Bronchopulmonary dysplasia (BPD) is a chronic lung disease, with its own clinical, radiological, and histopathological characteristics, which mainly affects premature newborns (NBs), resulting from a combination of factors that include immaturity, inflammation, and lung injury, in addition to therapy with mechanical ventilation and exposure to high concentrations of oxygen. However, even with advances in care for critically ill NBs, BPD continues to be a challenge for the care team and family members. This has been identified as one of the most important causes of morbidity and mortality due to prematurity and can have significant impacts on the quality of life of the affected patients. While interactions between the risk factors associated with BPD characterize it as multifactorial, its real pathogenesis still remains uncertain, as some NBs, despite having similar risk factors, do not develop it, suggesting, therefore, that susceptibility to BPD is genetically determined. Genetic variants in the glutathione S-transferase Mu-1/glutathione S-transferase theta-1-null (GSTM1/GSTT1) genes may be associated with a greater risk of developing BPD in premature NBs, as they affect the function of glutathione S-transferases (GSTs) enzymes and, consequently, the body’s ability to eliminate toxic or harmful pro-inflammatory substances. GSTM1/GSTT1-null individuals, due to the absence of gene expression, present loss of enzymatic activity of the respective GST enzymes, triggering failures in the detoxification process and the consequent development of numerous diseases resulting from oxidative damage such as infertility, chronic kidney disease, eryptosis, retinopathy of prematurity, necrotizing enterocolitis, periventricular leukomalacia, intraventricular hemorrhage. The objective of this narrative review was to highlight the role of genetic variants in the GSTM1/GSTT1 genes in the onset of BPD.

Highlights of the Study

  • Balance between pro-oxidant/antioxidant systems preserves cellular functions.

  • Oxidative stress is involved in the bronchopulmonary dysplasia (BPD) pathogenesis.

  • Oxidative damage resulting from glutathione S-transferase Mu-1/glutathione S-transferase theta-1-null genotype increases the risk of BPD.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease has its own clinical, radiological, and histopathological characteristics, and it mainly affects premature newborns (PTNB). It results from the combination of several factors, such as immaturity, mechanical ventilation therapy, and exposure to high concentrations of oxygen, which trigger pulmonary reactions like inflammation, apoptosis, and remodeling of the extracellular matrix. These reactions compromise the growth, function, immunity, alveolarization, and vascularization of lung tissue, thus affecting both lung repair and regeneration [1, 2].

It is one of the most serious, devastating, and challenging diseases affecting newborns (NBs) admitted to the neonatal intensive care unit. Despite advances in the care of critically ill NBs, BPD remains a significant challenge for both the care team and family members, with substantial impact on the quality of life of affected patients [1, 2]. Although the mortality rate of preterm infants is declining, the incidence of BPD remains high, as more NBs with extreme prematurity survive, leading to the development of associated complications. The incidence of BPD varies between different centers due to differences in neonatal risk factors, therapeutic management, and definitions or classifications. NBs weighing less than 1,250 grams represent 97% of BPD cases. In extremely preterm NBs, the incidence of BPD is estimated between 48% and 68%, being inversely proportional to the gestational age (GA) [1, 3, 4]. According to data obtained in 2001, by the Brazilian Neonatal Research Network, the incidence of BPD varies from 3.3% to 30%, for NBs with birth weight less than 1,500 g; and for NBs weighing between 500 and 750 g, the incidence increases to 70–85% [5].

In this narrative review, the pathophysiology related to oxidative stress and the GSTM1/GSTT1 genes would be emphasized in normal lung development and in the BPD. Scientific databases, including PubMed, Scopus, Web of Science, Google Scholar, and Medline Plus using the terms “bronchopulmonary dysplasia; glutathione transferase; free radicals and oxidative stress” were searched for this review. Within these search terms, every subtitle in the text was searched individually. Full-text papers were reviewed after removing duplicates and screening titles and abstracts, and the most relevant information found is presented in this review.

Normal Lung Development

Lung development is subdivided into three main periods: embryonic, fetal, and postnatal, depending on GA: (1) embryonic period (4–7 weeks) – beginning of lung organogenesis and the development of the main airways and pleura; (2) fetal period – divided into three phases: (a) pseudo-glandular (6–17 weeks) – continuation of the formation of the bronchial tree up to the terminal bronchioles and the appearance of the first acini, but still without the differentiated epithelium; (b) canicular (16–26 weeks) – formation of the most distal part of the airways and the alveolar-capillary barrier, differentiation of the acini epithelium and production of surfactant (between 22 and 24 weeks); (c) saccular phase (24–38 weeks) – cell differentiation occurs, completion of development and expansion of acini; (3) postnatal period: alveolar phase (36 weeks – adolescence) – septation and maturation of the alveoli occurs [6, 7].

Lung Development in BPD

In preterm NBs with BPD, lung development is interrupted in the transition from the end of the canicular phase to the saccular phase, therefore occurring: (a) decreased septation and alveolar hypoplasia with consequent smaller number and larger alveolar diameter, resulting in concomitant reduction of the surface area available for gas exchange; (b) imbalance in the development of the pulmonary vasculature, with thickening of the muscular layer of the pulmonary arterioles, leading to increased resistance in these vessels and consequently a greater risk of developing pulmonary hypertension. These aspects are characteristic of the so-called “new” BPD, the most common form today [8‒10]. This one contrasts with “classic” BPD, which is uncommon today and occurs in less immature NBs (GA >28 weeks) and is characterized by airway damage, bronchial smooth muscle hyperplasia, inflammation, interstitial edema, and parenchymal fibrosis. These pathological findings were caused by aggressive oxygen therapy and mechanical ventilation, at a time when less aggressive forms of ventilation, surfactant treatment, and the use of prenatal corticosteroid therapy were not yet available [8‒10].

The etiopathogenesis of BPD is multifactorial and involves the discontinuity of lung development due to prenatal, natal, and postnatal factors, which cause inflammation and damage in the lungs of premature babies. The factors that represent a high risk of developing BPD are (a) prenatal: genetic susceptibility, male sex, intrauterine growth retardation, chorioamnionitis, preeclampsia and angiogenesis disorder, oxidative stress, maternal smoking; (b) natal: prematurity, lung immaturity, and low birth weight; (c) postnatal: excessive or prolonged oxygen therapy, oxidative stress, mechanical ventilation, neonatal sepsis, patent ductus arteriosus, respiratory microbial dysbiosis [1, 3, 4, 11, 12]. These factors play a primary role in the disease. Additionally, antioxidant, antiprotease, and nutritional deficiencies, among others, further contribute to the inflammatory response with acute lung parenchymal injury, leading to damage to the airways (emphysema and atelectasis), pulmonary interstitium (fibrosis, decreased number of alveoli, and capillaries), and vascular system (pulmonary hypertension), which corresponds to the clinical-radiological picture [1, 3, 4, 11‒14].

BPD was first described in 1967 in a group of NBs with respiratory distress syndrome, which appeared to be due to the use of mechanical ventilation and high levels of oxygen therapy. Changes in the at-risk population (an increasing number of NBs of lower GA) and advances in neonatal care and therapy have promoted changes in the clinical course of the disease, with a major impact on the initial description. Because of this, it has been difficult to reach a consensus on the definition, leading to several conceptual revisions [15]. In 1988, BPD was redefined as the need for oxygen therapy at 36 weeks of postmenstrual or corrected gestational age (CGA). This definition was based on a positive predictive value of 63% for respiratory morbidity at 2 years. Although this definition is widely used in scientific research, due to its simplicity and objectivity, it does not include extremely premature infants (GA <28 weeks) nor the severity of respiratory failure [16]. In 2001, with the aim of reducing variability in BPD diagnostic criteria, the National Heart, Lung, and Blood Institute (NHLBI) together with the National Institute of Child Health and Human Development (NICHD) created a new criterion. This defined BPD as a condition which requires oxygen therapy for at least 28 days. NBs who met this criterion were divided into three groups at 36 weeks of CGA: mild BPD if they were on ambient air, moderate BPD if they required FiO2 <30%, or severe BPD if they required FiO2 >30% or positive pressure ventilation [17]. In 2003, a physiological test was proposed in order to standardize the oxygen requirement criteria, reducing the effect of variations in clinical practice in different centers. According to this test, it was considered that there would be a need for oxygen therapy if the peripheral oxygen saturation (SpO2), measured in ambient air for 60 min, fell below 90%. However, this definition does not include new methods of noninvasive ventilation (e.g., high-flow nasal cannula) nor lethal BPD cases before 36 weeks of CGA [18]. In 2018, BPD was again defined when present in premature infants under 32 weeks of GA with radiographic confirmation of lung parenchymal disease and who at 36 weeks of GA require one of the ventilation modalities for ≥3 consecutive days, to maintain SpO2 between 90 and 95%. The severity scale was changed to grades I–III, now including new modes of noninvasive ventilation and also included children with early lethal BPD in grade IIIA [19]. The radiological classification of BPD, defined in 1968, is an approach that helps in assessing the severity of lung disease in affected NBs. Chest X-rays are an important tool for monitoring the progression of BPD and helping to plan the therapeutic approach, as they take into account the radiological characteristics, the extent of the lung lesion, and the histopathological and clinical aspects distributed into four stages: (a) stage I (1st to 3rd day of life): it clinically and radiographically resembles uncomplicated respiratory distress syndrome, except for excessive mucosal necrosis; (b) stage II (4–10th day of life): it characterized by marked pulmonary opacity, especially in the basal areas of the lungs. Often referred to as the “pulmonary atelectasis” stage. Difficulty in reducing high O2 levels and cycles of alveolar injury and repair; (c) stage III (11–20th day of life): pulmonary cystic appearance with lesions of the respiratory mucosa, focal emphysema and persistence of hyaline membranes, and gradual weaning of high O2 levels; (d) stage IV (more than 30 days of life): there is a predominance of symptomatic chronic lung disease, with areas of lung parenchymal density, increased thoracic volume due to lung hyperinflation, and cardiomegaly, which may gradually disappear or progress to cor pulmonale and death [13, 14, 20].

While interactions between the risk factors associated with BPD characterize it as multifactorial, its real pathogenesis still remains uncertain, as some NBs, despite having similar risk factors, do not develop it, suggesting, therefore, that susceptibility to BPD is genetically determined [21‒25]. Biomarkers that can definitively diagnose the presence of BPD or identify a pre-BPD stage are urgently needed. The lack of biomarkers for early identification, together with still ineffective therapies, results in the significant prevalence of the disease. Inherited genetic differences among preterm infants dictate variability in the incidence and severity of BPD, as many genes influence the normal lung development and growth, resulting in heterogeneous and unfavorable susceptibility thresholds for BPD [21‒25].

Oxidative stress (OS) is involved in the pathogenesis of numerous diseases, including fetal and neonatal diseases. In PTNBs, antioxidant systems are still inefficient and therefore do not have the capacity to neutralize the harmful effects of free radicals (FRs), leading to “FR-related diseases” which cause cellular, tissue and organic damage to the gonads, kidneys, retina, intestines, brain, heart, red blood cells, lungs, as well as several other organs and tissues [26‒33]. The relationship between the generation of FRs, oxidative stress, and diseases mediated by FRs in the perinatal period is complex. It depends on factors such as the severity, intensity, and timing of the mechanisms responsible for the production of FR, the timing of the oxidative process, the degree of maturity of the organs, and the ability to neutralize the injury. Each of these factors has differential effects on different tissues, with certain specific cells being particularly vulnerable in the perinatal period. Excessive production of FR is largely responsible for cellular, tissue and organic damage due to compromised oxidative balance [26‒33]. During intrauterine life, many factors such as hypoxia, inflammation, and infections can induce the generation of FR. Whenever produced, FR can induce oxidative stress and tissue damage. High levels of OS biomarkers have been found in the amniotic fluid of pregnancies with fetuses that have intrauterine growth restriction, which is often exacerbated by intrauterine hypoxia and impaired blood flow to the fetus. Chronic restrictions in uterine blood flow provoke placental and fetal responses as a form of growth adaptation to hypoxia [34‒38]. Furthermore, OS injury can modify the strength and elasticity of collagen and cause premature rupture of membranes and premature births. Fetuses and premature babies are more susceptible to injuries in this system than full-term babies due to: (a) structural and functional changes in immature organs; (b) overload of aerobic metabolism with rapid and increasing energy demand; (c) possible emergence of conditions leading to excessive FR production; (d) presence of high levels of iron not bound to proteins; (e) lack of antioxidant systems that only reach maturity in the first year of life [34‒38]. FRs can be generated by endogenous (hypoxia, ischemia, ischemia-reperfusion, hyperoxia, inflammation, mitochondrial impairment) and exogenous mechanisms (pollutants, alcohol, tobacco, medications, toxins, ultra-processed foods, radiation). The burden of FR production is neutralized by intracellular antioxidant systems and maintaining this balance is essential for normal cellular functions. The harmful effects of FR are linked to their property of being very unstable molecules, their ability to react with polyunsaturated fats, cell membrane acids, proteins, polysaccharides and nucleic acids, causing intracellular functional changes [28, 32, 33, 35, 38‒42].

NBs, especially premature ones, are particularly vulnerable to oxygen toxicity due to accelerated production of FR, low antioxidant protection and susceptibility to injury in rapidly growing tissues. The numerous diseases resulting from oxidative injury are grouped and categorized as “FR-mediated diseases,” which include infertility, chronic kidney disease, eryptosis, patent ductus arteriosus, retinopathy of prematurity (ROP), necrotizing enterocolitis, periventricular leukomalacia, intraventricular hemorrhage, etc., including BPD [28, 32, 33, 35, 38‒42]. Several mediators are involved in the inflammatory cascade of these “FR-mediated diseases,” including cytokines that trigger the production of reactive oxygen species (ROS), reactive nitrogen species and other FRs. ROS are unstable molecules generated in large quantities during oxidative stress. They are extremely reactive and can transform and affect other molecules with which they collide, such as proteins, carbohydrates, lipids, and nucleic acids [2, 43‒49].

The transition from prenatal to postnatal life causes a significant increase in arterial oxygen tension and activation of metabolic pathways that allow the NB to adapt to the extrauterine environment. Although supplemental oxygen is frequently used as therapy in preterm infants with hypoxemic respiratory failure, excessive or prolonged exposure to the same oxygen results in increased ROS generation and the expression of pro-inflammatory cytokines. Generation of ROS and inflammation cause injury and impair the reparative processes in the developing lungs, which ultimately lead to the development of BPD [2, 43‒49].

Oxidative Stress and BPD

The oxidative stress plays a central role in pathogenesis of BPD, being one of the main factors responsible for the development of the disease due to the following pathophysiological mechanisms [2, 43‒49]: (1) immature antioxidant systems: preterm NBs have underdeveloped antioxidant systems, making them more vulnerable to oxidative stress. Their lungs have not yet fully developed enzymatic defenses, such as superoxide dismutase (SOD), catalase, glutathione peroxidase, etc., which combat ROS. This increases the risk of cellular damage when exposed to high oxygen levels or inflammation; (2) oxygen exposure and mechanical ventilation: high levels of inspired oxygen, both from oxygen therapy and/or mechanical ventilation, generate an excess of ROS, overwhelming the immature antioxidant defenses of PTNB. ROS can damage epithelial and endothelial cells in the lungs, triggering inflammatory and fibrotic responses that contribute to lung injury; (3) cellular damage caused by ROS: ROS damage lipids, proteins, and DNA of pulmonary cells, leading to apoptosis or necrosis. This affects alveolar development, disrupting the process of alveolar septation, which is key to the development of BPD. Cell death and structural damage lead to the formation of fibrotic areas in the lungs, a hallmark of BPD; (4) inflammation and oxidative stress: oxidative stress is closely linked to pulmonary inflammation by triggering the release of cytokines from the inflammatory cascade, in addition to growth factors, such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), among others. These mediators further inflame lung tissues, perpetuating the cycle of inflammation and oxidative damage, impairing lung development and leading to fibrosis and BPD [2, 43‒49].

Excessive production of FR is largely responsible for damage due to compromised oxidative balance. However, oxidative stress is a bidirectional reaction because, while excessive oxidation causes cellular, tissue and organics damage, the maintaining a physiological level of oxidative reaction, called oxidative eustress, is essential to maintain vital reactions through redox signaling [50‒52]. As antioxidant defense systems develop late during pregnancy, preterm infants present ineffective responses due to deficiencies in some non-enzymatic or extracellular antioxidant nutrients (vitamins A and E, iron, copper, zinc and selenium) or due to the immaturity of the systems endogenous or intracellular enzymatic antioxidants (enzymes superoxide dismutase, catalase, glutathione peroxidase, glutathione S-transferase [GST]). It also includes genetic variation in antioxidant systems, related to the risk of developing BPD [3, 24, 53‒56]. Antioxidant enzymes play a crucial role in neutralizing ROS and reactive nitrogen species (RNS), which are harmful byproducts of oxidative stress. These enzymes work together in a coordinated manner to reduce ROS and RNS, protecting cells from oxidative damage and maintaining the redox balance necessary for cellular function: (1) SOD catalyzes the conversion of superoxide radicals (O2) to hydrogen peroxide (H2O2) and oxygen (O2); (2) Catalase converts hydrogen peroxide (H2O2) into water (H2O) and oxygen (O2), thus preventing the formation of the highly reactive hydroxyl radical (OH), which can cause significant cellular damage; (3) glutathione peroxidase catalyzes the reduction of hydrogen peroxide (H2O2) and organic hydroperoxides using GSH as a substrate, converting them to water and alcohols, respectively; (4) GST detoxifies electrophilic compounds by conjugating them with reduced GSH. This includes the detoxification of products resulting from ROS and RNS damage, such as lipid peroxidation byproducts. GST helps neutralize toxic compounds and protect against oxidative stress, playing a significant role in the lung and liver, where detoxification is critical [52, 57‒60].

GSH – An Intracellular Antioxidant

Reduced GSH, a water-soluble antioxidant, is one of the most abundant intracellular nonprotein compound containing a thiol group (R−SH). Its primary function is to maintain the intracellular redox balance and play a role in cell signaling to activate genetic transcription [61, 62]. GSH has an important role in the storage and transport of cysteine, in cellular defense against FR, peroxides and xenobiotics, acting together with the enzymes glutathione peroxidase and GST. In addition to these functions, GSH also participates in the modulation of signal transduction, regulation of cell proliferation, regulation of the immune response, metabolism of leukotrienes and prostaglandins [61, 62]. GSH is a molecule that intervenes in several processes, such as antioxidant and detoxifier, in the transport of amino acids, synthesis of proteins and nucleic acids, maintenance of the active form of certain enzymes, protection of the organism against exposure to solar radiation and in the regulation of apoptosis [63‒67]. Therefore, it plays a central role in the cells' first line of defense against oxidative stress and in the biotransformation and elimination of reactive metabolites, making them water-soluble in order to facilitate their excretion. As it participates in numerous metabolic processes, the level of GSH in the body is a strong indicator of the respective physiological state, where its depletion can cause irreversible cellular damage [63‒67]. Relative GSH deficiency may therefore predispose to ROS-mediated diseases and increase ROS-induced tissue injury. During systemic inflammation and sepsis, the supply of amino acids necessary for GSH synthesis is altered, leading to decreased erythrocyte GSH content and synthesis rates in septic infants and children. In addition to the increase in ROS production causing low GSH production, a preexisting, genetically determined deficiency in antioxidants may also contribute to the development of inflammatory damage in diseases mediated by FRs, such as BPD [2, 63, 65, 66, 68]. The conjugation of reactive metabolites, which are produced in vivo in the presence of oxidative stress, with GSH is catalyzed by a family of GST enzymes. These enzymes are present in most tissues, although in higher concentrations in the liver, intestine, kidney, testicles, adrenal gland and lung, where they are located in the cytoplasm in a percentage of 95%, and in the endoplasmic reticulum around 5% [69‒71]. GST enzymes have the basic function of detoxification, mediating the conjugation of a large number of electrophilic compounds with reduced GSH, in a phase II metabolic reaction. These enzymes have the ability to detoxify reactive metabolites, preventing them from reacting with DNA and also act to protect against products of oxidative stress [69‒71].

GSTs comprise a family of multifunctional enzymes that catalyze the nucleophilic attack of the reduced form of GSH on water-soluble compounds. As described, the production of ROS is a natural consequence of aerobic respiration and can cause structural damage to many biomolecules, such as membrane lipids, DNA, proteins, carbohydrates, etc. [23, 71‒73]. Cells have an antioxidant system made up of multiple enzymes that are active in the process of cellular detoxification and the elimination of harmful substances, including products of oxidative stress. This process results in the formation of reactive metabolites, some of which can be highly genotoxic, and their excessive production can be controlled by the action of GST enzymes. Therefore, the balance between the pro-oxidant and antioxidant systems is necessary to preserve cellular functions [23, 71‒73]. Mammalian GSTs can be divided into three major families: cytosolic GST, mitochondrial GST and microsomal GST. The first two comprise soluble enzymes, while those of the microsomal type are associated with the membrane. The nomenclature system for cytosolic and mitochondrial GSTs is well established and predicts that glutathione transferases are divided according to amino acid and/or nucleotide sequence, immunological properties, enzyme kinetic parameters and/or tertiary and quaternary structure [73‒75].

Cytosolic GSTs are all dimeric, containing 199 to 244 amino acid residues in their primary structures, and based on amino acid sequence similarity, seven distinct enzymatic classes have been identified: alpha (GSTA), mu (GSTM), theta (GSTT), pi (GSTP), omega (GSTO), sigma (GSTS), and zeta (GSTZ), each class being encoded by a single gene. Mitochondrial GSTs, kappa class (GSTK), are also dimeric proteins and their subunits generally have 226 amino acid residues [73‒75]. At mu class, five genes (GSTM 1–5) were mapped on chromosome 1 (1p13.3), separated by approximately 20 kb (kilobases) and located in the following order: 5′…GSTM4 - GSTM2 - GSTM1 - GSTM5…3′. The GSTM3 gene is located after GSTM5, but in a 3′-5′ orientation. The glutathione S-transferase M1 (GSTM1) gene (OMIM 138350), within the mu class of human GSTs, in individuals with at least one of the two functional alleles (GSTM1*A and GSTM1*B), are called GSTM1-positive and have the same metabolic efficiency. However, individuals carrying the deletion of this gene are called GSTM1-null, as the deletion is often present in both alleles resulting in the homozygous null genotype. The GSTM1-null allele results from a homologous recombination involving 4.2 kb 5′ and 3′ repeats, which causes a 16 kb deletion containing the entire GSTM1 gene. Excision of this gene is precise, leaving adjacent genes intact [76‒78].

In the theta class, two genes (GSTT 1 and 2) are mapped on chromosome 22 (22q11.2) and separated by approximately 50 kb. The GSTT1 gene (OMIM 600436) consists of five exons, which range in size from 88 to 195 bp, while introns range from 205 to 2,363 bp. The GSTT1 gene is embedded in a region with extensive homologies and flanked by two 18 kb regions, HA3 and HA5, which are more than 90% homologous. The GSTT1-null allele arises by homologous recombination of both 403 bp repeats, which results in a 54 kb deletion containing the entire GSTT1 gene [76, 79, 80].

Genetic variants in the GSTM1/GSTT1 genes may be associated with a greater risk of developing the so-called “FR-mediated diseases” by affecting the function of the GSTM1/GSTT1 enzymes and, consequently, the body’s ability to eliminate toxic or pro-inflammatory substances. GSTM1/GSTT1-null individuals, due to the absence of gene expression, present loss of enzymatic activity of the respective GST enzymes, triggering failures in the detoxification process and the consequent development of numerous diseases resulting from oxidative damage, as in the case of BPD [28, 32, 35, 38‒42, 81‒83].

Relationship between GSTM1/GSTT1 Genes and BPD

The GSTM1 and GSTT1 genes encode enzymes from glutathione S-transferase (GST) family, which play a critical role in the detoxification of ROS and other oxidative stress byproducts. These enzymes are crucial in the defense mechanism of the lungs, particularly in premature infants who are highly susceptible to oxidative damage due to their immature antioxidant systems [35, 38‒42, 81‒83]. The relationship between these genes and BPD revolves around genetic polymorphisms, particularly null alleles or deletions that result in the absence of enzyme activity, by the following mechanisms: (1) oxidative stress defense and prematurity: PTNBs are exposed to high levels of oxygen during treatments such as mechanical ventilation, which increases ROS production. The GSTM1 and GSTT1 enzymes help detoxify ROS, preventing cellular damage. In PTNB with GSTM1/GSTT1-null genotypes, there is a lack of functional enzymes, reducing their ability to neutralize oxidative damage. This makes the lungs more vulnerable to injury, contributing to the development of BPD. (2) Polymorphisms and risk of BPD: PTNB who carry the GSTM1/GSTT-null genotypes are at a higher risk of developing BPD. Without the protective activity of these GST enzymes, oxidative damage to lung cells increases, promoting inflammation and fibrosis. This impaired response to oxidative stress is a key factor in the abnormal lung development seen in BPD. (3) Gene-environment interaction: environmental factors, such as oxygen therapy and mechanical ventilation, can exacerbate the effects of the null genotypes. The combination of high oxygen exposure and a genetic inability to detoxify ROS leads to increased lung injury and inflammation, further predisposing the PTNB to BPD. This highlights the potential for gene-environment interactions in determining disease severity [35, 38‒42, 81‒83].

The morbidity of BPD is due to the variety of clinical complications and long-term treatments for affected children associated with this chronic lung condition. The most impactful consequences are (1) chronic respiratory problems: they are the most prominent feature of BPD, which includes constant wheezing, dyspnea, increased susceptibility to respiratory infections such as pneumonia and bronchiolitis, and a propensity to develop asthma in childhood; (2) need for supplemental oxygen: it may persist for months or years after birth, affecting the child’s mobility and quality of life, in addition to financial challenges for the family; (3) ROP: exposure to high concentrations of oxygen can also increase the risk of developing ROP, an eye condition that can affect the retina and, in severe cases, require eye surgery; (4) cardiovascular complications: it occur due to stress on the cardiovascular system, such as pulmonary hypertension; (5) feeding complications: breathing difficulties can make feeding more challenging for babies with BPD, due to difficulty in sucking and swallowing; (6) delays in physical and cognitive growth and development: they are resulting from the need for intensive medical care and prolonged hospitalizations; (7) social and psychological impact: intensive care and the continuous need for medical attention can be stressful; (8) need for long-term medical monitoring: regular visits to a multidisciplinary team are required to monitor health in all aspects [84‒87].

It is important to emphasize that the degree and severity of the consequences of BPD can vary widely from one child to another. Some babies with BPD may make a complete recovery and have no significant long-term breathing problems, while others may face substantial challenges. Adequate medical monitoring and support are essential to optimize the quality of life of children affected by BPD and their families [84‒87].

Future perspectives for treating and managing BPD focus on improving outcomes by targeting both prevention and long-term lung development. The ongoing research and emerging therapies aim to address the underlying causes, such as oxidative stress, inflammation, and impaired lung maturation, while also improving the quality of life for infants affected by the disease, such as [88‒90]: (1) genetic and biomarkers: there is growing interest in understanding the genetic factors associated with BPD risk, such as polymorphisms in antioxidant-related genes (e.g., GSTM1, GSTT1). Identifying biomarkers that predict disease progression could allow for more personalized treatments, to mitigate oxidative stress. This includes developing genetic screening tools to identify NBs who are more susceptible to oxidative stress or inflammation, particularly those with null alleles, who are more vulnerable to oxidative damage [54, 91, 92]; (2) mesenchymal stem cells (MSCs): stem cell therapy, particularly with MSCs, shows promise in promoting lung repair and regeneration. MSCs can modulate immune responses and reduce inflammation, which is key in preventing chronic lung injury in preterm infants. Early clinical trials are underway, with promising results in reducing lung damage and improving alveolar growth [93‒95]; (3) advanced antioxidant therapies: the development of new antioxidant compounds, such as the N-acetyl lysyltyrosylcysteine amide (KYC), a myeloperoxidase inhibitor, is showing potential in reducing oxidative stress and inflammation in preclinical models and also offering potential new approaches to mitigate BPD severity [96, 97]; (4) anti-inflammatory therapies: drugs that can modulate pro-inflammatory cytokines which are implicated in BPD development. The goal is to reduce inflammation without suppressing the infant’s immune system, thus preventing lung injury while maintaining necessary defense mechanisms [98, 99]; (5) noninvasive ventilation and exogenous surfactants: modern ventilation techniques that minimize lung injury are being developed, such as noninvasive high-frequency ventilation and newer surfactant therapies. These aim to reduce the need for prolonged mechanical ventilation and the associated oxidative damage [100, 101]; (6) nutritional strategies: enhancing nutritional support, particularly with antioxidant-rich diets, and focusing on maternal health during pregnancy can help reduce the risk of BPD. Strategies include omega-3 fatty acids, vitamin A, and other micronutrients to support lung development [102, 103].

The review of the available literature on BPD highlights the need for a new look to broaden the horizons of understanding of this disease. The continuity in clinical, genetic, and translational research, involving the molecular approach to lung development during oxidative stress, is necessary, as it will allow for better and new diagnostic and therapeutic approaches associated with the underlying pathophysiology with the primary objective of obtaining individualized care to improve respiratory results in these NBs affected by BPD.

The authors thank their friend and translator, Cecília Meneguette Ferreira, for her considerable support.

An ethics statement is not applicable because this narrative review is based exclusively on the published literature.

The authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

Luana Vilches Cagnim Nuevo contributed in literature review, analysis and interpretation of data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content; Vânia Belintani Piatto designed the study, literature revision, drafting of the manuscript, critical revision of the manuscript for important intellectual content, technical or material support, and study supervision; and Luís Cesar Fava Spessoto was responsible for drafting of the manuscript, technical or material support, and study supervision. All authors approved the final manuscript.

All the data presented are included in this review.

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