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1.
Life Sci ; 259: 118285, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32798556

RESUMO

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.


Assuntos
Auranofina/farmacologia , Macrófagos Alveolares/metabolismo , Tiorredoxina Redutase 1/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Auranofina/metabolismo , Displasia Broncopulmonar/metabolismo , Displasia Broncopulmonar/fisiopatologia , Glutationa/metabolismo , Interleucina-1beta/efeitos dos fármacos , Interleucina-1beta/metabolismo , Lipopolissacarídeos/farmacologia , Pulmão/metabolismo , Macrófagos/metabolismo , Macrófagos Alveolares/fisiologia , Camundongos , Cultura Primária de Células , Selênio/metabolismo , Selênio/farmacologia , Tiorredoxina Redutase 1/antagonistas & inibidores , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Tiorredoxina Dissulfeto Redutase/metabolismo
2.
Arterioscler Thromb Vasc Biol ; 40(10): 2548-2556, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32847389

RESUMO

OBJECTIVE: Preterm birth has been associated with changes in arterial structure and function. Association with complications occurring during the neonatal period, including bronchopulmonary dysplasia, on vascular outcomes in adulthood is unknown. Approach and Results: We evaluated a cohort of 86 adults born preterm (below 30 weeks of gestation), compared to 85 adults born term, at a mean age of 23 years. We performed ultrasonographic assessment of the dimensions of the ascending aorta, carotid and brachial arteries, and estimated flow-mediated dilation, carotid-femoral pulse wave velocity, augmentation index corrected for heart rate, and carotid intima-media thickness. All analyses were performed with and without adjustment for potential confounding variables, including height, sex, and body mass index. Ascending aorta diameter in diastole was smaller in the preterm group, but carotid and brachial arteries were similar. Carotid and brachial strain, a marker of arterial distensibility, was smaller in the preterm group, while carotid-femoral pulse wave velocity, was similar between groups, indicating similar aortic stiffness. Carotid intima-media thickness, endothelial function flow-mediated dilation, blood nitrite, and nitrate levels were similar between groups. Individuals with bronchopulmonary dysplasia had lower brachial artery strain suggesting long-term association of this neonatal complication with vascular structure. Diastolic blood pressure was higher in the preterm group and was associated with decreased brachial and carotid distensibility. CONCLUSIONS: Young adults born preterm display alterations in arterial distensibility that are associated with a history of bronchopulmonary dysplasia.


Assuntos
Aorta/fisiopatologia , Artéria Braquial/fisiopatologia , Displasia Broncopulmonar/complicações , Artérias Carótidas/fisiopatologia , Recém-Nascido Prematuro , Doenças Vasculares/etiologia , Rigidez Vascular , Adolescente , Adulto , Fatores Etários , Aorta/diagnóstico por imagem , Pressão Arterial , Artéria Braquial/diagnóstico por imagem , Displasia Broncopulmonar/diagnóstico , Displasia Broncopulmonar/fisiopatologia , Artérias Carótidas/diagnóstico por imagem , Estudos de Casos e Controles , Estudos Transversais , Feminino , Idade Gestacional , Frequência Cardíaca , Humanos , Recém-Nascido , Masculino , Fatores de Risco , Doenças Vasculares/diagnóstico por imagem , Doenças Vasculares/fisiopatologia , Adulto Jovem
3.
J Pediatr ; 223: 20-28.e2, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32711747

RESUMO

OBJECTIVE: To evaluate the predictive value of cumulative oxygen exposure thresholds over the first 2 postnatal weeks, linking them to bronchopulmonary dysplasia (BPD) and 1-year pulmonary morbidity and lung function in extremely low gestational age newborns. STUDY DESIGN: Infants (N = 704) enrolled in the Prematurity and Respiratory Outcomes Program, a multicenter prospective cohort study, that survived to discharge were followed through their neonatal intensive care unit hospitalization to 1-year corrected age. Cumulative oxygen exposure (OxygenAUC14) thresholds were derived from univariate models of BPD, stratifying infants into high-, intermediate-, and low-oxygen exposure groups. These groups were then used in multivariate logistic regressions to prospectively predict post-prematurity respiratory disease (PRD), respiratory morbidity score (RMS) in the entire cohort, and pulmonary function z scores (N = 108 subset of infants) at 1-year corrected age. RESULTS: Over the first 14 postnatal days, infants exposed to high oxygen averaged ≥33.1% oxygen, infants exposed to intermediate oxygen averaged 29.1%-33.1%, and infants exposed to low oxygen were below both cutoffs. In multivariate models, infants exposed to high oxygen showed increased PRD and RMS, whereas infants exposed to intermediate oxygen demonstrated increased moderate/severe RMS. Infants in the high/intermediate groups had decreased forced expiratory volume at 0.5 seconds/forced vital capacity ratio. CONCLUSIONS: OxygenAUC14 establishes 3 thresholds of oxygen exposure that risk stratify infants early in their neonatal course, thereby predicting short-term (BPD) and 1-year (PRD, RMS) respiratory morbidity. Infants with greater OxygenAUC14 have altered pulmonary function tests at 1 year of age, indicating early evidence of obstructive lung disease and flow limitation, which may predispose extremely low gestational age newborns to increased long-term pulmonary morbidity. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01435187.


Assuntos
Displasia Broncopulmonar/etiologia , Oxigênio/efeitos adversos , Respiração Artificial/efeitos adversos , Displasia Broncopulmonar/fisiopatologia , Feminino , Humanos , Lactente , Recém-Nascido , Unidades de Terapia Intensiva Neonatal/estatística & dados numéricos , Masculino , Oxigênio/administração & dosagem , Estudos Prospectivos , Respiração Artificial/métodos , Respiração Artificial/mortalidade , Testes de Função Respiratória , Índice de Gravidade de Doença , Capacidade Vital
4.
J Cardiovasc Magn Reson ; 22(1): 50, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32698897

RESUMO

BACKGROUND: Bronchopulmonary dysplasia (BPD) associated with pulmonary hypertension (PH) is a significant source of morbidity and mortality in premature infants. Recent advances have allowed the use of cardiovascular magnetic resonance (CMR) in the assessment of respiratory and cardiac disease in infants with BPD. In adults and older pediatric patients, decreased CMR interventricular septal curvature correlates with increased mean pulmonary artery pressure and pulmonary vascular resistance. The current study sought to determine the relationship of CMR derived septal curvature in neonates with BPD and BPD-PH with a need for PH therapy. METHODS: Forty moderate or severe BPD and 12 mild BPD or control infants were imaged without contrast between 38 and 47 weeks post-menstrual age on a neonatal-sized, neonatal intensive care unit-sited 1.5 T CMR scanner. CMR indices including eccentricity index (CMR-EI) and septal curvature were measured and compared to BPD severity and clinical outcomes including hospital length of stay (LOS), duration of respiratory support, respiratory support level at discharge and PH therapy. RESULTS: CMR-EI was directly associated and septal curvature was inversely associated with BPD severity. In a univariate analysis, CMR-EI and septal curvature were associated with increased hospital LOS, duration of respiratory support, respiratory support at hospital discharge, and need for PH therapy. In multivariable analysis CMR-EI was associated with hospital LOS and duration of respiratory support and septal curvature was associated with respiratory support at hospital discharge. Septal curvature was the only clinical or CMR variable associated with need for PH therapy (R2 = 0.66, p = 0.0014) in multivariable analysis demonstrating improved discrimination beyond CMR-EI. CONCLUSIONS: CMR derived septal curvature correlates significantly with clinical outcomes including hospital LOS, duration of respiratory support, respiratory support level at hospital discharge, and PH therapy in neonates with BPD and BPD-PH. Further, CMR derived septal curvature demonstrated improved discrimination of need for PH therapy and respiratory support at discharge compared to clinical variables and other CMR indices, supporting septal curvature as a non-invasive marker of PH in this population with potential to guide management strategies.


Assuntos
Pressão Arterial , Displasia Broncopulmonar/diagnóstico por imagem , Hipertensão Pulmonar/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética , Artéria Pulmonar/fisiopatologia , Resistência Vascular , Septo Interventricular/diagnóstico por imagem , Anti-Hipertensivos/uso terapêutico , Pressão Arterial/efeitos dos fármacos , Displasia Broncopulmonar/complicações , Displasia Broncopulmonar/fisiopatologia , Displasia Broncopulmonar/terapia , Feminino , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar/terapia , Recém-Nascido , Tempo de Internação , Masculino , Valor Preditivo dos Testes , Artéria Pulmonar/efeitos dos fármacos , Terapia Respiratória , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Resistência Vascular/efeitos dos fármacos , Septo Interventricular/efeitos dos fármacos , Septo Interventricular/fisiopatologia
5.
Niger J Clin Pract ; 23(7): 980-987, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620729

RESUMO

Background: Perinatal and neonatal care for very low birth weight (VLBW) infants have changed significantly during the past two decades. However, it is unclear how these changes have affected neonatal mortality and morbidity in developing countries. Objectives: The aim of this study was to investigate the impact of the advanced neonatal care on short-term outcomes of VLBW infants. Methods: A retrospective study was performed to compare the mortality and morbidity of VLBW infants between period I (2007-2011) and period II (2012-2016) in our unit. Results: A total of 188 infants in period I and 214 infants in period II were evaluated. The overall in-hospital mortality for VLBW infants dropped from 26.1% in period I to 13.1% in period II. The incidence of birth asphyxia decreased significantly during period II (10.1% [period I] vs 3.7% [period II]). The rate of nasal continuous positive airway pressure (NCPAP) use (69.8% vs 87.1%) and the duration of NCPAP therapy (median: 3 days [period I] vs 5 days [period II]) increased significantly, while the proportion of infants treated with mechanical ventilation and the duration of mechanical ventilation significantly decreased. There was a significant increase in the proportion of survivors without major neonatal morbidity, mainly due to a significant increase in the incidence of survival without bronchopulmonary dysplasia (BPD) (72.7% vs 82.8%). In contrast, the incidence of late-onset sepsis increased significantly during period II (7.9% vs 19.4%). Conclusions: Active perinatal care is associated with improvements in survival and survival free of BPD for VLBW infants. However, late-onset sepsis is still a major concern.


Assuntos
Displasia Broncopulmonar/mortalidade , Mortalidade Infantil , Assistência Perinatal/métodos , Sepse/complicações , Displasia Broncopulmonar/etiologia , Displasia Broncopulmonar/fisiopatologia , Criança , Feminino , Mortalidade Hospitalar , Humanos , Incidência , Lactente , Recém-Nascido , Recém-Nascido de muito Baixo Peso , Masculino , Morbidade , Gravidez , Estudos Retrospectivos , Sepse/epidemiologia , Índice de Gravidade de Doença , Taxa de Sobrevida
6.
Sci Rep ; 10(1): 12368, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32704023

RESUMO

Preterm infants with bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH) have accelerated lung aging and poor long-term outcomes. Klotho is an antiaging protein that modulates oxidative stress, angiogenesis and fibrosis. Here we test the hypothesis that decreased cord Klotho levels in preterm infants predict increased BPD-PH risk and early Klotho supplementation prevents BPD-like phenotype and PH in rodents exposed to neonatal hyperoxia. In experiment 1, Klotho levels were measured in cord blood of preterm infants who were enrolled in a longitudinal cohort study. In experiment 2, using an experimental BPD-PH model, rat pups exposed to room air or hyperoxia (85% O2) were randomly assigned to receive every other day injections of recombinant Klotho or placebo. The effect of Klotho on lung structure, PH and cardiac function was assessed. As compared to controls, preterm infants with BPD or BPD-PH had decreased cord Klotho levels. Early Klotho supplementation in neonatal hyperoxia-exposed rodents preserved lung alveolar and vascular structure, attenuated PH, reduced pulmonary vascular remodeling and improved cardiac function. Together, these findings have important implications as they suggest that perinatal Klotho deficiency contributes to BPD-PH risk and strategies that preserve Klotho levels, may improve long-term cardiopulmonary outcomes in preterm infants.


Assuntos
Displasia Broncopulmonar/sangue , Sangue Fetal/metabolismo , Glucuronidase/sangue , Hipertensão Pulmonar/sangue , Recém-Nascido Prematuro/sangue , Biomarcadores/sangue , Displasia Broncopulmonar/fisiopatologia , Feminino , Humanos , Hipertensão Pulmonar/fisiopatologia , Recém-Nascido , Estudos Longitudinais , Masculino
8.
Pediatr Cardiol ; 41(6): 1115-1124, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32388668

RESUMO

Elective closure of atrial septal defect (ASD) is usually recommended during preschool ages. However, ASD may contribute to deteriorating health in the presence of significant comorbidity and, thus, may need earlier closure. There is a lack of clarity regarding the indications for and outcomes after ASD closure in infancy and early childhood. We investigated the benefits and safety of surgical ASD closure in symptomatic patients under 2 years of age. Retrospective chart review was conducted in patients who underwent surgical ASD closure within the first 2 years of life. Of 31 symptomatic ASD patients, 22 had persistent respiratory symptoms, 24 failure to thrive, and 9 pulmonary hypertension. Overall, 26 patients (84.0%) showed clinical improvement after ASD closure, including improved respiratory status (17/22; 77.3%), resumption of normal growth (15/24; 62.5%), and resolution of pulmonary hypertension (7/7; 100%, 2 patients unable to assess postoperatively). Two medically complicated patients died a few months after surgery unrelated to surgical complications. Four out of 8 ventilator-dependent patients were weaned from mechanical ventilation within 1 month after ASD closure. Closure of ASD did not improve those patients with highly advanced lung disease and/or medically complex conditions including underlying genetic abnormalities. Surgical complications were uncommon. Postoperative hospital stay was 4 to 298 days (median 8 days). The majority of our patients demonstrated significant clinical improvement after ASD closure. Early ASD closure is safe and beneficial for symptomatic infants and young children with associated underlying pulmonary abnormalities, especially bronchopulmonary dysplasia.


Assuntos
Comunicação Interatrial/cirurgia , Displasia Broncopulmonar/complicações , Displasia Broncopulmonar/fisiopatologia , Cateterismo Cardíaco/métodos , Pré-Escolar , Feminino , Comunicação Interatrial/complicações , Humanos , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/fisiopatologia , Lactente , Tempo de Internação , Masculino , Estudos Retrospectivos , Resultado do Tratamento
9.
Am J Respir Crit Care Med ; 202(7): 1024-1031, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32459506

RESUMO

Rationale: Bronchopulmonary dysplasia is a heterogeneous lung disease characterized by regions of cysts and fibrosis, but methods for evaluating lung function are limited to whole lung rather than specific regions of interest.Objectives: Respiratory-gated, ultrashort echo time magnetic resonance imaging was used to test the hypothesis that cystic regions of the lung will exhibit a quantifiable Vt that will correlate with ventilator settings and clinical outcomes.Methods: Magnetic resonance images of 17 nonsedated, quiet-breathing infants with severe bronchopulmonary dysplasia were reconstructed into end-inspiration and end-expiration images. Cysts were identified and measured by using density threshold combined with manual identification and segmentation. Regional Vts were calculated by subtracting end-expiration from end-inspiration volumes in total lung, noncystic lung, total-cystic lung, and individual large cysts.Measurements and Main Results: Cystic lung areas averaged larger Vts than noncystic lung when normalized by volume (0.8 ml Vt/ml lung vs. 0.1 ml Vt/ml lung, P < 0.002). Cyst Vt correlates with cyst size (P = 0.012 for total lung cyst and P < 0.002 for large cysts), although there was variability between individual cyst Vt, with 22% of cysts demonstrating negative Vt. Peak inspiratory pressure positively correlated with total lung Vt (P = 0.027) and noncystic Vt (P = 0.015) but not total lung cyst Vt (P = 0.8). Inspiratory time and respiratory rate did not improve Vt of any analyzed lung region.Conclusions: Cystic lung has greater normalized Vt when compared with noncystic lung. Ventilator pressure increases noncystic lung Vt, but inspiratory time does not correlate with Vt of normal or cystic lung.


Assuntos
Displasia Broncopulmonar/diagnóstico por imagem , Cistos/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Respiração Artificial/métodos , Volume de Ventilação Pulmonar/fisiologia , Displasia Broncopulmonar/fisiopatologia , Displasia Broncopulmonar/terapia , Cistos/fisiopatologia , Feminino , Humanos , Imageamento Tridimensional , Lactente , Lactente Extremamente Prematuro , Recém-Nascido , Masculino , Técnicas de Imagem de Sincronização Respiratória
10.
Neoreviews ; 21(4): e226-e237, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32238485

RESUMO

Bronchopulmonary dysplasia (BPD) is an acquired, developmental chronic lung disease that is a consequence of premature birth. In the most severe form of the disease, infants may require prolonged periods of positive pressure ventilation. BPD is a heterogeneous disease with lung mechanics that differ from those in respiratory distress syndrome; strategies to manage the respiratory support in infants with severe BPD should take this into consideration. When caring for these infants, practitioners need to shift from the acute care ventilation strategies that use frequent blood gases and support adjustments designed to minimize exposure to positive pressure. Infants with severe BPD benefit from a chronic care model that uses less frequent ventilator adjustments and provides the level of positive support that will achieve the longer-term goal of ongoing lung growth and repair.


Assuntos
Displasia Broncopulmonar/terapia , Suporte Ventilatório Interativo/normas , Ventilação não Invasiva/normas , Respiração com Pressão Positiva/normas , Displasia Broncopulmonar/fisiopatologia , Humanos , Recém-Nascido
11.
Life Sci ; 252: 117662, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32298739

RESUMO

AIMS: Bronchopulmonary dysplasia (BPD) is a severe respiratory complication in preterm infants. This study reveals the molecular mechanism of autophagic agonists regulating the Nrf2-ARE pathway via p62 to improve alveolar development in BPD rats. MAIN METHODS: Newborn Sprague-Dawley rats were randomly exposed to a hyperoxic environment (FiO2 = 0.85) for 14 days and rapamycin (RAPA) was intraperitoneally injected on alternate days into hyperoxia-exposed mice. Alveolar development was assessed using HE and RAC values. Markers associated with the p62-Keap1-Nrf2-ARE pathway were detected by western blot, immunohistochemistry, and RT-PCR. Co-localization of proteins was determined using double immunofluorescence staining. KEY FINDINGS: At the levels of lung tissue and primary type II alveolar epithelial cells, the enhanced binding between phosphorylated p62 and Keap1 disrupted the nuclear transport of Nrf2. The activated Nrf2 was insufficient to reverse alveolar simplification. The autophagy agonist was able to inhibit p62 phosphorylation, promote Keap1 degradation, increase Nrf2 nuclear transport, augment downstream antioxidant enzyme expression, and enhance antioxidant capacity, thereby improving the simplification of alveolar structure in BPD rats. SIGNIFICANCE: The use of autophagy agonists to enhance the Nrf2-ARE pathway activity and promote alveolar development could be a novel target in antioxidant therapy for BPD.


Assuntos
Autofagia/efeitos dos fármacos , Displasia Broncopulmonar/fisiopatologia , Alvéolos Pulmonares/metabolismo , Sirolimo/farmacologia , Animais , Animais Recém-Nascidos , Elementos de Resposta Antioxidante , Antioxidantes/metabolismo , Modelos Animais de Doenças , Humanos , Hiperóxia/complicações , Recém-Nascido , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Ratos Sprague-Dawley
12.
Am J Respir Crit Care Med ; 202(3): 422-432, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32302489

RESUMO

Rationale: Growth and development during adolescence may modify the respiratory and vascular differences seen among extremely preterm (EP) individuals in childhood and early adolescence.Objectives: To assess the trajectory of respiratory and cardiovascular outcomes during transition to adulthood in a national longitudinal cohort study of births before 26 weeks of gestation in the United Kingdom and Ireland.Methods: A total of 129 EP participants and 65 control subjects attended for a center-based evaluation at 19 years of age. Standardized measures of spirometry, hemodynamics, functional capacity, and markers of inflammation were obtained from EP subjects with and without neonatal bronchopulmonary dysplasia and term-born control subjects at 19 years of age and compared with previous assessments.Measurements and Main Results: Compared with the control group, the EP group was significantly impaired on all spirometric parameters (mean FEV1 z-score, -1.08 SD [95% confidence interval, -1.40 to -0.77]) and had lower fractional exhaled nitric oxide concentrations (13.9 vs. 24.4 ppb; P < 0.001) despite a higher proportion with bronchodilator reversibility (27% vs. 6%). The EP group had significantly impaired exercise capacity. All respiratory parameters were worse after neonatal bronchopulmonary dysplasia, and respiratory function differences were similar at 11 and 19 years. The augmentation index was 6% higher in the EP group and associated with increased total peripheral resistance (difference in means, 96.4 [95% confidence interval, 26.6-166.2] dyne/s/cm-5) and elevation in central, but not peripheral, blood pressure. Central systolic and diastolic blood pressures increased more quickly during adolescence in the EP group than in the control group.Conclusions: Clinicians should address both cardiovascular and respiratory risks in adult survivors of extremely preterm birth.


Assuntos
Asma/fisiopatologia , Pressão Sanguínea/fisiologia , Displasia Broncopulmonar/fisiopatologia , Doenças Cardiovasculares/fisiopatologia , Tolerância ao Exercício/fisiologia , Pulmão/fisiopatologia , Asma/epidemiologia , Testes Respiratórios , Displasia Broncopulmonar/epidemiologia , Proteína C-Reativa/imunologia , Doenças Cardiovasculares/epidemiologia , Estudos de Coortes , Creatinina , Feminino , Volume Expiratório Forçado , Taxa de Filtração Glomerular , Humanos , Lactente Extremamente Prematuro , Recém-Nascido , Inflamação/imunologia , Irlanda/epidemiologia , Estudos Longitudinais , Pulmão/fisiologia , Masculino , Manometria , Fluxo Máximo Médio Expiratório , Óxido Nítrico , Análise de Onda de Pulso , Espirometria , Reino Unido/epidemiologia , Resistência Vascular/fisiologia , Capacidade Vital , Teste de Caminhada , Adulto Jovem
13.
Thorax ; 75(6): 494-502, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32217779

RESUMO

BACKGROUND: Although erythropoiesis is impaired and anaemia frequent in neonates born preterm, haematopoiesis in adults born preterm has not been previously studied. OBJECTIVE: We, thus, aimed to evaluate haemoglobin and erythropoietin levels in young adults born preterm, to identify neonatal events associated with erythropoiesis in adulthood and to examine the relationships of haemoglobin levels with respiratory function and blood pressure. METHODS: We assessed a cohort of 101 young adults (ages 18-29) born preterm (≤29 weeks of gestation), in comparison to 105 full-term controls. We measured haemoglobin, erythropoietin levels and blood pressure. We also assessed respiratory function using spirometry. RESULTS: Compared with controls, tobacco use and sex-adjusted haemoglobin levels were 5.3 (95% CI 2.9 to 7.7) g/L higher in preterm-born individuals, but erythropoietin levels were similar. Duration of oxygen supplementation in the neonatal period was independently associated with higher haemoglobin levels in the preterm group. In young adults born preterm with bronchopulmonary dysplasia, airflow limitation was associated with higher haemoglobin levels. Both systolic (SBP) and diastolic (DBP) blood pressure were increased in individuals born preterm (p=0.042 and p=0.0008, respectively). Higher haemoglobin levels were associated with higher SBP and DBP, independently of term or preterm status. Mediation analysis suggests that haemoglobin increase contributes to 37% and 32% of the effect of preterm birth on SBP and DBP, respectively. CONCLUSIONS: Haemoglobin levels are higher in young adults born preterm, while erythropoietin levels are similar, especially in case of bronchopulmonary dysplasia and airflow limitation, and haemoglobin increase is associated with elevated blood pressure in this population.


Assuntos
Eritropoese , Hipertensão/fisiopatologia , Oxigenoterapia , Nascimento Prematuro/fisiopatologia , Adolescente , Adulto , Displasia Broncopulmonar/fisiopatologia , Estudos de Casos e Controles , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Testes de Função Respiratória , Fatores de Risco
14.
Pediatr Pulmonol ; 55(6): 1366-1374, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32212328

RESUMO

INTRODUCTION: Survivors of extreme prematurity may have disrupted lung development. We hypothesized that the multiple breath washout (MBW) index Scond, which is intended to reflect ventilation inhomogeneity from the conducting airways, could be a sensitive marker of respiratory impairment in this group. METHODS: Spirometry, TLco, and MBW were cross-sectionally evaluated at 8 to 14 years of age in children born at <28 weeks between 2004 and 2010 in Udine, Italy. Age-matched controls born at term were also included. Bronchopulmonary dysplasia (BPD) was defined as oxygen-dependence at 36 weeks postmenstrual age. The limits of normal were the 5th percentile of the reference population (Global Lung Initiative) for spirometry and TLco and the 95th percentile of controls for Lung Clearance Index, Scond, and Sacin from MBW. RESULTS: Results were obtained in 47 extremely preterm children (53% boys, mean ± standard deviation age 11.3 ± 2.0 years, 40% with BPD) and 60 controls (50% boys, 11.6 ± 1.9 years). There were significant differences between preterm children and controls in all lung function outcomes, except for Sacin. Among children born <28 weeks, Scond tended to be frequently abnormal than FEV1 z-score (29% vs 14%, P = .06). At multivariable linear regression, in the preterm group, current asthma was significantly associated with a higher Scond (B = 0.019, 95% confidence interval, 0.000-0.038), whereas BPD was not. CONCLUSION: Almost a third of extremely preterm children at school age showed Scond alterations that affected also children without BPD. Longitudinal studies should clarify the prognostic meaning of Scond abnormalities in this group.


Assuntos
Displasia Broncopulmonar/fisiopatologia , Lactente Extremamente Prematuro , Pulmão/fisiopatologia , Adolescente , Criança , Feminino , Humanos , Recém-Nascido , Masculino , Gravidez , Ventilação Pulmonar , Testes de Função Respiratória , Sobreviventes
15.
Am J Physiol Lung Cell Mol Physiol ; 318(5): L976-L987, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32186390

RESUMO

A significant proportion of preterm infants develop bronchopulmonary dysplasia (BPD) leading to poor lifelong respiratory health. Limited treatment options exist with continuous positive airway pressure (CPAP) ventilation being one of the few associated with diminished BPD. However, little is known about the effect of the distending pressure of CPAP on the developing lung exposed to hyperoxia. We aimed to identify the functional and structural effects of CPAP in a preterm hyperoxia rabbit model of BPD. Premature rabbit pups were randomized to normoxia, hyperoxia (≥95% O2), or hyperoxia plus 4 h daily CPAP [fraction of inspired oxygen (FiO2) 0.95, 5 cmH2O]. On day 7 postdelivery we performed invasive pressure-volume- and forced oscillation-based pulmonary function tests, before lung harvest for histological evaluation. Alveolar and vascular morphology, airway smooth muscle content, respiratory epithelium height, extracellular matrix components, and inflammatory cytokine expression were quantified. Hyperoxia-reared pups had restrictive lungs: alveolar walls were thickened, with the lung parenchymal tissue, collagen content, and airway smooth muscle content increased. In addition, peripheral pulmonary artery wall thickness was increased. CPAP increased alveolar recruitment and limited the structural effect of hyperoxia on the respiratory epithelium and pulmonary arteries. Additionally, CPAP improved lung function, mitigating hyperoxia-associated changes to respiratory system resistance, tissue damping, and tissue elastance. Hyperoxia disrupted functional and structural lung development. Daily intermittent CPAP limited hyperoxia-associated decreased lung function and attenuated structural changes to pulmonary arteries and respiratory epithelium while having no structural alveolar consequences. The mechanism by which CPAP has these beneficial effects needs further investigation.


Assuntos
Displasia Broncopulmonar/fisiopatologia , Hiperóxia/complicações , Hipertensão Pulmonar/fisiopatologia , Lesão Pulmonar/fisiopatologia , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Humanos , Hiperóxia/metabolismo , Hipertensão Pulmonar/patologia , Pulmão/patologia , Pulmão/fisiopatologia , Alvéolos Pulmonares/patologia , Coelhos , Testes de Função Respiratória
16.
Am J Pathol ; 190(3): 711-722, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32093901

RESUMO

Bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH) is an infantile lung disease characterized by aberrant angiogenesis and impaired resolution of lung injury. Adrenomedullin (AM) signals through calcitonin receptor-like receptor and receptor activity-modifying protein 2 and modulates lung injury initiation. However, its role in lung injury resolution and the mechanisms by which it regulates angiogenesis remain unclear. Consequently, we hypothesized that AM resolves hyperoxia-induced BPD and PH via endothelial nitric oxide synthase (NOS3). AM-sufficient (ADM+/+) or -deficient (ADM+/-) mice were exposed to normoxia or hyperoxia through postnatal days (PNDs) 1 to 14, and the hyperoxia-exposed mice were allowed to recover in normoxia for an additional 56 days. Lung injury and development and PH were quantified at different time points. Human pulmonary microvascular endothelial cells were also used to examine the effects of AM signaling on the NOS3 pathway and angiogenesis. Lung blood vessels and NOS3 expression decreased and the extent of hyperoxia-induced BPD and PH increased in ADM+/- mice compared with ADM+/+ mice. Hyperoxia-induced apoptosis and PH resolved by PND14 and PND70, respectively, in ADM+/+ mice but not in ADM+/- mice. Knockdown of ADM, calcitonin receptor-like receptor, and receptor activity-modifying protein 2 in vitro decreased NOS3 expression, nitric oxide generation, and angiogenesis. Furthermore, NOS3 knockdown abrogated the angiogenic effects of AM. Collectively, these results indicate that AM resolves hyperoxic lung injury via NOS3.


Assuntos
Adrenomedulina/farmacologia , Displasia Broncopulmonar/tratamento farmacológico , Hiperóxia/complicações , Hipertensão Pulmonar/tratamento farmacológico , Óxido Nítrico Sintase Tipo III/metabolismo , Animais , Displasia Broncopulmonar/etiologia , Displasia Broncopulmonar/fisiopatologia , Células Endoteliais/patologia , Feminino , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Pulmão/fisiopatologia , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo III/genética , Proteína 2 Modificadora da Atividade de Receptores/genética , Proteína 2 Modificadora da Atividade de Receptores/metabolismo , Transdução de Sinais
17.
Am J Respir Crit Care Med ; 201(9): 1120-1134, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32101461

RESUMO

Rationale: Antenatal factors, such as chorioamnionitis, preeclampsia, and postnatal injury, are associated with an increased risk for bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH) after preterm birth. IGF-1 (insulin-like growth factor-1) is markedly decreased in normal preterm infants, but whether IGF-1 treatment can prevent BPD or PH is unknown.Objectives: To evaluate whether postnatal treatment with rhIGF-1 (recombinant human IGF-1)/BP3 (binding peptide 3) improves lung growth and prevents PH in two antenatal models of BPD induced by intraamniotic exposure to endotoxin (ETX) or sFlt-1 (soluble fms-like tyrosine kinase 1), and in a postnatal model due to prolonged hyperoxia.Methods: ETX or sFlt-1 were administered into the amniotic sac of pregnant rats at Embryonic Day 20 to simulate antenatal models of chorioamnionitis and preeclampsia, respectively. Pups were delivered by cesarean section at Embryonic Day 22 and treated with rhIGF-1/BP3 (0.02-20 mg/kg/d intraperitoneal) or buffer for 2 weeks. Study endpoints included radial alveolar counts (RACs), vessel density, and right ventricular hypertrophy (RVH). Direct effects of rhIGF-1/BP3 (250 ng/ml) on fetal lung endothelial cell proliferation and tube formation and alveolar type 2 cell proliferation were studied by standard methods in vitro.Measurements and Main Results: Antenatal ETX and antenatal sFlt-1 reduced RAC and decreased RVH in infant rats. In both models, postnatal rhIGF-1/BP3 treatment restored RAC and RVH to normal values when compared with placebo injections. rhIGF-1/BP3 treatment also preserved lung structure and prevented RVH after postnatal hyperoxia. In vitro studies showed that rhIGF-1/BP3 treatment increased lung endothelial cell and alveolar type 2 cell proliferation.Conclusions: Postnatal rhIGF-1/BP3 treatment preserved lung structure and prevented RVH in antenatal and postnatal BPD models. rhIGF-1/BP3 treatment may provide a novel strategy for the prevention of BPD in preterm infants.


Assuntos
Displasia Broncopulmonar/tratamento farmacológico , Hipertensão Pulmonar/prevenção & controle , Recém-Nascido Prematuro/crescimento & desenvolvimento , Fator de Crescimento Insulin-Like I/uso terapêutico , Pulmão/efeitos dos fármacos , Pulmão/crescimento & desenvolvimento , Cuidado Pós-Natal/métodos , Animais , Animais Recém-Nascidos/crescimento & desenvolvimento , Displasia Broncopulmonar/fisiopatologia , Feminino , Humanos , Hipertensão Pulmonar/fisiopatologia , Lactente , Recém-Nascido , Masculino , Modelos Animais , Gravidez , Ratos , Ratos Sprague-Dawley
18.
Trials ; 21(1): 125, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005282

RESUMO

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a complex lung pathological lesion secondary to multiple factors and one of the most common chronic lung diseases. It has a poor prognosis, especially in preterm infants. However, effective therapies for this disease are lacking. Stem-cell therapy is a promising way to improve lung injury and abnormal alveolarization, and the human umbilical cord (hUC) is a good source of mesenchymal stem cells (MSCs), which have demonstrated efficacy in other diseases. We hypothesized that intravenously administered allogeneic hUC-MSCs are safe and effective for severe BPD. METHODS: The MSC-BPD trial is a randomized, single-center, open-label, dose-escalation, phase-II trial designed to investigate the safety and efficacy of hUC-MSCs in children with severe BPD. In this study, 72 patients will be enrolled and randomly divided into two intervention groups and one control group. Patients in the intervention groups will receive a low dose of hUC-MSCs (n = 24; 2.5 million cells/kg) or a high dose of hUC-MSCs (n = 24; 5 million cells/kg) in combination with traditional supportive treatments for BPD. The patients in the control group (n = 24) will be treated with traditional supportive treatments alone without hUC-MSCs. The primary outcome measures will be cumulative duration of oxygen therapy. Follow-up assessments will be performed at 1, 3, 6, 12, and 24 months post intervention, and the key outcome during follow-up will be changes on chest radiography. Statistical analyses will evaluate the efficacy of the hUC-MSC treatment. DISCUSSION: This will be the first randomized controlled trial to evaluate the safety and efficacy of intravenously administered hUC-MSCs in children with severe BPD. Its results should provide a new evidence-based therapy for severe BPD. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03601416. Registered on 26 July 2018.


Assuntos
Displasia Broncopulmonar/terapia , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Pulmão , Células-Tronco Mesenquimais/fisiologia , Administração Intravenosa , Displasia Broncopulmonar/diagnóstico , Displasia Broncopulmonar/fisiopatologia , Ensaios Clínicos Fase II como Assunto , Feminino , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro/fisiologia , Pulmão/diagnóstico por imagem , Pulmão/fisiopatologia , Masculino , Avaliação de Resultados em Cuidados de Saúde/métodos , Oxigenoterapia/estatística & dados numéricos , Radiografia Torácica/estatística & dados numéricos , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença
19.
Curr Opin Pediatr ; 32(2): 252-260, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32084032

RESUMO

PURPOSE OF REVIEW: To summarize the current literature evaluating long-term pulmonary morbidity among surviving very preterm infants with bronchopulmonary dysplasia (BPD). RECENT FINDINGS: BPD predisposes very preterm infants to adverse respiratory signs and symptoms, greater respiratory medication use, and more frequent need for rehospitalization throughout early childhood. Reassuringly, studies also indicate that older children and adolescents with BPD experience, on average, similar functional status and quality of life when compared to former very preterm infants without BPD. However, measured deficits in pulmonary function may persist in those with BPD and indicate an increased susceptibility to early-onset chronic obstructive pulmonary disease during adulthood. Moreover, subtle differences in exercise tolerance and activity may put survivors with BPD at further risk of future morbidity in later life. SUMMARY: Despite advances in neonatal respiratory care, a diagnosis of BPD continues to be associated with significant pulmonary morbidity over the first two decades of life. Long-term longitudinal studies are needed to determine if recent survivors of BPD will also be at increased risk of debilitating pulmonary disease in adulthood.


Assuntos
Displasia Broncopulmonar/fisiopatologia , Recém-Nascido Prematuro , Pulmão/fisiopatologia , Qualidade de Vida , Adolescente , Adulto , Displasia Broncopulmonar/psicologia , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Recém-Nascido de muito Baixo Peso , Morbidade
20.
Sci Rep ; 10(1): 613, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31953419

RESUMO

We need a better risk stratification system for the increasing number of survivors of extreme prematurity suffering the most severe forms of bronchopulmonary dysplasia (BPD). However, there is still a paucity of studies providing scientific evidence to guide future updates of BPD severity definitions. Our goal was to validate a new predictive model for BPD severity that incorporates respiratory assessments beyond 36 weeks postmenstrual age (PMA). We hypothesized that this approach improves BPD risk assessment, particularly in extremely premature infants. This is a longitudinal cohort of premature infants (≤32 weeks PMA, n = 188; Washington D.C). We performed receiver operating characteristic analysis to define optimal BPD severity levels using the duration of supplementary O2 as predictor and respiratory hospitalization after discharge as outcome. Internal validation included lung X-ray imaging and phenotypical characterization of BPD severity levels. External validation was conducted in an independent longitudinal cohort of premature infants (≤36 weeks PMA, n = 130; Bogota). We found that incorporating the total number of days requiring O2 (without restricting at 36 weeks PMA) improved the prediction of respiratory outcomes according to BPD severity. In addition, we defined a new severity category (level IV) with prolonged exposure to supplemental O2 (≥120 days) that has the highest risk of respiratory hospitalizations after discharge. We confirmed these findings in our validation cohort using ambulatory determination of O2 requirements. In conclusion, a new predictive model for BPD severity that incorporates respiratory assessments beyond 36 weeks improves risk stratification and should be considered when updating current BPD severity definitions.


Assuntos
Displasia Broncopulmonar/fisiopatologia , Hospitalização/estatística & dados numéricos , Doenças do Prematuro/fisiopatologia , Oxigênio/administração & dosagem , Displasia Broncopulmonar/terapia , Feminino , Idade Gestacional , Humanos , Lactente Extremamente Prematuro , Recém-Nascido , Doenças do Prematuro/terapia , Estudos Longitudinais , Masculino , Curva ROC , Medição de Risco , Índice de Gravidade de Doença , Fatores de Tempo
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