers in biofluids, which are non-invasively and painlessly obtained.

Introduction

Oxidative stress is most commonly triggered by reactive oxygen species (ROS) (e.g. hydroxyl radicals, superoxide anions, hydrogen peroxides) generated under certain physiologic conditions in the mitochondria and other cell organelles (peroxisomes, Golgi, endoplasmic reticulum). ROS are originated as a consequence of a normal leak amounting 2% of the electrons transported along the electron transport chain (ETC), and in the endoplasmic reticulum or nuclear and cell membranes, but there are also generated when the antioxidant system renders incapable of scavenge ROS in excess [[1], [2], [3]]. In addition, enzymes, such as NADPH oxidases are great generators of ROS and constitute one of the most important sources of hydrogen peroxide [1,3]. Free radicals are highly reactive chemical species that instantaneously interact with nearby existing biomolecules in the cell (proteins, lipids, DNA and others) producing oxidized derivatives [[4], [5], [6]]. Some of them, show high reactivity and may form adducts with proteins, as well as oxidize other biomolecules, altering specific molecular pathways [7] (see Fig. 1).

The main causes of oxidative stress in the newborn period are associated with oxygen administration [8], mechanical ventilation [9], intermittent hypoxia and apnea episodes [10], and asphyxia [11]. In general, the fetal-to-neonatal transition is characterized by intermittent hypoxia periods, involving over-production of oxidative substances and a disequilibrium in important cellular pathways, such as oxidation or inflammation biomolecules [12]. Preterm newborns have an immature antioxidant defense system and are, therefore, prone to oxidative damage. As a consequence, preterm infants will develop some conditions related to the production of free radicals with short-and-long-term consequences [13]. In this sense, recent research has focused on the impact of perinatal oxidative stress on the human brain development and its associated morbidities [14,15]. Moreover, these oxidative stress conditions are related to some chronic pathologies such as necrotizing enterocolitis (NEC) [16,17], bronchopulmonary dysplasia (BPD) [[18], [19], [20]], retinopathy of prematurity (ROP) [21], cardiac dysfunction [22], and acute kidney injury [23]. Therefore, oxidative stress monitoring and control would be highly desirable in the neonatal period to avoid its negative consequences and to improve outcomes of preterm children. In the last few years, some potential treatments that could reduce oxidative stress levels in preterm infants have been studied, such as melatonin or surfactant, but more clinical trials are required in order to confirm their clinical applicability [24].

There is an increasing need in the development of reliable tools to evaluate, control, and reduce oxidative stress in preterm newborns [25]. A promising evaluation at molecular level is based on biomarkers obtained from biomolecules oxidation [26].

Biomarkers derived from lipids peroxidation play an important role in brain damage assessment, since brain is characterized by high lipid composition and oxygen consumption. Among these compounds, malondialdehyde (MDA) has been the most studied, and it has been determined in plasma and bronchoalveolar lavage samples from preterm newborns [[27], [28], [29]], using the thiobarbituric acid reactive substances (TBARS) assay. Thus, high levels of TBARS were found in studies carried out with neonatal blood samples a few days after birth [30]. However, most of the TBARS formed in vivo are not related to lipid oxidation [31]. In addition, plasma and serum isoprostanes offer a reliable measurement of in vivo oxidative stress [32,33], and constitute biomarkers that are increasingly used. Regarding DNA and protein oxidation biomarkers, 8-hydroxy-2′-deoxyguanosine (8-OHdG) and carbonyl proteins have been the most studied compounds, respectively [34]. In this sense, 8-OHdG is used as oxidative stress biomarker from blood and tracheal aspirates samples [35,36]. Also, some protein oxidation products, such as carbonylated proteins, are evaluated as oxidative stress biomarkers from plasma and bronchoalveolar lavage fluid samples [37,38].

In general, most of the studies have evaluated oxidative stress in blood samples, and a few of them used tracheal aspirates and bronchoalveolar lavage fluid samples. However, the invasiveness and pain derived from these sampling procedures limit their sequential use for monitoring evolving conditions.

Therefore, non-invasively obtained samples could allow to monitor levels of biomarkers with desired frequency, without causing pain or distress to the infants and thus, providing clinicians with very relevant information [39]. In addition, the antioxidant profile evaluation would allow a personalized treatment avoiding oxidative stress related pathologies [40].

The aim of this article is to review oxidative stress biomarkers determined in non-invasive samples as oxidative status evaluation in preterm infants, which could be used as diagnosis, prognosis and monitorization of different treatments.

Section snippets

Non-invasive monitoring of oxidative stress in preterm newborns

In Table 1 we have summarized some studies that have determined oxidative stress biomarkers in non-invasively obtained samples from preterm infants.

Analytical methods development and applications

Most of the analytical methods applied to determine oxidative stress biomarkers in non-invasive samples are based on immunoassays, colorimetric assays, commercial kits and spectrophotometric measures (Table 1). These techniques show some disadvantages, such as, low sensitivity and specificity, high number of interferences and matrix effect, and low precision.

Recently, our group has validated reliable analytical methods to determine cortisol and isoprostanoids in non-invasive samples, such as

Oxidative stress monitoring proposal in the neonatal period

Non-invasive monitoring of oxidative stress damage in preterm newborns could be reliably performed with salivary and urinary determinations of different oxidized products. Brain is one of the most important organs affected by oxidative stress in preterm newborns, and considering its high lipid composition, the determination of lipid peroxidation biomarkers in saliva or urine samples could be highly specific of neurological damage [80]. In this sense, it is important to highlight the

Conflicts of interest

The authors report no conflict of interest.

Acknowledgements

CC-P acknowledges a post-doctoral “Miguel Servet I” Grant (CP16/00082) from the Health Research Institute Carlos III (Spanish Ministry of Economy and Competitiveness).

CP-B acknowledges a pre-doctoral Grant (associated to “Miguel Servet” project CP16/00082) from the Health Research Institute Carlos III (Spanish Ministry of Economy, Industry and Competitiveness).

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