Prenatal vitamin D supplementation mitigates inflammation-related alveolar remodeling in neonatal mice.

The development of chronic lung disease in the neonate, also known as bronchopulmonary dysplasia (BPD), is the most common long-term complication in prematurely born infants. In BPD, the disease-characteristic inflammatory response culminates in nonreversible remodeling of the developing gas exchange area, provoked by the impact of postnatal treatments such as mechanical ventilation (MV) and oxygen treatment. To evaluate the potential of prenatal treatment regimens to modulate this inflammatory response and thereby impact the vulnerability of the lung toward postnatal injury, we designed a multilayered preclinical mouse model. After administration of either prenatal vitamin D-enriched (VitD+; 1,500 IU/g food) or -deprived (VitD-; <10 IU/kg) food during gestation in C57B6 mice (the onset of mating until birth), neonatal mice were exposed to hyperoxia (FiO2 = 0.4) with or without MV for 8 h at days 5-7 of life, whereas controls spontaneously breathed room air. Prenatal vitamin D supplementation resulted in a decreased number of monocytes/macrophages in the neonatal lung undergoing postnatal injury together with reduced TGF-ß pathway activation. In consequence, neonatal mice that received a VitD+ diet during gestation demonstrated less extracellular matrix (ECM) remodeling upon lung injury, reflected by the reduction of pulmonary α-smooth muscle actin-positive fibroblasts, decreased collagen and elastin deposition, and lower amounts of interstitial tissue in the lung periphery. In conclusion, our findings support strategies that attempt to prevent vitamin D insufficiency during pregnancy as they could impact lung health in the offspring by mitigating inflammatory changes in neonatal lung injury and ameliorating subsequent remodeling of the developing gas exchange area.NEW & NOTEWORTHY Vitamin D-enriched diet during gestation resulted in reduced lung inflammation and matrix remodeling in neonatal mice exposed to clinically relevant, postnatal injury. The results underscore the need to monitor the subclinical effects of vitamin D insufficiency that impact health in the offspring when other risk factors come into play.

Chitin-Derived AVR-48 Prevents Experimental Bronchopulmonary Dysplasia (BPD) and BPD-Associated Pulmonary Hypertension in Newborn Mice.

Bronchopulmonary dysplasia (BPD) is the most common complication of prematurity and a key contributor to the large health care burden associated with prematurity, longer hospital stays, higher hospital costs, and frequent re-hospitalizations of affected patients through the first year of life and increased resource utilization throughout childhood. This disease is associated with abnormal pulmonary function that may lead to BPD-associated pulmonary hypertension (PH), a major contributor to neonatal mortality and morbidity. In the absence of any definitive treatment options, this life-threatening disease is associated with high resource utilization during and after neonatal intensive care unit (NICU) stay. The goal of this study was to test the safety and efficacy of a small molecule derivative of chitin, AVR-48, as prophylactic therapy for preventing experimental BPD in a mouse model. Two doses of AVR-48 were delivered either intranasally (0.11 mg/kg), intraperitoneally (10 mg/kg), or intravenously (IV) (10 mg/kg) to newborn mouse pups on postnatal day (P)2 and P4. The outcomes were assessed by measuring total inflammatory cells in the broncho-alveolar lavage fluid (BALF), chord length, septal thickness, and radial alveolar counts of the alveoli, Fulton's Index (for PH), cell proliferation and cell death by immunostaining, and markers of inflammation by Western blotting and ELISA. The bioavailability and safety of the drug were assessed by pharmacokinetic and toxicity studies in both neonatal mice and rat pups (P3-P5). Following AVR-48 treatment, alveolar simplification was improved, as evident from chord length, septal thickness, and radial alveolar counts; total inflammatory cells were decreased in the BALF; Fulton's Index was decreased and lung inflammation and cell death were decreased, while angiogenesis and cell proliferation were increased. AVR-48 was found to be safe and the no-observed-adverse-effect level (NOAEL) in rat pups was determined to be 100 mg/kg when delivered via IV dosing with a 20-fold safety margin. With no reported toxicity and with a shorter half-life, AVR-48 is able to reverse the worsening cardiopulmonary phenotype of experimental BPD and BPD-PH, compared to controls, thus positioning it as a future drug candidate.

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.

Genipin attenuates hyperoxia-induced lung injury and pulmonary hypertension via targeting glycogen synthase kinase-3 ß in neonatal rats.

OBJECTIVES: Bronchopulmonary dysplasia is the most common chronic lung disease of infancy and is associated with pulmonary hypertension (PH). Inhibition of glycogen synthase kinase (GSK)-3 ß has been shown to attenuate lung injury and PH in hyperoxia-exposed newborn rats. Genipin has been widely used for the treatment of inflammatory diseases. The aim of this study was to show that genipin decreased the expression of GSK-3 ß in lung tissues of hyperoxia-exposed rat pups. METHODS: We established models of hyperoxia-exposed rat pups, evaluated lung injury and pulmonary hypertension and detected the mRNA and protein expression of key molecules. RESULTS: Hyperoxia resulted in the reduction of survival rate and histologic injury of lung tissues; an increase of the messenger RNA (mRNA) expression of transforming growth factor-ß1, extracellular matrix proteins collagen-I and fibronectin, and α-smooth muscle actin; an increase of right ventricular (RV) systolic pressure and the weight ratio of RV to left ventriclar (LV) plus septum (S) (RV/LV + S) were inhibited by genipin. Genipin also decreased the levels of tumor necrosis factor-α, interleukin-1 ß, and interleukin-6 in both bronchoalveolar lavage fluid and lung tissues after hyperoxia exposure. In addition, genipin inhibited p65 nuclear factor-κB nuclear translocation and matrix metalloproteinase-2 and -9 expression. Moreover, hyperoxia resulted in an increase of methane dicarboxylic aldehyde content and a decrease of superoxide dismutase activity, catalytic subunit of glutamate-cysteine ligase, modified subunit of glutamate-cysteine ligase, and nuclear factor erythroid 2-related factor 2 expression were inhibited by genipin. All these effects induced by genipin were blocked by upregulation of GSK-3 ß. Genipin downregulated GSK-3 ß expression, decreased nuclear factor-κB translocation, increased nuclear factor erythroid 2-related factor 2 expression, attenuated inflammation and oxidative stress, leading to amelioration of lung injury and PH in hyperoxia-exposed rat pups. CONCLUSION: Overall, genipin may provide a novel therapeutic option for preventing and treating infants with bronchopulmonary dysplasia.

[Effect of rhubarb on neonatal rats with bronchopulmonary dysplasia induced by hyperoxia].

OBJECTIVE: To study the effect of rhubarb on neonatal rats with bronchopulmonary dysplasia (BPD) induced by hyperoxia. METHODS: A total of 64 rats (postnatal day 4) were randomly divided into four groups: air control, rhubarb control, hyperoxia model, and hyperoxia+rhubarb (n=16 each). The rats in the hyperoxia model and hyperoxia+rhubarb groups were exposed to hyperoxia (60% O2) to establish a BPD model. The rats in the rhubarb control and hyperoxia+rhubarb groups were given rhubarb extract suspension (600 mg/kg) by gavage daily. The pathological changes of lung tissue were evaluated by hematoxylin-eosin staining on postnatal days 14 and 21. The content of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) were measured by spectrophotometry. The mRNA and protein expression levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) were determined by RT-PCR and Western blot respectively. RESULTS: The hyperoxia model group showed reduced alveolar number, increased alveolar volume, and simplified alveolar structure, which worsened over the time of exposure to hyperoxia. These pathological changes were significantly reduced in the hyperoxia+rhubarb group. On postnatal days 14 and 21, compared with the air control and rhubarb control groups, the hyperoxia model group had significantly reduced radical alveolar count (RAC), significantly reduced activity of SOD in the lung tissue, and significantly increased content of MDA and mRNA and protein expression levels of TNF-α and IL-6 (P<0.05). Compared with the hyperoxia model group, the hyperoxia+rhubarb group had significantly increased RAC, significantly increased activity of SOD in the lung tissue, and significantly reduced content of MDA and mRNA and protein expression levels of TNF-α and IL-6 (P<0.05). CONCLUSIONS: Rhubarb may play a protective role in rats with BPD induced by hyperoxia through inhibiting inflammatory response and oxidative stress.

Quercetin attenuates the hyperoxic lung injury in neonatal mice: Implications for Bronchopulmonary dysplasia (BPD).

Quercetin (QU) is one of the most common flavonoids that are present in a wide variety of fruits, vegetables, and beverages. This compound possesses potent anti-inflammatory and anti-oxidant properties. Supplemental oxygen is routinely administered to premature infants with pulmonary insufficiency. However, hyperoxia is one of the major risk factors for the development of bronchopulmonary dysplasia (BPD), which is also termed chronic lung disease in premature infants. Currently, no preventive approaches have been reported against BPD. The treatment of BPD is notably limited to oxygen administration, ventilatory support, and steroids. Since QU has been shown to be effective in reducing inflammation and oxidative stress in various disease models, we hypothesized that the postnatal QU treatment of newborn mice will protect against hyperoxic lung injury by the upregulation of the phase I (CYP1A/B) and/or phase II, NADPH quinone reductase enzymes. Newborn C57BL/6J mice within 24 h of birth with the nursing dams were exposed to either 21% O2 (air) and/or 85% O2 (hyperoxia) for 7 days. The mice were treated, intraperitoneally (i.p.) once every other day with quercetin, at a concentration of 20 mg/kg, or saline alone from postnatal day (PND) 2-6. The mice were sacrificed on day 7, and lung and liver tissues were collected. The expression levels of CYP1A1, CYP1B1, NQO1 proteins and mRNA as well as the levels of MDA-protein adducts were analyzed in lung and liver tissues. The findings indicated that QU attenuated hyperoxia-mediated lung injury by reducing inflammation and improving alveolarization with decreased number of neutrophil and macrophage infiltration. The attenuation of this lung injury correlated with the upregulation of CYP1A1/CYP1B1/NQO1 mRNA, proteins and the down regulation of NF-kB levels and MDA-protein adducts in lung and liver tissues. The present study demonstrated the potential therapeutic value of quercetin in the prevention and/or treatment of BPD.

El rol de la hipertensión pulmonar en la displasia broncopulmonar / The role of pulmonary hypertension on bronchopulmonary dysplasia

Resumen Hace 50 años Northway describió la Displasia Broncopulmonar (DBP), en nacidos de pretérmino expuestos a ventilación mecánica. Desde entonces, ha aumentado la sobrevida de ellos; sin embar go, ha aparecido una "nueva DBP" y la incidencia de esta no ha disminuido. Una de las caracte rísticas de esta patología es la remodelación vascular anómala, que en su expresión más severa se conoce como Hipertensión Pulmonar (HP); con una incidencia de 17%, que es proporcional a la severidad de la DBP (33% en DBP severa); y como un factor de mortalidad (hasta un 48% mortali dad a 2 años con HP por DBP). Debido a esto resulta importante conocer los métodos diagnósticos y alternativas terapéuticas, tema que se discute en esta revisión. Considerando la alta mortalidad de la asociación HP-DBP, adquiere importancia una estrategia de tamizaje en la población de riesgo. El gold standard para el diagnóstico de HP es el cateterismo cardíaco, sin embargo, el ecocardio-grama transtorácico es una herramienta útil para el tamizaje y diagnóstico de HP en pacientes dis-plásicos, con mediciones cuantitativas y cambios cualitativos en la evaluación diagnóstica. A nivel sanguíneo el péptido natriurético tipo B (BNP), ha mostrado ser útil en el seguimiento; en cuanto a imágenes, la tomografía computarizada se utiliza en casos severos. En cuanto a las terapias, se han propuesto el óxido nítrico inhalado como vasodilatador pulmonar, los inhibidores de la fosfodies-terasas -sildenafil-, los antagonistas de la endotelina -bosentán- y los análogos de prostaciclinas -iloprost-. Aún no se cuenta con evidencia de alta calidad para su uso, dosis y duración del trata miento, pero hay variadas experiencias clínicas. Además, es relevante el cuidado interdisciplinario, destacando optimizar la nutrición. El desafío es lograr una prevención efectiva de la DBP y de sus complicaciones. Un protocolo de tamizaje de HP debe asociarse a una estratificación de riesgo y directrices de tratamiento.

Abstract 50 years ago, Northway described Broncopulmonary Dysplasia (BPD) in preterm infants exposed to mechanical ventilation. Since then, their survival has increased, nevertheless a "new BPD" has appeared and its incidence has not diminished. One of the characteristics of this pathology is the the abnormal vascular remodeling, which in its most severe expression is known as Pulmonary Hyper tension (PH); with an incidence of 17% in patients with BPD, which is proportional to the severity of the disease (33% in severe BPD), and as mortality factor (up to 48% 2-year mortality in PH-BPD). Thereby, it is important to know the diagnostic methods and therapeutic alternatives, topics discus sed in this review. Considering the high mortality in BPD associated PH, screening strategies in at risk population become important. The gold standard is cardiac catheterization; however, transtho-rathic echocardiography is a useful tool for the screening and diagnosis of PH in displasic patients, using cuantitive measures and cualitative changes in the evaluation. Seric type-B natriuretic peptide has shown to be useful for follow-up; regarding images, CT scan is used in severe cases. In terms of therapy; inhaled Nitric Oxide as a pulmonary vasodilator, phosphodiesterase inhibitors -sildenafil-, endotelin antagonists -bosentan-, and prostacyclin analogues -iloprost-, have been proposed. Their use, dosis and treatment lenght still lack support of high quality evidence, but diverse clinical expe riences have been described. Interdisciplinary care is also important, highlighting to optimize nu trition. Therefore, the challenge is to effectively prevent BPD and its complications. A PH screening protocol should be associated with risk stratification and treatment guidelines.

[The role of pulmonary hypertension on bronchopulmonary dysplasia]. / El rol de la hipertensión pulmonar en la displasia broncopulmonar.

50 years ago, Northway described Broncopulmonary Dysplasia (BPD) in preterm infants exposed to mechanical ventilation. Since then, their survival has increased, nevertheless a "new BPD" has appeared and its incidence has not diminished. One of the characteristics of this pathology is the the abnormal vascular remodeling, which in its most severe expression is known as Pulmonary Hyper tension (PH); with an incidence of 17% in patients with BPD, which is proportional to the severity of the disease (33% in severe BPD), and as mortality factor (up to 48% 2-year mortality in PH-BPD). Thereby, it is important to know the diagnostic methods and therapeutic alternatives, topics discus sed in this review. Considering the high mortality in BPD associated PH, screening strategies in at risk population become important. The gold standard is cardiac catheterization; however, transtho-rathic echocardiography is a useful tool for the screening and diagnosis of PH in displasic patients, using cuantitive measures and cualitative changes in the evaluation. Seric type-B natriuretic peptide has shown to be useful for follow-up; regarding images, CT scan is used in severe cases. In terms of therapy; inhaled Nitric Oxide as a pulmonary vasodilator, phosphodiesterase inhibitors -sildenafil-, endotelin antagonists -bosentan-, and prostacyclin analogues -iloprost-, have been proposed. Their use, dosis and treatment lenght still lack support of high quality evidence, but diverse clinical expe riences have been described. Interdisciplinary care is also important, highlighting to optimize nu trition. Therefore, the challenge is to effectively prevent BPD and its complications. A PH screening protocol should be associated with risk stratification and treatment guidelines.

Pharmacokinetics, microbial response, and pulmonary outcomes of multidose intravenous azithromycin in preterm infants at risk for Ureaplasma respiratory colonization.

The study objectives were to refine the population pharmacokinetics (PK) model, determine microbial clearance, and assess short-term pulmonary outcomes of multiple-dose azithromycin treatment in preterm infants at risk for Ureaplasma respiratory colonization. Fifteen subjects (7 of whom were Ureaplasma positive) received intravenous azithromycin at 20 mg/kg of body weight every 24 h for 3 doses. Azithromycin concentrations were determined in plasma samples obtained up to 168 h post-first dose by using a validated liquid chromatography-tandem mass spectrometry method. Respiratory samples were obtained predose and at three time points post-last dose for Ureaplasma culture, PCR, antibiotic susceptibility testing, and cytokine concentration determinations. Pharmacokinetic data from these 15 subjects as well as 25 additional subjects (who received either a single 10-mg/kg dose [n = 12] or a single 20-mg/kg dose [n = 13]) were analyzed by using a nonlinear mixed-effect population modeling (NONMEM) approach. Pulmonary outcomes were assessed at 36 weeks post-menstrual age and 6 months adjusted age. A 2-compartment model with all PK parameters allometrically scaled on body weight best described the azithromycin pharmacokinetics in preterm neonates. The population pharmacokinetics parameter estimates for clearance, central volume of distribution, intercompartmental clearance, and peripheral volume of distribution were 0.15 liters/h · kg(0.75), 1.88 liters · kg, 1.79 liters/h · kg(0.75), and 13 liters · kg, respectively. The estimated area under the concentration-time curve over 24 h (AUC24)/MIC90 value was ∼ 4 h. All posttreatment cultures were negative, and there were no drug-related adverse events. One Ureaplasma-positive infant died at 4 months of age, but no survivors were hospitalized for respiratory etiologies during the first 6 months (adjusted age). Thus, a 3-day course of 20 mg/kg/day intravenous azithromycin shows preliminary efficacy in eradicating Ureaplasma spp. from the preterm respiratory tract.

Astragalus polysaccharides exert protective effects in newborn rats with bronchopulmonary dysplasia by upregulating the expression of EGFL7 in lung tissue.

The aim of this study was to explore the effects of Astragalus polysaccharides (APS) on the mRNA expression of epidermal growth factor-like domain 7 (EGFL7) in lung tissue in newborn rats with bronchopulmonary dysplasia (BPD). For this purpose, a total of 96 newborn SD rats were randomly divided into 4 groups (n=24): the control group, air room plus APS group, BPD group and the APS group (20 mg/kg/day). Lung tissues were obtained on days 4, 10 and 14 after birth. Morphological changes were observed and the protein and mRNA expression levels of EGFL7, Bax and Bcl-2 were determined. The rats in the BPD group (BPD induced by hyperoxia) presented with an arrest in alveolar and vascular development and low mRNA and protein expression levels of of EGFL7, Bcl-2 and high levels of Bax compared with the rats in the control group. However, lung damage in the APS intervention group was attenuated compared with the BPD group. The protein and mRNA expression levels of EGFL7 and Bcl-2 were also increased and the level of Bax was decreased in the APS intervention group (P<0.01) compared with the BPD model group after birth on days 4, 10 and 14. Our data demonstrate that APS reduce airway remodeling and alveolar damage by upregulating the expression of EGFL7 and exert protective effects against BPD in neonatal rats. Thus, APS may have potential for use as a therapeutic strategy for BPD.

Arginyl-glutamine dipeptide or docosahexaenoic acid attenuate hyperoxia-induced lung injury in neonatal mice.

OBJECTIVES: Supplementation studies of glutamine, arginine, and docosahexaenoic acid (DHA) have established the safety of each of these nutrients in neonates. However, the potential for a more stable and soluble dipeptide, arginyl-glutamine (Arg-Gln) or DHA, a long-chain ω-3 fatty acid with anti-inflammatory properties, to exert benefits on hyperoxia-induced lung injury has not to our knowledge been investigated. The aim of this study was to investigate whether Arg-Gln dipeptide or DHA could attenuate markers of injury and inflammation in neonatal mouse lungs exposed to hyperoxia. METHODS: Seven-day-old mouse pups were placed with their dams in 75% oxygen for 5 d. After 5 d of hyperoxic exposure (postnatal days 7-12), pups were removed from hyperoxia and allowed to recover in atmospheric conditions for 5 d (postnatal days 12-17). Mouse pups received Arg-Gln (5 g · kg⁻¹ · d⁻¹) or DHA (5 g · kg⁻¹ · d⁻¹) or saline orally from postnatal days 12 through 17. Histologic changes, myeloperoxidase, lactate dehydrogenase, inflammatory cytokines, and nuclear factor-κB inhibitor levels were checked in each group. RESULTS: The Arg-Gln and DHA prevented the development of key markers of injury, including histologic changes, myeloperoxidase, lactate dehydrogenase, and inflammatory cytokines interleukin-6 and C-X-C motif ligand 1 (CXCL1)/keratinocyte-derived chemokine (KC). The highly beneficial effects of Arg-Gln on the reversal of oxygen-induced lung damage was associated with restoration of levels of nuclear factor-κB inhibitor. CONCLUSION: The Arg-Gln and DHA, with protective effects on hyperoxic lung injury in neonatal mice, are promising nutritional adjuncts that may prevent lung damage owing to oxygen toxicity in infants.

Calcium absorption in very low birth weight infants with and without bronchopulmonary dysplasia.

OBJECTIVE: To evaluate the effects of early bronchopulmonary dysplasia (BPD) on calcium (Ca) metabolism and growth in very low birth weight (VLBW) infants. STUDY DESIGN: A dual-tracer, stable isotope method was used to assess Ca absorption in VLBW infants. Infants with early BPD received energy-dense feedings and mild fluid restriction. RESULTS: Sixteen of 41 preterm infants were classified as having early BPD. Fractional Ca absorption (early BPD, 58.4 ± 4.6% versus no early BPD, 50.3 ± 4.0%, P = .2), total Ca absorption (early BPD, 127 ± 14 mg/kg/d versus no early BPD, 104 ± 9 mg/kg/d, P = .9), and Ca retention (early BPD, 99.6 ± 10.0 mg/kg/d versus no early BPD, 91.0 ± 9.8 mg/kg/d, P = .2) were similar among groups. There was no significant difference in weight gain, linear growth, or head circumference growth between groups. CONCLUSIONS: The ability of VLBW infants with early BPD and fluid restriction to grow and accrete calcium is similar to those without early BPD. The use of high caloric density feedings in VLBW infants with early BPD can help achieve bone and overall growth outcomes close to those achievable in utero.

Progress in discovery and evaluation of treatments to prevent bronchopulmonary dysplasia.

BACKGROUND: Recent improvements in the survival of extremely preterm infants have been accompanied by evolution in the pathogenesis and histopathology of bronchopulmonary dysplasia (BPD). Although oxygen and barotrauma-induced injury remain important contributing factors, pulmonary developmental arrest appears to play an equally important causal role in prolonged respiratory illness, especially among the most immature surviving preterm newborns. To date, clinical trials have failed to demonstrate a substantial benefit of a single treatment or preventive strategy for BPD. OBJECTIVES: To evaluate the current evidence in favor of treatments that might prevent BPD. METHODS: Review of clinical studies of preventive treatment strategies for BPD. RESULTS: High frequency oscillatory ventilation, permissive hypercapnea, and inhaled nitric oxide might offer benefit to infants at risk of BPD. These and other potential preventive therapies for BPD, such as superoxide dismutase, inositol, and alpha(1)-proteinase inhibitor, deserve further study. CONCLUSIONS: Although some current treatments offer promise, no preventive therapy for BPD has proven safe and effective, except for intramuscular vitamin A. Additional studies of respiratory technologies, management strategies, and protective molecules are needed.

Pulmonary antioxidant concentrations and oxidative damage in ventilated premature babies.

OBJECTIVE: To determine the relation between lipid peroxidation and the antioxidants ascorbate, urate, and glutathione in epithelial lining fluid in ventilated premature babies, and to relate the biochemical findings to clinical outcome. DESIGN: A cohort study conducted between January 1999 and June 2001. SETTING: A NHS neonatal intensive care unit. PATIENTS: An opportunity sample of 43 ventilated babies of less than 32 weeks gestation. MAIN OUTCOME MEASURES: The duration of supplementary oxygen according to the definition of bronchopulmonary dysplasia (BPD; oxygen dependency at 36 weeks gestational age). METHODS: Epithelial lining fluid was sampled by bronchoalveolar lavage. Ascorbate, urate, glutathione, and malondialdehyde (a marker of lipid peroxidation) were measured. RESULTS: Babies who developed BPD had significantly lower initial glutathione concentrations (mean (SEM) 1.89 (0.62) v 10.76 (2.79) microM; p = 0.043) and higher malondialdehyde concentrations (mean (SEM) 1.3 (0.31) v 0.345 (0.09) microM; p < 0.05) in the epithelial lining fluid than those who were not oxygen dependent. These variables were poor predictors of the development of BPD. Gestational age, endotracheal infection, and septicaemia had good predictive power. The level of oxidative damage was associated with the presence of endotracheal infection/septicaemia rather than inspired oxygen concentration. CONCLUSIONS: Endotracheal infection, septicaemia, and gestational age, rather than antioxidant concentrations, are the most powerful predictors of the development of BPD.

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.

Evidence for magnesium deficiency in the pathogenesis of bronchopulmonary dysplasia (BPD).

Bronchopulmonary dysplasia (BPD) has been defined as a requirement for oxygen for more than 28 days because of chronic pulmonary changes, usually in a premature infant. About 50 per cent of very low birth weight (VLBW) infants who weigh 1 kg at birth and who survive 28 days will develop BPD. Since 80 per cent of fetal accretion of magnesium occurs during the third trimester, this population is also at risk for magnesium deficiency. This paper reviews evidence for a role of magnesium deficiency in the pathogenesis of BPD. Pathology in BPD that may be caused or aggravated by magnesium deficiency is noted. Agents or mediators that are increased in BPD and in BPD include: oxygen free radicals; the inflammatory cytokines interleukin (IL)-1 and IL-6, and tumour necrosis factor-alpha; vaso- and bronchoconstrictors thromboxane A2 (TXA2) and serotonin: vasoconstrictor, endothelin-1 (ET-1); and bronchoconstrictor, histamine. Magnesium deficiency increases the susceptibility of cells and tissues to peroxidation, worsens the inflammatory reaction, reduces the immune response, exaggerates catecholamine release in stress, and diminishes energy metabolism. Possibly because of the danger of magnesium toxicity and the difficulty in studying the preterm VLBW neonate, little is known about magnesium supplementation in this group. Such information must be gained through controlled studies on the effect of antepartum exposure to maternally administered magnesium sulphate on the VLBW infant, through carefully monitored postnatal administration of magnesium in an intensive care setting, or through evaluations of combined pre- and postnatal supplementation.

The effects of illness on neonatal metabolism and nutritional management.

In summary, careful attention to nutrient delivery in the IUGR infant is important to prevent and treat neonatal metabolic derangements and to improve postnatal growth. Carbohydrates are the essential fuel in the first days of life, to prevent hypoglycemia. Subsequent delivery of protein and fat helps rectify reduced muscle and fat stores and promotes weight gain. Calcium supplementation to prevent further bone demineralization and iron supplementation to replete iron stores may be necessary. Of special interest is that the neurologic outcome of these infants appears linked to the rate of catch-up growth. The rate of postnatal head growth depends on many perinatal and neonatal risk factors, and is a strong predictor of early developmental outcome in low-birthweight infants. Insufficient energy delivery beyond 2 weeks postnatal age in SGA premature infants results in failure to initiate subsequent catch-up head growth, with consequently smaller head circumferences at 1-year follow-up.

The protective role of bilirubin in oxygen-radical diseases of the preterm infant.

We hypothesized that because bilirubin is a potent free-radical quencher, infants without disorders that have oxygen-radical disease (ORD)-mediated mechanisms may have higher bilirubin levels than infants suffering from conditions possibly associated with ORD-mediated mechanisms (e.g., necrotizing enterocolitis, broncopulmonary dysplasia, intraventricular hemorrhage, and retinopathy of prematurity). We identified 25 infants (birth weight 912 +/- 208 gm, gestational age 27 +/- 3 weeks) who comprised the ORD group and compared them with 57 controls (birth weight 1242 +/- 248 gm, gestational age 31 +/- 3 weeks). Infants with ORD had lower peak serum bilirubin concentrations, later ages at peak, and lower incidence of peak bilirubin concentrations exceeding 10 or 15 mg/dl. In addition, these infants exhibited a slower rate of bilirubin rise and a smaller area under the bilirubin-time curve measure compared with controls. To control for different birth weights, we analyzed subgroups weighing < 1000 gm. Significant differences were again identified in peak bilirubin concentrations, age at peak, phototherapy duration, and area under the curve. In this population of preterm infants, higher bilirubin levels were associated with a lower incidence of oxygen radical-mediated injury.