Although the antecedent for oxidative stress in pregnancies with abnormal growth trajectories is unknown, there is evolving evidence that UPI may result from abnormal placental implantation and development which initiates the pathogenic cascade. These states likely lead to altered gene expression and epigenetic changes that indefinitely affect the aberrant grown infants through adulthood. With the rising incidence of obesity and common incidence of UPI, effects of abnormal fetal growth states are likely to have public health implications unless the oxidative stress state can be addressed.
Obesity affects more than a third of reproductive age women in the United States with a prevalence that has more than doubled over the last two generations. Subsequently, the chronic physiologic stress alters the maternal environment, which has physiologic effects on the developing fetus and continues in the neonate following delivery Table 2. Summary of the oxidative stress state related to altered fetal and maternal growth status.
The antioxidant systems of term neonates from obese mothers are induced during gestation with increased relative activity of CAT and SOD at birth. For many critically ill neonates, exposure to inflammation begins prenatally. Prenatal inflammation has been associated with a variety of adverse neonatal outcomes, including preterm birth, neonatal sepsis, respiratory distress, NEC, intraventricular hemorrhage, and adverse neurodevelopmental outcomes, underscoring the close relationship between inflammation and oxidative stress in a pathogenesis of a wide variety of neonatal diseases.
Studies showing increased inflammatory markers in infants with NEC,[ 70 — 72 ] as well as in neonates who go on to develop BPD,[ 73 , 74 ] illustrate how ubiquitous inflammation is in neonatal diseases associated with increased oxidative stress. The close link between ROS and inflammation was first understood when the oxidative burst of PMNs were described almost 50 years ago. The inflammatory process can ultimately be a source of excessive ROS production with subsequent damage to cellular components and endothelial dysfunction when inflammatory responses are sustained.
The interplay of inflammation and oxidative stress has been studied in animal models of NEC where, through a variety of insults to the premature intestine, tissue damage and epithelial injury lead to an inflammatory response. Increased levels of pro-inflammatory cytokines have been described in neonates with NEC,[ 70 , 72 , 75 ] and in animal models of the disease. Inflammation has also been implicated in pathogenesis of BPD with increased levels of pro-inflammatory cytokines documented in infants who go on to develop BPD.
The complex interplay between inflammation and oxidative stress also appears to be important in pathogenesis of neonatal brain injury. Several studies have demonstrated increased oxidative stress in intraventricular hemorrhage, hypoxic-ischemic encephalopathy HIE , and epilepsy. Although much work has been done to elucidate the interplay between inflammation and oxidative stress, the exact mechanisms linking inflammation, oxidative stress, and neonatal pathology remain poorly understood.
The end result of excessive inflammation appears to be a vicious cycle whereby oxidative stress induces cytokine release, which then go on to increase ROS production further. While neonatal lung injury is often a result of a multitude of etiologic factors, oxidative stress has been recognized as a critical factor in pathophysiology of several neonatal lung diseases, including PPHN and BPD.
Oxidative stress is also a common endpoint for multiple events, including inflammation, hyperoxia, and mechanical ventilation, that contribute to sustained lung injury and result in impaired lung function. The production of oxidative stress originates from a variety of sources and, when combined with immature antioxidant defenses, may ultimately result in oxidative lung injury in an at-risk neonate. Evidence from animal models of PPHN linking increased oxidative stress to negative effects on NO signaling pathways and aberrant pulmonary vasodilatory responses supports the idea that ROS play an important role in the pathogenesis of PPHN.
When Dr. Northway first described BPD more than 50 years ago, he outlined the toxic effects of oxygen exposure on the preterm lung as it induced the disease phenotype. Finally, impaired antioxidant capacity in the premature pulmonary endothelium and epithelium can potentially result in an imbalance between ROS production and antioxidant abilities of the lung, leading to increased oxidative stress. Due to the crosstalk between the pulmonary endothelium and epithelium during development,[ ] the fact that PPHN and BPD have overlapping oxidative stress and antioxidant mechanisms is not surprising.
While pulmonary epithelial and endothelial cells have distinct mechanisms of oxidative stress production in hyperoxic lung injury models,[ 17 , 18 , — ] there are similarities in mechanisms of ROS generation between the PPHN and BPD disease models. Gene regulation in response to oxidative stress is complex and incompletely understood. As gene expression and regulation are organ specific, and in many cases cell-type specific, research on neonatal organ development and response to injury can be a challenge.
Recent work with the LungMAP project has demonstrated that the neonatal period is a dynamic phase of shifting gene expression in order to direct organ maturation. Therefore, neonatal disease modeling is further complicated by this superimposed developmental trajectory.
Neonatal murine hyperoxic lung injury models are versatile and allow research at the molecular level in tissues. When rodents are born at term, their lungs are developmentally in the saccular stage. In a murine neonatal hyperoxic lung injury model inducing BPD-like alveolar simplification, we determined mRNA gene expression in lung tissue of young mice using microarray technique.
Revhaug C, Saugstad OD, unpublished data Additionally, significant enrichment was observed regarding cytokine-cytokine receptor interactions, the PAKT, and B cell receptor signaling pathways. Any stress or alteration in cellular environment results in some cell or organ response. Gene regulation will change to produce proteins that may protect and repair the cell after damage or exposure to potentially damaging forces. Oxidative stress changes gene expression preferably by up-regulating antioxidant genes and regulating genes responsible for repairing cell damage.
ROS also act as messengers to induce expression of genes via signal transduction. In addition to the direct effects on gene expression, oxidative stress can also result in epigenetic changes. Epigenetic mechanisms regulate the availability of genes for transcription, resulting in altered gene expression without changes to the DNA sequence. The main methods of epigenetic regulation are DNA methylation and histone modifications chromatin structuring and remodeling that can lead to short-term and long-term effect on gene regulation.
There are some studies that have looked at oxygen treatment and ROS [ ] and the effect of oxygen and redox systems in the cells on the enzymes methylating DNA and histones [ ]. ROS can have both direct and indirect effects on epigenetic mechanisms. Studies on human autopsy lung samples, from preterm infants and stillborn fetuses, have demonstrated a developmental shift in gene methylation affecting gene expression. In patients with established BPD, 32 genes were shown to have differential methylation compared to controls including differential expression of genes in pathways like GSH-mediated detoxification.
Indirectly, ROS can affect gene regulation via epigenetic changes both locally and globally.
In the future the role of posttranslational epigenetic changes, like N 6 -methyladenosine m 6 A , may be of interest, as these mechanisms are largely not well understood. A recent study demonstrated that hypoxia induces an increase in methylation of mRNA and that increased m 6 A stabilizes mRNA, however, the impact of these changes remains to be further elucidated. There is strong evidence that the antioxidant defense system in premature infants is profoundly underdeveloped; however, attempts to therapeutically target these systems have yielded inconsistent results.
Antioxidant therapy developments have been limited by biochemical impediments such as compound half-life, poor cell penetrance, and difficulty targeting intracellular organelles.
Moreover, there is a lack of physiologic knowledge regarding ideal antioxidant levels, gestationally appropriate enzyme activity, the relationship between trace element cofactor levels and enzyme activity in the premature neonate, as well as the appropriate disease endpoints to assess therapeutic effect.
The very act of labor may prime the antioxidant system to deal with the transition to extrauterine life. Labor and vaginal delivery change the oxidative state in the mother, as well as in the fetus and the neonate, due to fluctuations in tissue oxygenation tension. Increased neonatal SOD, maternal MDA and placental xanthine oxidase activity have been reported in women who labored versus deliveries accomplished by caesarean without labor.
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This supports the theory that the oxidative stress burden produced during labor and delivery induces antioxidant enzyme expression and activity to deal with the transition to extrauterine life. Animal models have shown beneficial effects of antioxidant therapies regarding prevention and improvement of neonatal disease phenotypes. Mitochondria-targeted antioxidants improve adult mouse survival in hyperoxia, and attenuate alveolar simplification and right ventricular hypertrophy in neonatal hyperoxic lung injury models.
Supplementation of several different antioxidants, such as all- trans -retinoic acid, N-acetylcysteine, or astragaloside, all decreased the incidence of experimental NEC in the rat model likely through convergent mechanisms of lowering intestinal lipid oxidation as measured by MDA levels. Due to the direct oxygen toxicity on the lungs that occurs following premature birth, many groups have attempted to prevent BPD with antioxidant therapies ranging from vitamin and cofactor supplementation to replacement of antioxidant enzymes deficient in preterm infants.
Supplementation with vitamin E and the enzyme co-factor selenium did not decrease the incidence of BPD in several studies. The significant treatment effect was small, but the implementation of this therapy has been variable, likely due to the lack of prolonged clinical effect.
Application of flow cytometry in the early diagnosis of neonatal sepsis. Analyses were then stratified by chorionicity. While the incidence of stillbirth was greater in MCDA twins 3. Mazaki-Tovi S, Vaisbuch E. Reference lists of published guidelines and articles were reviewed. Protein Structures. However, moaning and grunting may be encouraged to help lessen pain.
Although underpowered for this outcome, Vitamin A therapy showed no difference in neurodevelopmental or pulmonary outcomes at 18—22 months. Although the rhSOD intervention did not decrease early death or BPD, at one year, survivors at one year had decreased pulmonary disease burden quantified by less emergency room visits, medications and pulmonary readmissions. Similar to BPD, animal models and patient studies have implicated oxidative stress and ROS generation in other neonatal disorders such as NEC, IVH and HI; but therapies have not become standard of care as the investigations have been limited by marginal effect or study size.
Melatonin has anti-oxidant, anti-apoptotic and anti-inflammatory properties, and has shown promise in published results from pre — and clinical intervention trials. Physiologic reasoning supports using antioxidant therapy to prevent or address neonatal diseases where oxidative stress and ROS generation are central to the pathophysiology; despite the promising results in preclinical animal studies, human trials for antioxidant therapies have demonstrated a marginal benefit at best and in most cases no disease effect Table 3.
In addition to the biochemical and physiologic limitations listed above, successful transition of antioxidant therapies from pre-clinical to clinical studies have been limited by poor understanding of the correlations between histologic changes in animal models and physiologic changes in human disease. Many animal models demonstrate a histopathologic change in the target organ and the treatment effect is similarly assessed; however these findings are difficult to translate to the clinical disease spectrum present in humans.
Further work is needed to understand the antioxidant system in premature neonates, determine ideal enzyme activity and understand how histopathologic improvements in animals models correlate with physiologic outcomes in human neonates. Oxidative stress is involved in a wide spectrum of newborn disease. Although not addressed in as much detail here, previous reviews have detailed the evidence regarding retinopathy of prematurity as an oxygen dependent condition. Since those early articles linking neonatal disease to oxidative stress more than 30 years ago, the complexity and interplay between different ROS mechanisms and cell types have progressed significantly.
The specific role and significance of mitochondrial derived oxidative stress has enhanced our understanding how oxidative stress may contribute to disease and injury especially in the newborn. Taken together with a better understanding of risk factors for oxidative stress, such as growth restriction and neonatal oxygen exposure, there is a hope that development of a new generation of antioxidants, in combination with other modulators, may contribute to prevention of oxidative stress induced injury of the newborn.
Genetic and epigenetic regulation occurs through several mechanisms; moreover, evidence supports that oxygen exposure induces epigenetic changes. Whether these are transitory or more permanent remains to be proven.
However, such genetic and epigenetic investigations are also of importance for augmentation of our understanding how to prevent newborn disease; perhaps most importantly, how neonatal diseases and interventions have lasting effects into adult life, and thus subsequently contribute to adult diseases. In figure 1 are summarized some of the concepts discussed in this review. Aberrant growth, maternal disease, such as obesity and UPI, infection, like chorioamnionitis, may all have more profound effects on the premature than the term infant.
Free Radic Biol Med. Author manuscript; available in PMC Oct PMID: Saugstad b, c. Marta Perez a. Mary E. Robbins a. Cecilie Revhaug c. When these were normally distributed, results were expressed as mean values and SD, otherwise median values and interquartile range were used IQR; 25—75 th percentile.
All tests were two-sided.
Association between quantitative variables was evaluated by Spearman non parametric correlation. Obstetric complications observed among the 70 enrolled pregnant women were observed in 29 cases In regard to the tested electrocardiographic values, no differences were found in the two groups. Moreover, maternal and neonatal ANA titre were highly correlated as evaluated by the Spearman rho 0. Thirty-seven Our observations, in agreement with data reported by other authors, confirmed a higher frequency of miscarriages, of premature births and of low birth weight infants born to women with autoimmune disease compared to epidemiologic data of general obstetric population in developed countries [ 11 ].
autoconfig.simonetti.eu.org/149.php Our findings, instead, did not reveal any neonatal lupus disease in the off-spring from positive mothers. We therefore supposed that the CHB has possibly been prevented by an adequate and carefully monitored pharmacological treatment during pregnancy.