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1.
BMC Pulm Med ; 19(1): 138, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31362742

RESUMO

BACKGROUND: Caffeine therapy for apnea of prematurity reduces the incidence of bronchopulmonary dysplasia (BPD) in premature neonates. Several mechanisms, including improvement in pulmonary mechanics underly beneficial effects of caffeine in BPD. As vascular development promotes alveologenesis, we hypothesized that caffeine might enhance angiogenesis in the lung, promoting lung growth, thereby attenuating BPD. METHODS: C57Bl/6 mice litters were randomized within 12 h of birth to room air (RA) or 95%O2 to receive caffeine (20 mg/kg/day) or placebo for 4 days and recovered in RA for 12wks. The lung mRNA and protein expression for hypoxia-inducible factors (HIF) and angiogenic genes performed on day 5. Lung morphometry and vascular remodeling assessed on inflation fixed lungs at 12wks. RESULTS: Caffeine and hyperoxia in itself upregulate HIF-2α and vascular endothelial growth factor gene expression. Protein expression of HIF-2α and VEGFR1 were higher in hyperoxia/caffeine and angiopoietin-1 lower in hyperoxia. An increase in radial alveolar count, secondary septal count, and septal length with a decrease in mean linear intercept indicate an amelioration of hyperoxic lung injury by caffeine. An increase in vessel surface area and a significant reduction in smooth muscle thickness of the pulmonary arterioles may suggest a beneficial effect of caffeine on vascular remodeling in hyperoxia, especially in male mice. CONCLUSIONS: Postnatal caffeine by modulating angiogenic gene expression early in lung development may restore the pulmonary microvasculature and alveolarization in adult lung.


Assuntos
Cafeína/farmacologia , Hiperóxia/complicações , Lesão Pulmonar/tratamento farmacológico , Neovascularização Fisiológica , Alvéolos Pulmonares/efeitos dos fármacos , Angiopoietina-1/metabolismo , Animais , Animais Recém-Nascidos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Displasia Broncopulmonar/tratamento farmacológico , Displasia Broncopulmonar/metabolismo , Modelos Animais de Doenças , Pulmão/patologia , Lesão Pulmonar/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Alvéolos Pulmonares/metabolismo , Distribuição Aleatória , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo
2.
Eur J Pharmacol ; 860: 172588, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31377154

RESUMO

Bronchopulmonary dysplasia (BPD) is a chronic lung disease that often occurs in preterm infants. However, there is still no effective treatment for BPD. Recent studies demonstrated that connective tissue growth factor (CTGF) is involved in the development of BPD in experimental models. CTGF, also known as CCN2, is the second member of the CCN family and is necessary for normal lung development. The expression of CTGF is increased in lung tissues in infants with BPD. Hyperoxia, inflammation and mechanic ventilation increase CTGF expression which may promote fibroblast proliferation, matrix production and vascular remodeling. Conditional overexpression of CTGF in alveolar epithelial type II cells disrupts alveolarization and vascular development, induces vascular remodeling, and results in pulmonary hypertension, the pathological hallmarks of severe BPD. Further studies have shown that inhibition of CTGF by a CTGF monoclonal antibody improved alveolarization and vascular development, and decreased pulmonary vascular remodeling and pulmonary hypertension in a rodent model of BPD induced by hyperoxia. CTGF may be a novel target for BPD therapy in preterm infants.


Assuntos
Displasia Broncopulmonar/tratamento farmacológico , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Terapia de Alvo Molecular/métodos , Animais , Displasia Broncopulmonar/metabolismo , Displasia Broncopulmonar/patologia , Humanos
3.
Respir Res ; 20(1): 88, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31077204

RESUMO

BACKGROUND: While additional oxygen supply is often required for the survival of very premature infants in intensive care, this also brings an increasing risk of progressive lung diseases and poor long-term lung outcomes. Caffeine is administered to neonates in neonatal intensive care for the prevention and treatment of apneas and has been shown to reduce BPD incidence and the need for mechanical ventilation, although it is still unclear whether this is due to a direct pulmonary action via antagonism of adenosine receptors and/or an indirect action. This experimental study aims to investigate the action of caffeine on the oxidative stress response in pulmonary tissue in a hyperoxia-based model of bronchopulmonary dysplasia in newborn rats. METHODS: Newborn Wistar rats were exposed to 21% or 80% oxygen for 3 (P3) or 5 (P5) postnatal days with or without recovery on room air until postnatal day 15 (P15) and treated with vehicle or caffeine (10 mg/kg) every 48 h beginning on the day of birth. The lung tissue of the rat pups was examined for oxidative stress response at P3 and P5 immediately after oxygen exposure or after recovery in ambient air (P15) by immunohistological staining and analysis of lung homogenates by ELISA and qPCR. RESULTS: Lungs of newborn rats, corresponding to the saccular stage of lung development and to the human lung developmental stage of preterms, showed increased rates of total glutathione and hydrogen peroxide, oxidative damage to DNA and lipids, and induction of second-phase mediators of antioxidative stress response (superoxide dismutase, heme oxygenase-1, and the Nrf2/Keap1 system) in response to hyperoxia. Caffeine reduced oxidative DNA damage and had a protective interference with the oxidative stress response. CONCLUSION: In addition to the pharmacological antagonism of adenosine receptors, caffeine appears to be a potent antioxidant and modulates the hyperoxia-induced pulmonary oxidative stress response and thus protective properties in the BPD-associated animal model. Free-radical-induced damage caused by oxidative stress seems to be a biological mechanism progress of newborn diseases. New aspects of antioxidative therapeutic strategies to passivate oxidative stress-related injury should be in focus of further investigations.


Assuntos
Antioxidantes/uso terapêutico , Displasia Broncopulmonar/tratamento farmacológico , Cafeína/uso terapêutico , Modelos Animais de Doenças , Hiperóxia/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Antioxidantes/farmacologia , Displasia Broncopulmonar/sangue , Cafeína/sangue , Cafeína/farmacologia , Feminino , Hiperóxia/sangue , Estresse Oxidativo/fisiologia , Gravidez , Distribuição Aleatória , Ratos , Ratos Wistar , Resultado do Tratamento
4.
Clin Perinatol ; 46(2): 291-310, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31010561

RESUMO

Rates of bronchopulmonary dysplasia (BPD) are increasing. After preterm birth, there are important developmental periods in which neonates are more vulnerable to stressful events. These periods are opportunities for pharmacologic interventions. Many drugs remain inadequately tested and no new drugs have been approved in more than 25 years for BPD prevention or therapy. More progress is needed in defining appropriate end points based on the pathophysiology of BPD and postdischarge chronic pulmonary insufficiency of prematurity and to develop effective new drugs. In addition, much work is needed to better define perinatal factors, early postnatal findings, and physiologic phenotypes or endotypes.


Assuntos
Displasia Broncopulmonar/tratamento farmacológico , Displasia Broncopulmonar/prevenção & controle , Administração por Inalação , Corticosteroides/uso terapêutico , Broncodilatadores/uso terapêutico , Cafeína/uso terapêutico , Diuréticos/uso terapêutico , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Fator de Crescimento Insulin-Like I/uso terapêutico , Transplante de Células-Tronco Mesenquimais , Óxido Nítrico/uso terapêutico , Oxigenoterapia , Inibidores da Fosfodiesterase 5/uso terapêutico , Inibidores de Fosfodiesterase/uso terapêutico , Gravidez , Cuidado Pré-Natal , Progesterona/uso terapêutico , Progestinas/uso terapêutico , Surfactantes Pulmonares/uso terapêutico , Citrato de Sildenafila/uso terapêutico , Vitamina A/uso terapêutico , Vitaminas/uso terapêutico
5.
Med Sci Monit ; 25: 1886-1893, 2019 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-30862773

RESUMO

BACKGROUND Bronchopulmonary dysplasia (BPD) is a chronic lung disease common in preterm infants. Montelukast, an effective cysteinyl leukotriene (cysLT) receptor antagonist, has a variety of pharmacological effects and has protective effects against a variety of diseases. Currently, the efficacy and safety of montelukast sodium in treating BPD has been revealed, however, the precise molecular mechanism of the effect of montelukast on BPD development remain largely unclear. Therefore, this study aimed to investigate the effect and mechanism of montelukast on BPD in vivo and in vitro. MATERIAL AND METHODS A mouse BPD model and hyperoxia-induced lung cell injury model were established and treated with montelukast. Then mean linear intercept (MLI), radial alveolar count (RAC), lung weight/body weight (LW/BW) ratio, pro-inflammatory factors, and oxidative stress-related factors in lung tissues were determined. Cell viability and apoptosis were detected using MTT assay and flow cytometer respectively. RESULTS The results showed that montelukast treatment relieved mouse BPD, evidenced by increased RAC and decreased MLI and LW/BW ratios. We also found that montelukast treatment reduced pro-inflammatory factors (TNF-alpha, IL-6, and IL-1ß) production, enhanced superoxide dismutase (SOD) activity, and reduced malondialdehyde (MDA) content in the lung tissues of BPD mice. Besides, montelukast eliminated the reduced cell viability and enhanced cell apoptosis induced by hyperoxia exposure in vitro. Moreover, the upregulated pro-inflammatory factors production and p-p65 protein level in lung cells caused by hyperoxia were decreased by montelukast treatment. CONCLUSIONS Montelukast protected against mouse BPD induced by hyperoxia through inhibiting inflammation, oxidative stress, and lung cell apoptosis.


Assuntos
Acetatos/farmacologia , Displasia Broncopulmonar/tratamento farmacológico , Quinolinas/farmacologia , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Displasia Broncopulmonar/fisiopatologia , Modelos Animais de Doenças , Hiperóxia/complicações , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Pulmão/metabolismo , Lesão Pulmonar/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Receptores de Leucotrienos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
6.
Pediatr Pulmonol ; 54(2): 165-170, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30537393

RESUMO

OBJECTIVE: To determine the association of timing of steroid therapy for bronchopulmonary dysplasia (BPD) and outcomes. METHODS: Retrospective cohort study of preterm infants treated with low-dose dexamethasone for BPD. Infants treated with steroids at day of life (DOL) 14-28 (moderately late group) were compared to infants treated at DOL 29-42 (delayed group). Inverse probability of treatment weighting (IPTW) adjusted propensity scores were used to correct for potential confounders. The primary outcome of interest was postmenstrual age (PMA) at discharge. RESULTS: Fifty-five infants (25 with moderately late treatment; 30 with delayed treatment) were identified. The mean age at treatment was 23 days in the moderately late group and 35 days in the delayed group. At time of treatment, infants treated moderately late were more likely to be on high frequency ventilation (96% vs 47%, P < 0.0001) and had higher fraction of inspired oxygen (70.7 ± 17.9% vs 56.2 ± 18.4%, P = 0.005) compared to infants treated later. Despite being the sicker group, moderately late treated infants were discharged at an earlier corrected age compared to infants with delayed treatment (PMA 42.9 ± 4.5 vs 47.5 ± 8.3 weeks, IPTW adjusted P = 0.03). Moderately late treatment was also associated with fewer days on mechanical ventilation (46.0 ± 19.0 days vs 77.4 ± 67.0 days, IPTW adjusted P = 0.02) and fewer days on supplemental oxygen (114.3 ± 40.8 days vs 149.8 ± 57.0 days, IPTW adjusted P = 0.005). CONCLUSIONS: Among preterm infants at high risk of BPD, delaying treatment with postnatal steroids is associated with comparatively worse short-term outcomes as compared to earlier treatment.


Assuntos
Anti-Inflamatórios/administração & dosagem , Displasia Broncopulmonar/tratamento farmacológico , Dexametasona/administração & dosagem , Glucocorticoides/administração & dosagem , Esquema de Medicação , Feminino , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Respiração Artificial , Estudos Retrospectivos , Resultado do Tratamento
7.
Nutrition ; 57: 237-244, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30196116

RESUMO

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.


Assuntos
Displasia Broncopulmonar/tratamento farmacológico , Gardenia/química , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipertensão Pulmonar/complicações , Iridoides/uso terapêutico , Lesão Pulmonar/prevenção & controle , Oxigênio/metabolismo , Animais , Animais Recém-Nascidos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Displasia Broncopulmonar/etiologia , Displasia Broncopulmonar/metabolismo , Modelos Animais de Doenças , Humanos , Hiperóxia/complicações , Hipertensão Pulmonar/metabolismo , Recém-Nascido , Interleucinas/metabolismo , Iridoides/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Lesão Pulmonar/etiologia , Lesão Pulmonar/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo
8.
Semin Perinatol ; 42(7): 459-470, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30446300

RESUMO

Over 50 years after its first description, Bronchopulmonary Dysplasia (BPD) remains a devastating pulmonary complication in preterm infants with respiratory failure and develops in 30-50% of infants less than 1000-gram birth weight. It is thought to involve ventilator- and oxygen-induced damage to an immature lung that results in an inflammatory response and ends in aberrant lung development with dysregulated angiogenesis and alveolarization. Significant morbidity and mortality are associated with this most common chronic lung disease of childhood. Thus, any therapies that decrease the incidence or severity of this condition would have significant impact on morbidity, mortality, human costs, and healthcare expenditure. It is clear that an inflammatory response and the elaboration of growth factors and cytokines are associated with the development of BPD. Numerous approaches to control the inflammatory process leading to the development of BPD have been attempted. This review will examine the anti-inflammatory approaches that are established or hold promise for the prevention or treatment of BPD.


Assuntos
Anti-Inflamatórios/uso terapêutico , Displasia Broncopulmonar/imunologia , Inflamação/imunologia , Transdução de Sinais/imunologia , Animais , Displasia Broncopulmonar/tratamento farmacológico , Displasia Broncopulmonar/fisiopatologia , Modelos Animais de Doenças , Humanos , Lactente Extremamente Prematuro , Recém-Nascido , Recém-Nascido de muito Baixo Peso , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Mediadores da Inflamação , Camundongos
9.
Semin Perinatol ; 42(7): 444-452, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30343941

RESUMO

Bronchopulmonary dysplasia (BPD) is a complex disorder with multiple factors implicated in its etiopathogenesis. Despite the scientific advances in the field of neonatology, the incidence of BPD has remained somewhat constant due to increased survival of extremely premature infants. Surfactant deficiency in the immature lung, exposure to invasive mechanical ventilation leading to volutrauma, barotrauma and lung inflammation are some of the critical contributing factors to the pathogenesis of BPD. Hence, strategies to prevent BPD in the postnatal period revolve around mitigation of this injury and inflammation. This article reviews the progress made in the last 5 years in the development of new preparations of surfactant, use of corticosteroids and non-invasive ventilation in the prevention of BPD. Emerging techniques of surfactant delivery through minimally invasive and non-invasive routes are also discussed.


Assuntos
Corticosteroides/uso terapêutico , Displasia Broncopulmonar/tratamento farmacológico , Neonatologia , Ventilação não Invasiva/efeitos adversos , Surfactantes Pulmonares/uso terapêutico , Displasia Broncopulmonar/fisiopatologia , Displasia Broncopulmonar/prevenção & controle , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Recém-Nascido de muito Baixo Peso , Ventilação não Invasiva/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Tensoativos/uso terapêutico
10.
Physiol Rep ; 6(17): e13821, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30187692

RESUMO

Premature infants have a high incidence of bronchopulmonary dysplasia (BPD). Systemic hypertension, arterial thickness and stiffness, and increased systemic afterload may all contribute to BPD pathophysiology by altering left ventricular (LV) function and increasing pulmonary venous congestion by lowering end-diastolic compliance. This case series studied the usefulness of angiotensin-converting enzyme (ACE) inhibition by measuring clinical and echocardiographic improvements in six consecutive infants with "severe" BPD unresponsive to conventional therapy. The range of gestation and birthweight were 23-29 weeks and 505-814 g, respectively. All required mechanical ventilation (including high-frequency oscillation) and all but one were administered postnatal corticosteroids. Other treatments including sildenafil and diuretics made no clinical improvements. Captopril was started for systemic hypertension after cardiac and vascular ultrasounds which were repeated 5 weeks later. A significant reduction in oxygen (55 ± 25 to 29 ± 3%, two-tailed P = 0.03) and ventilator requirements, and improved cardiovascular parameters were noted. This included a trend toward reduction in aorta intima media thickness [840 ± 94 to 740 ± 83 µm, P = 0.07] and an increased pulsatile diameter [36 ± 14 to 63 ± 25 µm, P = 0.04]). Improvements were observed for both systolic (increased LV output, 188 ± 13 to 208 ± 13 mL/kg/min, P = 0.046 and mean velocity of circumferential fiber shortening, 1.6 ± 0.2 to 2.5 ± 0.3 [circ/sec], P = 0.0004) and diastolic (decreased isovolumic relaxation time, 69.6 ± 8.2 to 59.4 ± 5 msec, P = 0.044) function which was accompanied by increased pulmonary vein flow. Right ventricular output increased accompanied by a significant lowering of pulmonary vascular resistance. These findings suggest that improving respiratory and cardiac indices (especially diastolic function) warrants further exploration of ACE inhibition in BPD infants unresponsive to conventional therapy.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Displasia Broncopulmonar/tratamento farmacológico , Captopril/uso terapêutico , Coração/fisiopatologia , Hemodinâmica , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Aorta/diagnóstico por imagem , Aorta/fisiopatologia , Displasia Broncopulmonar/fisiopatologia , Captopril/administração & dosagem , Feminino , Coração/diagnóstico por imagem , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Contração Miocárdica , Veias Pulmonares/fisiopatologia , Túnica Íntima/diagnóstico por imagem
11.
Early Hum Dev ; 125: 26-30, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30193125

RESUMO

BACKGROUND: At very high doses, furosemide is linked to ototoxicity in adults, but little is known about the risk of hearing loss in premature infants exposed to furosemide. AIMS: Evaluate the association between prolonged furosemide exposure and abnormal hearing screening in premature infants. STUDY DESIGN: Using propensity scoring, infants with prolonged (≥28 days) exposure to furosemide were matched to infants never exposed. The matched sample was used to estimate the impact of prolonged furosemide exposure on the probability of an abnormal hearing screen prior to hospital discharge. SUBJECTS: A cohort of infants 501-1250 g birth weight and 23-29 weeks gestational age discharged home from 210 neonatal intensive care units in the United States (2004-2013). OUTCOME MEASURES: We defined abnormal hearing screen as a result of either "fail" or "refer" for either ear. RESULTS: Altogether, 1020 infants exposed to furosemide for ≥28 days were matched to 790 unique infants never exposed, yielding a total of 1042 matches due to sampling with replacement and propensity score ties. Matching resulted in a population similar in baseline characteristics. After adjusting for covariates, the proportion of infants with an abnormal hearing screen in the furosemide-exposed group was not significantly higher than the never-exposed group (absolute difference 3.0% [95% CI -0.2-6.2%], P = 0.07). CONCLUSIONS: Prolonged furosemide exposure was associated with a positive, but not statistically significant, difference in abnormal hearing screening in premature infants. Additional studies with post-hospital discharge audiology follow-up are needed to further evaluate the safety of furosemide in this population.


Assuntos
Diuréticos/efeitos adversos , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Furosemida/efeitos adversos , Perda Auditiva/induzido quimicamente , Displasia Broncopulmonar/tratamento farmacológico , Diuréticos/uso terapêutico , Feminino , Furosemida/uso terapêutico , Idade Gestacional , Perda Auditiva/diagnóstico , Testes Auditivos , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Unidades de Terapia Intensiva Neonatal , Masculino , Gravidez
12.
Am J Physiol Lung Cell Mol Physiol ; 315(5): L858-L869, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30113228

RESUMO

Bronchopulmonary dysplasia in premature infants is a common and often severe lung disease with long-term sequelae. A genetic component is suspected but not fully defined. We performed an ancestry and genome-wide association study to identify variants, genes, and pathways associated with survival without bronchopulmonary dysplasia in 387 high-risk infants treated with inhaled nitric oxide in the Trial of Late Surfactant study. Global African genetic ancestry was associated with increased survival without bronchopulmonary dysplasia among infants of maternal self-reported Hispanic white race/ethnicity [odds ratio (OR) = 4.5, P = 0.01]. Admixture mapping found suggestive outcome associations with local African ancestry at chromosome bands 18q21 and 10q22 among infants of maternal self-reported African-American race/ethnicity. For all infants, the top individual variant identified was within the intron of NBL1, which is expressed in midtrimester lung and is an antagonist of bone morphogenetic proteins ( rs372271081 , OR = 0.17, P = 7.4 × 10-7). The protective allele of this variant was significantly associated with lower nitric oxide metabolites in the urine of non-Hispanic white infants ( P = 0.006), supporting a role in the racial differential response to nitric oxide. Interrogating genes upregulated in bronchopulmonary dysplasia lungs indicated association with variants in CCL18, a cytokine associated with fibrosis and interstitial lung disease, and pathway analyses implicated variation in genes involved in immune/inflammatory processes in response to infection and mechanical ventilation. Our results suggest that genetic variation related to lung development, drug metabolism, and immune response contribute to individual and racial/ethnic differences in respiratory outcomes following inhaled nitric oxide treatment of high-risk premature infants.


Assuntos
Displasia Broncopulmonar/genética , Administração por Inalação , Displasia Broncopulmonar/tratamento farmacológico , Cromossomos/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Pulmão/efeitos dos fármacos , Masculino , Óxido Nítrico/administração & dosagem , Surfactantes Pulmonares/administração & dosagem , Respiração Artificial/métodos , Insuficiência Respiratória/tratamento farmacológico , Insuficiência Respiratória/genética , Regulação para Cima/genética
13.
Turk J Med Sci ; 48(4): 892-900, 2018 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-30121057

RESUMO

Background/aim: Hyperoxia- and inflammation-induced lung injury is an important cause of the development of bronchopulmonary dysplasia (BPD) in premature infants. We aimed to ascertain the beneficial effects of ginger ( Zingiber officinale ) on rat pups exposed to hyperoxia and inflammation. Materials and methods: Thirty-six newborn Wistar rats were randomly divided into 3 groups as the hyperoxia (95% O 2 ) + lipopolysaccharide (LPS) group, the hyperoxia + LPS + ginger-treated group, and the control/no treatment group (21% O 2 ). Pups in the hyperoxia + LPS + ginger group were administered oral ginger at a dose of 1000 mg/kg daily during the study period. Histopathologic, immunochemical (SMA and lamellar body), and biochemical evaluations including total antioxidant status (TAS), total oxidant status (TOS), malondialdehyde (MDA), myeloperoxidase (MPO), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), and caspase-3 activities were performed. Results: Better weight gain and survival rates were shown in the hyperoxia + LPS + ginger group (P < 0.05). In the histopathologic and immunochemical evaluation, severity of lung damage was significantly reduced in the hyperoxia + LPS + ginger group, as well as decreased apoptosis (ELISA for caspase-3) (P < 0.05). Tissue TAS levels were significantly protected, and TOS, MDA, and MPO levels were significantly lower in the hyperoxia + LPS + ginger group (P < 0.05). Tissue TNF-α, IL-1ß, and IL-6 concentrations were significantly decreased in the ginger-treated group (P < 0.05). Conclusion: Ginger efficiently reduced the lung damage and protected the lungs from severe damage due to hyperoxia and inflammation. Therefore, ginger may be an alternative option for the treatment of BPD.


Assuntos
Displasia Broncopulmonar/tratamento farmacológico , Gengibre , Recém-Nascido Prematuro , Inflamação/complicações , Pulmão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Oxigênio/efeitos adversos , Animais , Animais Recém-Nascidos , Antioxidantes/metabolismo , Apoptose , Displasia Broncopulmonar/sangue , Displasia Broncopulmonar/etiologia , Corioamnionite , Modelos Animais de Doenças , Feminino , Humanos , Hiperóxia , Recém-Nascido , Inflamação/sangue , Inflamação/induzido quimicamente , Mediadores da Inflamação/sangue , Pulmão/patologia , Pneumopatias/tratamento farmacológico , Pneumopatias/etiologia , Malondialdeído/sangue , Oxigênio/administração & dosagem , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Gravidez , Ratos Wistar
14.
Gene ; 678: 177-183, 2018 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-30098433

RESUMO

With the progress of modern medicine, oxygen therapy has become a crucial measure for the treatment of premature infants. As an environmental stimulus, in the normal development of lungs, oxygen plays a very important regulatory role. However, the problem is that long-term exposure to hyperoxia can interfere with the development of lungs, leading to irreversible developmental abnormalities. Now, the incidence of bronchopulmonary dysplasia (BPD) is increasing year by year. The existing related research shows that although BPD is a multi-factor triggered disease, its main risk factors are the premature exposure to hyperoxia and the role of reactive oxygen species (ROS). As for premature infants, especially very premature babies and those with very low birth weight, prolonged exposure to high oxygen can affect and alter the normal developmental trajectories of lung tissue and vascular beds, triggering developmental disorders, such as BPD. In the relevant studies about human BPD, a large number of them support that ROS is associated with impaired lung development. Neonates, due to the damage in the development of alveolar, are specific to hyperoxia-induced inflammatory damage. This review while focusing on the role of oxidative stress in the pathogenesis of BPD, suggests that antioxidant measures may be effective to guard against BPD of preterm infants.


Assuntos
Displasia Broncopulmonar/epidemiologia , Displasia Broncopulmonar/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fatores Etários , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Displasia Broncopulmonar/tratamento farmacológico , Estudos de Coortes , Humanos , Recém-Nascido Prematuro , Estresse Oxidativo/efeitos dos fármacos
15.
PLoS One ; 13(7): e0200243, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29985964

RESUMO

The objective of this study was to determine the impact of postnatal dexamethasone treatment on the neonatal unit on the school age lung function of very prematurely born children. Children born prior to 29 weeks of gestational age had been entered into a randomised trial of two methods of neonatal ventilation (United Kingdom Oscillation Study). They had comprehensive lung function measurements at 11 to 14 years of age. One hundred and seventy-nine children born at a mean gestational age of 26.9 (range 23-28) weeks were assessed at 11 to 14 years; 50 had received postnatal dexamethasone. Forced expiratory flow at 75% (FEF75), 50%, 25% and 25-75% of the expired vital capacity, forced expiratory volume in one second, peak expiratory flow and forced vital capacity and lung volumes including total lung capacity and residual volume were assessed. Lung function outcomes were compared between children who had and had not been exposed to dexamethasone after adjustment for neonatal factors using linear mixed effects regression. After adjustment for confounders all the mean spirometry results were between 0.38 and 0.87 standard deviations lower in those exposed to dexamethasone compared to the unexposed. For example, the mean FEF75 z-score was 0.53 lower (95% CI 0.21 to 0.85). The mean lung function was lower as the number of courses of dexamethasone increased. In conclusion, postnatal dexamethasone exposure was associated with lower mean lung function at school age in children born extremely prematurely. Our results suggest the larger the cumulative dose the greater the adverse effect on lung function at follow-up.


Assuntos
Displasia Broncopulmonar/tratamento farmacológico , Dexametasona/administração & dosagem , Volume Expiratório Forçado/efeitos dos fármacos , Glucocorticoides/administração & dosagem , Pulmão/efeitos dos fármacos , Capacidade Vital/efeitos dos fármacos , Adolescente , Criança , Dexametasona/uso terapêutico , Feminino , Seguimentos , Glucocorticoides/uso terapêutico , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Pulmão/fisiopatologia , Masculino , Testes de Função Respiratória , Resultado do Tratamento
16.
Am J Physiol Lung Cell Mol Physiol ; 315(4): L535-L544, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29952221

RESUMO

Cyclooxygenase-2 (COX-2/PTGS2) mediates hyperoxia-induced impairment of lung development in newborn animals and is increased in the lungs of human infants with bronchopulmonary dysplasia (BPD). COX-2 catalyzes the production of cytoprotective prostaglandins, such as prostacyclin (PGI2), as well as proinflammatory mediators, such as thromboxane A2. Our objective was to determine whether iloprost, a synthetic analog of PGI2, would attenuate hyperoxia effects in the newborn mouse lung. To test this hypothesis, newborn C57BL/6 mice along with their dams were exposed to normoxia (21% O2) or hyperoxia (85% O2) from 4 to 14 days of age in combination with daily intraperitoneal injections of either iloprost 200 µg·kg-1·day-1, nimesulide (selective COX-2 antagonist) 100 mg·kg-1·day-1, or vehicle. Alveolar development was estimated by radial alveolar counts and mean linear intercepts. Lung function was determined on a flexiVent, and multiple cytokines and myeloperoxidase (MPO) were quantitated in lung homogenates. Lung vascular and microvascular morphometry was performed, and right ventricle/left ventricle ratios were determined. We determined that iloprost (but not nimesulide) administration attenuated hyperoxia-induced inhibition of alveolar development and microvascular density in newborn mice. Iloprost and nimesulide both attenuated hyperoxia-induced, increased lung resistance but did not improve lung compliance that was reduced by hyperoxia. Iloprost and nimesulide reduced hyperoxia-induced increases in MPO and some cytokines (IL-1ß and TNF-α) but not others (IL-6 and KC/Gro). There were no changes in pulmonary arterial wall thickness or right ventricle/left ventricle ratios. We conclude that iloprost improves lung development and reduces lung inflammation in a newborn mouse model of BPD.


Assuntos
Displasia Broncopulmonar/tratamento farmacológico , Hiperóxia/fisiopatologia , Iloprosta/farmacologia , Pneumonia/prevenção & controle , Alvéolos Pulmonares/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Displasia Broncopulmonar/etiologia , Displasia Broncopulmonar/metabolismo , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/etiologia , Pneumonia/metabolismo , Gravidez , Alvéolos Pulmonares/irrigação sanguínea , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/patologia , Vasodilatadores/farmacologia
17.
Respir Med ; 140: 94-100, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29957288

RESUMO

AIM: Ex-premature school children show mild-to-moderate airway obstruction and decreased CO diffusing capacity. Multiple breath nitrogen washout (N2MBW) and NO diffusing capacity (DLNO) measurements may provide new insight into long-term pulmonary and vascular impairment in bronchopulmonary dysplasia (BPD). METHODS: We examined a randomly selected group of 70 ex-premature children (gestational age <28 weeks or birth weight <1500 g; 42 with and 28 without BPD) and 38 term-born healthy controls of 8-13 years of age. Subjects performed N2MBW (lung clearance index, LCI; Sacin, and Scond), DLNO (membrane related diffusing capacity, Dm and pulmonary capillary volume, Vc), Fractional exhaled NO, CO diffusing capacity, conventional spirometry (FEV1, FVC, FEF25-75) and plethysmography (RV, TLC). Respiratory symptoms were assessed by questionnaire. RESULTS: Compared to healthy controls, the BPD group had higher z-scores for lung clearance index (P = 0.003), Sacin (P = 0.005), lower CO diffusing capacity (P = 0.025), DLNO (P = 0.022), DLNO/VA z-scores (P = 0.025) and a significant larger proportion had respiratory complaints. Amongst ex-premature children, the BPD group did not differ from the non-BPD group except for a decreased Dm (P = 0.023). Ex-premature with BPD showed predominantly airway obstruction (FEV1/FVC; P < 0.0001), signs of hyperinflation (RV/TLC-ratio; P = 0.028), and 25% had a positive bronchodilator response (>12% in FEV1). CONCLUSION: Ex-premature school children exhibited relatively mild but significant long-term respiratory symptoms and pulmonary peripheral impairment judged by N2MBW and DLNO measurements along with well-known airway obstruction. Larger longitudinal studies are needed to assess the clinical use of these advanced methods of assessing ventilation inhomogeneity and DLNO.


Assuntos
Displasia Broncopulmonar/fisiopatologia , Recém-Nascido Prematuro/fisiologia , Capacidade de Difusão Pulmonar/fisiologia , Adolescente , Peso ao Nascer/fisiologia , Broncodilatadores/uso terapêutico , Displasia Broncopulmonar/tratamento farmacológico , Monóxido de Carbono , Estudos de Casos e Controles , Criança , Feminino , Seguimentos , Idade Gestacional , Humanos , Recém-Nascido , Masculino , Óxido Nítrico , Nascimento Prematuro/fisiopatologia , Capacidade de Difusão Pulmonar/efeitos dos fármacos , Espirometria/métodos
18.
Pediatr Pulmonol ; 53(9): 1318-1325, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29905405

RESUMO

Phosphodiesterases (PDEs) are a superfamily of enzymes that catalyze the hydrolysis of phosphodiester bonds of 3',5' cyclic adenosine and guanosine monophosphate (cAMP and cGMP). PDEs control hydrolysis of cyclic nucleotides in many cells and tissues. Inhibition of PDEs by selective or nonselective PDE inhibitors represents an effective targeted strategy for the treatment of various diseases including respiratory disorders. Recent data have demonstrated that PDE inhibitors can also be of benefit in respiratory distress in neonates. This article outlines the pharmacological properties of nonselective and selective PDE inhibitors and provides up-to-date information regarding their use in experimental models of neonatal respiratory distress as well as in clinical studies.


Assuntos
Apneia/tratamento farmacológico , Displasia Broncopulmonar/tratamento farmacológico , AMP Cíclico/metabolismo , Síndrome de Aspiração de Mecônio/tratamento farmacológico , Síndrome da Persistência do Padrão de Circulação Fetal/tratamento farmacológico , Inibidores de Fosfodiesterase/farmacologia , Síndrome do Desconforto Respiratório do Recém-Nascido/tratamento farmacológico , Animais , Catálise , Humanos , Inibidores de Fosfodiesterase/uso terapêutico
19.
Am J Respir Cell Mol Biol ; 59(5): 623-634, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29894205

RESUMO

Mechanical ventilation with O2-rich gas (MV-O2) inhibits alveologenesis and lung growth. We previously showed that MV-O2 increased elastase activity and apoptosis in lungs of newborn mice, whereas elastase inhibition by elafin suppressed apoptosis and enabled lung growth. Pilot studies suggested that MV-O2 reduces lung expression of prosurvival factors phosphorylated epidermal growth factor receptor (pEGFR) and Krüppel-like factor 4 (Klf4). Here, we sought to determine whether apoptosis and lung growth arrest evoked by MV-O2 reflect disrupted pEGFR-Klf4 signaling, which elafin treatment preserves, and to assess potential biomarkers of bronchopulmonary dysplasia (BPD). Five-day-old mice underwent MV with air or 40% O2 for 8-24 hours with or without elafin treatment. Unventilated pups served as controls. Immunoblots were used to assess lung pEGFR and Klf4 proteins. Cultured MLE-12 cells were exposed to AG1478 (EGFR inhibitor), Klf4 siRNA, or vehicle to assess effects on proliferation, apoptosis, and EGFR regulation of Klf4. Plasma elastase and elafin levels were measured in extremely premature infants. In newborn mice, MV with air or 40% O2 inhibited EGFR phosphorylation and suppressed Klf4 protein content in lungs (vs. unventilated controls), yielding increased apoptosis. Elafin treatment inhibited elastase, preserved lung pEGFR and Klf4, and attenuated the apoptosis observed in lungs of vehicle-treated mice. In MLE-12 studies, pharmacological inhibition of EGFR and siRNA suppression of Klf4 increased apoptosis and reduced proliferation, and EGFR inhibition decreased Klf4. Plasma elastase levels were more than twofold higher, without a compensating increase of plasma elafin, in infants with BPD, compared to infants without BPD. These findings indicate that pEGFR-Klf4 is a novel prosurvival signaling pathway in lung epithelium that MV disrupts. Elafin preserves pEGFR-Klf4 signaling and inhibits apoptosis, thereby enabling lung growth during MV. Together, our animal and human data raise the question: would elastase inhibition prevent BPD in high-risk infants exposed to MV-O2?


Assuntos
Apoptose/efeitos dos fármacos , Displasia Broncopulmonar/tratamento farmacológico , Elafina/farmacologia , Receptores ErbB/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Alvéolos Pulmonares/efeitos dos fármacos , Respiração Artificial/efeitos adversos , Animais , Animais Recém-Nascidos , Displasia Broncopulmonar/metabolismo , Displasia Broncopulmonar/fisiopatologia , Sobrevivência Celular , Células Cultivadas , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Estudos Longitudinais , Camundongos , Camundongos Endogâmicos BALB C , Organogênese , Elastase Pancreática/metabolismo , Inibidores de Proteases/farmacologia , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/patologia , Transdução de Sinais
20.
J Pediatr ; 199: 16-21, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29753546

RESUMO

OBJECTIVE: To assess whether sildenafil is associated with worsening retinopathy of prematurity (ROP) in very low birth weight (VLBW) infants (≤1500 g) with bronchopulmonary dysplasia (BPD). STUDY DESIGN: This retrospective case-control study included VLBW infants admitted to the neonatal intensive care unit between January 1, 2006, and December 31, 2012. Each infant treated with sildenafil was assigned 3 unexposed controls matched for gestational age, birth weight, and BPD diagnosis. Severe ROP was defined as stage ≥3 ROP. Worsening ROP was defined as increased stage of ROP within 8 weeks + 4 days after initiation of sildenafil or matched postmenstrual age. RESULTS: Twenty-three exposed infants and 69 matched controls met the inclusion criteria for the study (mean birth weight, 715 ± 210 g; mean gestational age, 25 ± 1 weeks). The mean postmenstrual age at sildenafil treatment was 42 ± 8 weeks. Exposed infants had more days of respiratory support (mean, 208 ± 101 days vs 102 ± 33 days; P < .001). Exposed infants had a higher prevalence of severe ROP (26% [6 of 23] vs 7% [5 of 69]; OR, 6.4; 95% CI, 1.2-32.9; P = .026). Five exposed infants and 2 unexposed infants had severe ROP before starting sildenafil and were excluded from the analysis for worsening ROP. The rate of worsening ROP did not differ significantly between exposed infants and unexposed infants ((41% [7 of 17] vs 24% [12 of 51]; OR, 8.4; 95% CI, 0.9-78.6; P = .061). CONCLUSION: Although sildenafil treatment was not statistically significantly associated with worsening of ROP, the raw difference in ROP rate is concerning. Larger studies are warranted to confirm this finding.


Assuntos
Displasia Broncopulmonar/tratamento farmacológico , Recém-Nascido de muito Baixo Peso , Retinopatia da Prematuridade/diagnóstico , Citrato de Sildenafila/administração & dosagem , Acuidade Visual/efeitos dos fármacos , Displasia Broncopulmonar/complicações , Estudos de Casos e Controles , Progressão da Doença , Relação Dose-Resposta a Droga , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Masculino , Inibidores da Fosfodiesterase 5/administração & dosagem , Retinopatia da Prematuridade/complicações , Retinopatia da Prematuridade/fisiopatologia , Estudos Retrospectivos , Resultado do Tratamento
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