The role of cytochrome P450 (CYP) enzymes in hyperoxic lung injury.

INTRODUCTION: Hyperoxic lung injury is a condition that can occur in patients in need of supplemental oxygen, such as premature infants with bronchopulmonary dysplasia or adults with acute respiratory distress syndrome. Cytochrome P450 (CYP) enzymes play critical roles in the metabolism of endogenous and exogenous compounds. AREAS COVERED: Through their complex pathways, some subfamilies of these enzymes may contribute to or protect against hyperoxic lung injury. Oxidative stress from reactive oxygen species (ROS) production is most likely a major contributor of hyperoxic lung injury. CYP1A enzymes have been shown to protect against hyperoxic lung injury while CYP1B enzymes seem to contribute to it. CYP2J2 enzymes help protect against hyperoxic lung injury by triggering EET production, thereby, increasing antioxidant enzymes. The metabolism of arachidonic acid to ω-terminal hydroxyeicosatetraenoic acid (20-HETEs) by CYP4A and CYP4F enzymes could impact hyperoxic lung injury via the vasodilating effects of 20-HETE. CYP2E1 and CYP2A enzymes may contribute to the oxidative stress in the lungs caused by ethanol- and nicotine-metabolism, respectively. EXPERT OPINION: Overall, the CYP enzymes, depending upon the isoform, play a contributory or protective role in hyperoxic lung injury, and are, therefore, ideal candidates for developing drugs that can treat oxygen-mediated lung injury.

Selenium-independent antioxidant and anti-inflammatory effects of thioredoxin reductase inhibition in alveolar macrophages.

AIMS: Interleukin-1ß (IL-1ß) contributes to the development of bronchopulmonary dysplasia (BPD). Thioredoxin reductase-1 (Txnrd1) inhibition activates nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent responses. Txnrd1 activity is selenium (Se) dependent and Se deficiency is common in prematurity. Auranofin (AFN), a Txnrd1 inhibitor, decreases IL-1ß levels and increases Nrf2 activation in lipopolysaccharide (LPS) treated alveolar macrophages. In lung epithelia, AFN-induced Nrf2 activation is Se dependent. We tested the hypothesis that the effects of Txnrd1 inhibition in alveolar macrophages are Se dependent. MAIN METHODS: To establish Se sufficient (Se+) and deficient (Se-) conditions, alveolar (MH-S) macrophages were cultured in 2.5% fetal bovine serum (FBS) ± 25 nM Na2SeO3. Se- (2.5% FBS) and Se+ (2.5% FBS + 25 nM Na2SeO3) cells were cultured in the presence or absence of 0.05 µg/mL LPS and/or 0.5 µM AFN. Nrf2 activation was determined by measuring NADPH quinone oxidoreductase-1 (Nqo1) and glutathione levels. IL-1ß mRNA (Il1b) and protein levels were measured using qRT-PCR and ELISA. Data were analyzed by ANOVA followed by Tukey's post-hoc. KEY FINDINGS: We detected an independent effect of AFN, but not LPS, on Nqo1 expression and GSH levels in Se+ and Se- cells. LPS significantly increased Il1b and IL-1ß levels in both groups. AFN-mediated attenuation of this effect was not impacted by Se status. SIGNIFICANCE: The beneficial effects of Txnrd1 inhibition in alveolar macrophages are Se-independent and therefore unlikely to be diminished by clinical Se deficiency.

Mitochondrial bioenergetics and pulmonary dysfunction: Current progress and future directions.

This review summarizes current understanding of mitochondrial bioenergetic dysfunction applicable to mechanisms of lung diseases and outlines challenges and future directions in this rapidly emerging field. Although the role of mitochondria extends beyond the term of cellular "powerhouse", energy generation remains the most fundamental function of these organelles. It is not counterintuitive to propose that intact energy supply is important for favorable cellular fate following pulmonary insult. In this review, the discussion of mitochondrial dysfunction focuses on those molecular mechanisms that alter cellular bioenergetics in the lungs: (a) inhibition of mitochondrial respiratory chain, (b) mitochondrial leak and uncoupling, (c) alteration of mitochondrial Ca2+ handling, (d) mitochondrial production of reactive oxygen species and self-oxidation. The discussed lung diseases were selected according to their pathological nature and relevance to pediatrics: Acute lung injury (ALI), defined as acute parenchymal lung disease associated with cellular demise and inflammation (Acute Respiratory Distress Syndrome, ARDS, Pneumonia), alveolar developmental failure (Bronchopulmonary Dysplasia, BPD or chronic lung disease in premature infants), obstructive airway diseases (Bronchial asthma) and vascular remodeling affecting pulmonary circulation (Pulmonary Hypertension, PH). The analysis highlights primary mechanisms of mitochondrial bioenergetic dysfunction contributing to the disease-specific pulmonary insufficiency and proposes potential therapeutic targets.

Antioxidants & bronchopulmonary dysplasia: Beating the system or beating a dead horse?

Preterm birth is a primary cause of worldwide childhood mortality. Bronchopulmonary dysplasia, characterized by impaired alveolar and lung vascular development, affects 25-50% of extremely low birth weight (BW; <1 kg) infants. Abnormalities in lung function persist into childhood in affected infants and are second only to asthma in terms of childhood respiratory disease healthcare costs. While advances in the medical care of preterm infants have reduced mortality, the incidence of BPD has not decreased in the past 10 years. Reactive oxygen intermediates play a key role in the development of lung disease but, despite promising preclinical therapies, antioxidants have failed to translate into meaningful clinical interventions to decrease the incidence of lung disease in premature infants. In this review we will summarize the state of the art research developments in regards to antioxidants and premature lung disease and discuss the limitations of antioxidant therapies in order to more fully comprehend the reasons why therapeutic antioxidant administration failed to prevent BPD. Finally we will review promising therapeutic strategies and targets.

Nutrition and Lung Growth.

Experimental evidence from animal models and epidemiology studies has demonstrated that nutrition affects lung development and may have a lifelong impact on respiratory health. Chronic restriction of nutrients and/or oxygen during pregnancy causes structural changes in the airways and parenchyma that may result in abnormal lung function, which is tracked throughout life. Inadequate nutritional management in very premature infants hampers lung growth and may be a contributing factor in the pathogenesis of bronchopulmonary dysplasia. Recent evidence seems to indicate that infant and childhood malnutrition does not determine lung function impairment even in the presence of reduced lung size due to delayed body growth. This review will focus on the effects of malnutrition occurring at critical time periods such as pregnancy, early life, and childhood, on lung growth and long-term lung function.

Impact of Nutrition on Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) remains a common morbidity of prematurity. Although the pathogenesis of BPD is recognized to be both multifactorial and complex, the role of nutrition in the pathophysiology of BPD is typically limited to management after a diagnosis has been made. Infants born small for gestational age and those who experience postnatal growth failure are more likely to have BPD. Therapies for lung disease, such as fluid restriction, diuretics, and corticosteroids, can negatively impact postnatal growth. Future research is needed to optimize nutritional strategies in the neonatal intensive care unit and following hospital discharge.

La nueva displasia broncopulmonar desde el punto de vista de neumólogo pediatra / New bronchopulmonary dysplasia, from a pediatric pulmonologist´s perspective

Bronchopulmonary dysplasia (BPD) is the most prevalent chronic lung disease of prematurity. The so-called new BPD has replaced the classic BPD described by Northway, as a result of maternal use of corticosteroids, early surfactant and less aggressive mechanical ventilation and the survival of younger premature, born during the canalicular stage and that completed their alveolization outside the uterus. The new BPD is a less severe disease, but lung function is impaired in the long-term. An update of the new BPD, focused on the management after discharge from neonatology, from a pediatric pulmonologist perspective is presented.

La Displasia Broncopulmonar (DBP) es la enfermedad pulmonar crónica más prevalente del prematuro. La denominada nueva DBP ha reemplazado a la DBP clásica descripta por Northway, como consecuencia del uso de corticoides maternos, surfactante precoz, ventilación mecánica menos agresiva y la sobrevivencia de prematuros más pequeños, que nacen en etapa canalicular de su desarrollo pulmonar y completan su alveolización fuera del útero. La nueva DBP es una patología menos severa, pero con compromiso funcional respiratorio a largo plazo. A continuación se describe una actualización de la nueva DBP, enfocada en el manejo realizado luego del alta de neonatología, desde el punto de vista del Neumólogo Pediatra.

Utility of large-animal models of BPD: chronically ventilated preterm lambs.

This paper is focused on unique insights provided by the preterm lamb physiological model of bronchopulmonary dysplasia (BPD). Connections are also made to insights provided by the former preterm baboon model of BPD, as well as to rodent models of lung injury to the immature, postnatal lung. The preterm lamb and baboon models recapitulate the clinical setting of preterm birth and respiratory failure that require prolonged ventilation support for days or weeks with oxygen-rich gas. An advantage of the preterm lamb model is the large size of preterm lambs, which facilitates physiological studies for days or weeks during the evolution of neonatal chronic lung disease (CLD). To this advantage is linked an integrated array of morphological, biochemical, and molecular analyses that are identifying the role of individual genes in the pathogenesis of neonatal CLD. Results indicate that the mode of ventilation, invasive mechanical ventilation vs. less invasive high-frequency nasal ventilation, is related to outcomes. Our approach also includes pharmacological interventions that test causality of specific molecular players, such as vitamin A supplementation in the pathogenesis of neonatal CLD. The new insights that are being gained from our preterm lamb model may have important translational implications about the pathogenesis and treatment of BPD in preterm human infants.

Progress in the diagnosis and management of pulmonary hypertension in children.

PURPOSE OF REVIEW: Pulmonary hypertension is a complex disease that extends beyond merely elevated pulmonary blood pressures and right ventricular dysfunction. Its multiple causes and ever-expanding diagnostic tools and therapeutic approaches make it a heterogeneous disease with widely variable clinical sequelae. There are still many unanswered questions that challenge our understanding of this disease. RECENT FINDINGS: The study of pulmonary hypertension in the pediatric patient is as robust as ever, with the creation and inclusion of pediatric-specific disease characteristics in the most recent WHO classification system, improved understanding of the pathophysiology of pulmonary hypertension in pediatric diseases such as bronchopulmonary dysplasia, and increasingly expanding diagnostic tools and management possibilities. Although the use of pulmonary hypertension therapies in children previously often relied on expert opinion and inferences from studies involving adults, pediatric-targeted research is becoming more widely supported and pursued, and has even come under recent debate, which at the very least stimulates further collaboration and discussion. SUMMARY: This review will highlight the changes in the pulmonary hypertension classification system, briefly explore pulmonary hypertension in bronchopulmonary dysplasia, and provide updates on the diagnostic and management tools used by experts in the field.

Advances in bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is a chronic respiratory condition primarily affecting infants born less than 28 weeks gestational age. BPD and the diagnostic criteria that define it have evolved since the initial description of the disease more than four decades ago. BPD is one of the most common and serious complications of extreme premature birth. Despite advances in neonatal care and continued research into therapeutic strategies the incidence of BPD remains unchanged. Pharmacologic approaches to the management of BPD include methylxanthines, corticosteroids, and vitamin A supplementation. Supportive therapies including the increased use of non-invasive ventilation and careful oxygen delivery strive to reduce injury inflicted on the developing lung. Stem cell-based therapies are a new investigational strategy showing promise for the prevention or treatment of BPD. The goal of this review is to highlight the evolution of BPD and review current and potential future therapeutic strategies for BPD.

[Magnesium and bronchopulmonary dysplasia].

Bronchopulmonary dysplasia (BPD) is a chronic lung disease that occurs in premature infants who have needed mechanical ventilation and oxygen therapy. BPD is defined as the presence of persistent respiratory symptoms, the need for supplemental oxygen to treat hypoxemia, and an abnormal chest radiograph at 36 weeks gestational age. Proinflammatory cytokines and altered angiogenic gene signaling impair prenatal and postnatal lung growth, resulting in BPD. Postnatal hyperoxia exposure further increases the production of cytotoxic free radicals, which cause lung injury and increase the levels of proinflammatory cytokines. Magnesium is the fourth most abundant metal in the body. It is commonly used for the treatment of preeclamsia, as well as for premature labor alleviation. Magnesium's role in BPD development is not clear. A significant association between high magnesium levels at birth and respiratory distress syndrome (RDS), pulmonary interstitial emphysema in the extremely low birth weight, respiratory failure, and later development BPD was found. Conversely, low magnesium intake is associated with lower lung functions, and hypomagnesemia was found in 16% of patients with acute pulmonary diseases. Magnesium is used for the treatment of asthmatic attacks. Magnesium deficiency in pregnant women is frequently seen due to low intake. Hypomagnesemia was also found among preterm neonates and respiratory distress syndrome (RDS). Experimental hypomagnesemia evokes an inflammatory response, and oxidative damage of tissues. These were accompanied by changes in gene expression mostly involved in regulation of cell cycle, apoptosis and remodeling, processes associated with BPD. It is rational to believe that hypomagnesemia can contribute to BPD pathogenesis.

L-citrulline attenuates arrested alveolar growth and pulmonary hypertension in oxygen-induced lung injury in newborn rats.

Bronchopulmonary dysplasia (BPD) is characterized by arrested alveolar development and complicated by pulmonary hypertension (PH). NO promotes alveolar growth. Inhaled NO (iNO) ameliorates the BPD phenotype in experimental models and in some premature infants. Arginosuccinate synthetase (ASS) and arginosuccinate lyase (ASL) convert L-citrulline to L-arginine; L-citrulline is regenerated during NO synthesis from L-arginine. Plasma levels of these NO precursors are low in PH. We hypothesized that L-citrulline prevents experimental O2-induced BPD in newborn rats. Rat pups were assigned from birth through postnatal day (P) 14 to room air (RA), RA + L-citrulline, 95% hyperoxia (BPD model), and 95%O2 + L-citrulline. Rat pups exposed to hyperoxia had fewer and enlarged air spaces and decreased capillary density, mimicking human BPD. This was associated with decreased plasma L-arginine and L-citrulline concentrations on P7. L-citrulline treatment significantly increased plasma L-arginine and L-citrulline concentrations and increased ASL protein expression in hyperoxia. L-citrulline preserved alveolar and vascular growth in O2-exposed pups and decreased pulmonary arterial medial wall thickness (MWT) and right ventricular hypertrophy (RVH). Increased lung arginase (ARG) activity in O2-exposed pups was reversed by L-citrulline treatment. L-citrulline supplementation prevents hyperoxia-induced lung injury and PH in newborn rats. L-citrulline may represent a novel therapeutic alternative to iNO for prevention of BPD.

Prevention of bronchopulmonary dysplasia.

Considerable effort has been devoted to the development of strategies to reduce the incidence of bronchopulmonary dysplasia (BPD), including use of medications, nutritional therapies, and respiratory care practices. Unfortunately, most of these strategies have not been successful. To date, the only two treatments developed specifically to prevent BPD whose efficacy is supported by evidence from randomized, controlled trials are the parenteral administration of vitamin A and corticosteroids. Two other therapies, the use of caffeine for the treatment of apnea of prematurity and aggressive phototherapy for the treatment of hyperbilirubinemia, were evaluated for the improvement of other outcomes and found to reduce BPD. Cohort studies suggest that the use of continuous positive airway pressure as a strategy for avoiding mechanical ventilation might also be beneficial. Other therapies reduce lung injury in animal models but do not appear to reduce BPD in humans. The benefits of the efficacious therapies have been modest, with an absolute risk reduction in the 7-11% range. Further preventive strategies are needed to reduce the burden of this disease. However, each will need to be tested in randomized, controlled trials, and the expectations of new therapies should be modest reductions of the incidence of the disease.

A comparison of the effect of vitamin A on cytokine secretion by mononuclear cells of preterm newborns and adults.

BACKGROUND: For a long time vitamin A has been known to be essential for immune defense of the organism and protection against infections. Vitamin A deficiency in children is associated with morbidity and mortality from infectious diseases which could be prevented and even alleviated by vitamin A supplementation. Moreover, this vitamin is involved in the modulation of immunological and inflammatory responses by regulation of cytokine production. The aim of the study was to compare the in vitro effect of vitamin A on the production of pro-inflammatory (IL-1beta and IL-6) and anti-inflammatory (IL-1 receptor antagonist (ra) and IL-10) cytokines, as well as IL-2 and IFNgamma by cord blood mononuclear cells (CBMC) of preterm newborns to that of peripheral blood mononuclear cells (PBMC) from adults. METHODS: Mononuclear cells (MC) from individuals of the two age groups were incubated with vitamin A (retinyl palmitate) at various concentrations in the presence of phytohemagglutinin for IL-2 and IFNgamma production or LPS for IL-1beta, IL-1ra, IL-6 and IL-10 secretion. The level of the cytokines in the supernatants was tested by ELISA. RESULTS: Vitamin A exerted an in vitro inhibitory effect on the production of the anti-inflammatory cytokine IL-1ra by MC of preterm newborns and adults, but did not affect the secretion of the pro-inflammatory cytokines IL-1beta, IL-6 and IFNgamma. Vitamin A caused inhibition of IL-10 secretion by cells from adults, but it did not significantly affect this function in cells from newborns except when high unphysiological doses were applied. In addition vitamin A stimulated the secretion of IL-2 by cells isolated from adults but had no effect on those derived from premature neonates. CONCLUSIONS: The results indicate that vitamin A may affect the immune function of premature infants via inhibition of IL-1ra secretion. It is suggested that the beneficial effect of vitamin A on the clinical course of bronchopulmonary dysplasia (BPD) may be due to the reduced production of anti-inflammatory cytokines by neonatal CBMC. This may indicate the importance of the pro-inflammatory cytokines in the management of severe lung diseases and BPD.

Increased energy intake for preterm infants with (or developing) bronchopulmonary dysplasia/ chronic lung disease.

BACKGROUND: Preterm infants with bronchopulmonary dysplasia/chronic lung disease have nutritional deficits that may contribute to short and long term morbidity and mortality. Increasing the daily energy intake for these infants may improve their respiratory, growth and neurodevelopmental outcomes. OBJECTIVES: To assess the effect of increased energy intake on mortality and respiratory, growth and neurodevelopmental outcomes for preterm infants with (or developing) CLD/BPD. Secondarily, the review examines any adverse effects associated with increased energy intake. SEARCH STRATEGY: The standard search strategy of the Cochrane Neonatal Review Group was used. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2006) , MEDLINE (accessed via Ovid), references cited in previous relevant Cochrane reviews and in other relevant studies, review articles, standard textbooks, and manuals of neonatal medicine. Hand search results of the Cochrane Neonatal Review Group were also assessed. SELECTION CRITERIA: All randomized and quasi-randomized trials comparing the outcomes of preterm infants with (or developing) CLD/BPD who had either increased (> 135 kcal/kg/day) or standard energy intake (98 to 135 kcal/kg/day). Increasing energy intake might be achieved enterally and/or parenterally, enterally by increasing the energy content of the milk, increasing feed volume, or by nutrient supplementation with protein, carbohydrate or fat. The primary outcomes were the development of CLD and neonatal mortality; secondary outcomes included respiratory morbidities, growth, neurodevelopmental status and possible complications with increased energy intake. DATA COLLECTION AND ANALYSIS: We planned to extract data using the standard methods of the Cochrane Neonatal Review Group. Relevant trials would be scrutinized for methodological quality independently by the reviewers to determine their eligibility for inclusion. Data of the included trials would be expressed as relative risk, risk difference, NNT and weighted mean difference where appropriate, using a fixed effect model. MAIN RESULTS: No eligible trials were identified. Twelve studies that appeared to be relevant were excluded, as no study directly compared increased versus standard energy intakes in infants with CLD/BPD. However, two excluded trials provided some insights into the topic. One study showed that infants with CLD/BPD who were fed formula enriched with protein and minerals had improved growth parameters up until the cessation of the intervention at three months of corrected age. The other study compared different energy density of formula but identical energy intake by setting different feed volumes for both groups. It showed that both groups were unable to achieve the pre-designated feed volumes, and that there were no differences in growth, respiratory outcomes, oedema and the diuretic requirements. AUTHORS' CONCLUSIONS: To date, no randomized controlled trials are available that examine the effects of increased versus standard energy intake for preterm infants with (or developing) CLD/BPD. Research should be directed at evaluating the effects of various levels of energy intake on this group of infants on clinically important outcomes like mortality, respiratory status, growth and neurodevelopment. The benefits and harms of various ways of increasing energy intake, including higher energy density of milk feed and/or fluid volume (clinically realistic target volume should be set), parenteral nutrition, and the use of various constituents of energy like carbohydrate, protein and fat for this purpose also need to be assessed.

Bronchopulmonary dysplasia in preterm infants: pathophysiology and management strategies.

Bronchopulmonary dysplasia (BPD) has classically been described as including inflammation, architectural disruption, fibrosis, and disordered/delayed development of the infant lung. As infants born at progressively earlier gestations have begun to survive the neonatal period, a 'new' BPD, consisting primarily of disordered/delayed development, has emerged. BPD causes not only significant complications in the newborn period, but is associated with continuing mortality, cardiopulmonary dysfunction, re-hospitalization, growth failure, and poor neurodevelopmental outcome after hospital discharge. Four major risk factors for BPD include premature birth, respiratory failure, oxygen supplementation, and mechanical ventilation, although it is unclear whether any of these factors is absolutely necessary for development of the condition. Genetic susceptibility, infection, and patent ductus arteriosus have also been implicated in the pathogenesis of the disease. The strategies with the strongest evidence for effectiveness in preventing or lessening the severity of BPD include prevention of prematurity and closure of a clinically significant patent ductus arteriosus. Some evidence of effectiveness also exists for single-course therapy with antenatal glucocorticoids in women at risk for delivering premature infants, surfactant replacement therapy in intubated infants with respiratory distress syndrome, retinol (vitamin A) therapy, and modes of respiratory support designed to minimize 'volutrauma' and oxygen toxicity. The most effective treatments for ameliorating symptoms or preventing exacerbation in established BPD include oxygen therapy, inhaled glucocorticoid therapy, and vaccination against respiratory pathogens.Many other strategies for the prevention or treatment of BPD have been proposed, but have weaker or conflicting evidence of effectiveness. In addition, many therapies have significant side effects, including the possibility of worsening the disease despite symptom improvement. For instance, supraphysiologic systemic doses of glucocorticoids lessen the incidence of BPD in infants at risk for the disease, and promote weaning of oxygen and mechanical ventilation in infants with established BPD. However, the side effects of systemic glucocorticoid therapy, most notably the recently recognized adverse effects on neurodevelopment, preclude their routine use for the prevention or treatment of BPD. Future research in BPD will most probably focus on continued incremental improvements in outcome, which are likely to be achieved through the combined effects of many therapeutic modalities.

Bronchopulmonary dysplasia-oxidative stress and antioxidants.

There is increasing evidence that oxidative stress is implicated in the development of bronchopulmonary dysplasia. Several important factors contribute to augmented oxidative stress in the newborn and especially the preterm infant: first, because of its immaturity, the lung of preterm infants is frequently exposed to oxygen therapy and hyperoxia. Second, the antioxidant defense and its ability to be induced during an hyperoxic challenge are impaired. Third, the preterm infant has an increased susceptibility to infection and inflammation, which increases oxidative stress. Fourth, free iron, which catalyzes the production of toxic reactive oxygen species, can be detected in preterm infants. The molecular and cellular mechanisms for free radical-induced injury are now understood in more detail, and it is clear that oxidative stress plays an important role in triggering apoptosis, in serving as second messenger and in signal transduction. This new insight might lead to novel and efficient therapies. So far, there has been no significant breakthrough regarding antioxidant therapies. Care should, however, be exercised in supplementing the preterm infant with antioxidants since this may affect growth and development.

Chronic pulmonary insufficiency in children and its effects on growth and development.

Conditions leading to chronic pulmonary insufficiency can affect infants and children. These can lead to growth failure and delayed development. Among the most common and severe of these are bronchopulmonary dysplasia (BPD) and cystic fibrosis. In addition to the respiratory consequences of these diseases, there is ample evidence that they lead to decreased growth as a result of decreased energy intake and increased energy expenditure. Furthermore, there is evidence that infants with BPD may also have delayed development, independent of the effects of their prematurity. Enhancing the long-term outlook for these conditions may therefore require consideration of both improved pulmonary management and aggressive nutritional management to limit growth failure and potentially enhance developmental outcome. Specific micronutrient supplementation, such as antioxidant therapy, may also enhance pulmonary and nutritional status.