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1.
Arch. bronconeumol. (Ed. impr.) ; 55(9): 465-471, sept. 2019. tab, graf
Artigo em Inglês | IBECS | ID: ibc-186156

RESUMO

Introduction: Endocan levels were found to be associated with severity and mortality of the respiratory system diseases. Objective: We aimed to figure out whether endocan was an important marker for the diagnosis, severity and follow-up of bronchopulmonary dysplasia (BPD). Materials and methods: Infants with moderate/severe BPD, and who required hydrocortisone treatment were included in the study group. Infants without BPD were allocated in the control group. Endocan levels were compared between the control group and the study group, and before and after the treatment in the study group. Results: A total of 148 infants, 74 infants in the control group and 74 infants in the BPD group, were included. The endocan level was higher in the BPD group than in the control group (P = .001). Endocan levels before treatment in the BPD group was found to be higher than endocan level after treatment (P = .021). Conclusion: Our study found that endocan levels increased in moderate/severe BPD. Serum endocan levels may be a safe and novel indicator for the follow-up of response to treatment and the prognosis of the severity of the disease


Introducción: Los niveles de endocan se han asociado con la mortalidad y la gravedad de enfermedades del aparato respiratorio. Objetivo: El objetivo fue averiguar si el endocan es un marcador útil para el diagnóstico, la gravedad y el seguimiento de la displasia broncopulmonar (DBP). Materiales y métodos: Se incluyeron en el estudio lactantes con DBP moderada/grave que requirieron tratamiento con hidrocortisona (grupo DBP). El grupo control lo constituyeron lactantes sin DBP. Los niveles de endocan se compararon entre el grupo control y el grupo de estudio y, en este último, tanto antes como después del tratamiento. Resultados: Se incluyeron un total de 148 lactantes; 74 en el grupo control y 74 en el grupo DBP. Los niveles de endocan fueron más elevados en el grupo DBP que en el grupo control (p = 0,001). Los niveles de endocan también resultaron superiores en el grupo DBP antes del tratamiento que después del mismo (p = 0,021). Conclusión: Nuestro estudio halló que los niveles de endocan se encuentran incrementados en la DBP moderada/grave. Los niveles séricos de endocan podrían utilizarse como un nuevo indicador seguro para el seguimiento de la respuesta al tratamiento y el pronóstico de gravedad de la enfermedad


Assuntos
Humanos , Lactente , Pulmão/patologia , Displasia Broncopulmonar/sangue , Recém-Nascido de muito Baixo Peso/sangue , Prognóstico , Proteoglicanas/análise , Pulmão/fisiopatologia , Biomarcadores/sangue , Displasia Broncopulmonar/diagnóstico , Displasia Broncopulmonar/patologia , Índice de Gravidade de Doença , Hidrocortisona/uso terapêutico
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.
Cardiol Young ; 29(7): 945-953, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31287038

RESUMO

INTRODUCTION: Prematurity impacts myocardial development and may determine long-term outcomes. The objective of this study was to test the hypothesis that preterm neonates develop right ventricle dysfunction and adaptive remodelling by 32 weeks post-menstrual age that persists through 1 year corrected age. MATERIALS AND METHODS: A subset of 80 preterm infants (born <29 weeks) was selected retrospectively from a prospectively enrolled cohort and measures of right ventricle systolic function and morphology by two-dimensional echocardiography were assessed at 32 weeks post-menstrual age and at 1 year of corrected age. Comparisons were made to 50 term infants at 1 month and 1 year of age. Sub-analyses were performed in preterm-born infants with bronchopulmonary dysplasia and/or pulmonary hypertension. RESULT: In both term and preterm infants, right ventricle function and morphology increased over the first year (p < 0.01). The magnitudes of right ventricle function measures were lower in preterm-born infants at each time period (p < 0.01 for all) and right ventricle morphology indices were wider in all preterm infants by 1 year corrected age, irrespective of lung disease. Measures of a) right ventricle function were further decreased and b) morphology increased through 1 year in preterm infants with bronchopulmonary dysplasia and/or pulmonary hypertension (p < 0.01). CONCLUSION: Preterm infants exhibit abnormal right ventricle performance with remodelling at 32 weeks post-menstrual age that persists through 1 year corrected age, suggesting a less developed intrinsic myocardial function response following preterm birth. The development of bronchopulmonary dysplasia and pulmonary hypertension leave a further negative impact on right ventricle mechanics over the first year of age.


Assuntos
Displasia Broncopulmonar/complicações , Hipertensão Pulmonar/complicações , Doenças do Prematuro/patologia , Disfunção Ventricular Direita/etiologia , Disfunção Ventricular Direita/patologia , Remodelação Ventricular , Displasia Broncopulmonar/patologia , Ecocardiografia , Feminino , Humanos , Hipertensão Pulmonar/patologia , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/diagnóstico por imagem , Doenças do Prematuro/etiologia , Masculino , Estudos Retrospectivos , Disfunção Ventricular Direita/diagnóstico por imagem
4.
Rev Mal Respir ; 36(4): 447-450, 2019 Apr.
Artigo em Francês | MEDLINE | ID: mdl-31010755

RESUMO

Chronic obstructive pulmonary disease, a disease of increasing incidence, is related mainly to smoking. Although symptoms only appear at adulthood, the disease can develop from early life events. For example, bronchopulmonary dysplasia, which occurs in preterm infants, is characterized by airspace enlargement and could lead to late lung consequences. Once the lesions are established, no curative treatment is available. Stimulating lung regeneration from endogenous stem cells is therefore an exciting research domain, particularly through the activation of the mesenchymal contingent located in the lung stem cell niche.


Assuntos
Suscetibilidade a Doenças , Pulmão/fisiologia , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/terapia , Regeneração/fisiologia , Adulto , Displasia Broncopulmonar/patologia , Displasia Broncopulmonar/fisiopatologia , Suscetibilidade a Doenças/diagnóstico , Suscetibilidade a Doenças/fisiopatologia , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Pulmão/crescimento & desenvolvimento , Pulmão/patologia , Doença Pulmonar Obstrutiva Crônica/patologia , Regeneração/genética , Transplante de Células-Tronco/métodos , Células-Tronco/fisiologia
5.
Neonatology ; 115(4): 384-391, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30974430

RESUMO

Bronchopulmonary dysplasia (BPD) is one of the few diseases in neonatal medicine that has continued to evolve since its first description about 50 years ago. Over these years, advancements in neonatal medicine such as antenatal steroids and exogenous surfactant therapy have significantly reduced neonatal mortality and lowered the limits of viability for preterm infants. Although the incidence of BPD continues to be high, especially in extremely low birth weight infants, the clinical picture has evolved into a milder disease with low mortality or significant morbidities. This new BPD is the result of complex interactions between altered alveolar and vascular development, injury by ante- and postnatal pathogenic factors, and reparative processes in the lung. There has been significant progress in our understanding of risk factors for BPD, but challenges persist in its definition, and in finding effective preventive strategies. There are promising developments with newer preventive interventions such as mesenchymal stem cells, exosomes, immunomodulators, and growth factors, but they are still in preclinical stage. The future challenges include finding ways to define BPD based on the severity of lung pathology, which can better predict long-term outcomes, development of early predictors of lung disease, and finding innovative and evidence-based preventive and management strategies.


Assuntos
Displasia Broncopulmonar/patologia , Displasia Broncopulmonar/prevenção & controle , Displasia Broncopulmonar/terapia , Recém-Nascido Prematuro , Prática Clínica Baseada em Evidências , Humanos , Recém-Nascido de Peso Extremamente Baixo ao Nascer , Recém-Nascido , Alvéolos Pulmonares/patologia , Surfactantes Pulmonares/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Respiração Artificial , Fatores de Risco , Esteroides/uso terapêutico
6.
Am J Physiol Cell Physiol ; 316(6): C815-C827, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30917030

RESUMO

We studied the role of bone marrow mesenchymal stem cells (MSCs) in our established model of bronchopulmonary dysplasia (BPD) induced by intrauterine hypoxia in the rat. First, we found that intrauterine hypoxia can reduce the number of MSCs in lungs and bone marrow of rat neonates, whereas the administration of granulocyte colony-stimulating factor or busulfan to either motivate or inhibit bone marrow MSCs to lungs altered lung development. Next, in vivo experiments, we confirmed that intrauterine hypoxia also impaired bone marrow MSC proliferation and decreased cell cycling activity. In vitro, by using the cultured bone marrow MSCs, the proliferation and the cell cycling activity of MSCs were also reduced when N-methyl-d-aspartic acid (NMDA) was used as an NMDA receptor (NMDAR) agonist. When MK-801 or memantine as NMDAR antagonists in vitro or in vivo was used, the reduction of cell cycling activity and proliferation were partially reversed. Furthermore, we found that intrauterine hypoxia could enhance the concentration of glutamate, an amino acid that can activate NMDAR, in the bone marrow of neonates. Finally, we confirmed that the increased concentration of TNF-ɑ in the bone marrow of neonatal rats after intrauterine hypoxia induced the release of glutamate and reduced the cell cycling activity of MSCs, and the latter could be partially reversed by MK-801. In summary, intrauterine hypoxia could decrease the number of bone marrow MSCs that could affect lung development and lung function through excessive activation of NMDAR that is partially caused by TNF-ɑ.


Assuntos
Displasia Broncopulmonar/metabolismo , Displasia Broncopulmonar/prevenção & controle , Citoproteção/fisiologia , Células-Tronco Mesenquimais/metabolismo , Alvéolos Pulmonares/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Animais Recém-Nascidos , Células da Medula Óssea/metabolismo , Displasia Broncopulmonar/patologia , Células Cultivadas , Feminino , Hipóxia Fetal/complicações , Hipóxia Fetal/metabolismo , Hipóxia Fetal/patologia , Masculino , Gravidez , Alvéolos Pulmonares/crescimento & desenvolvimento , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
7.
J Perinat Med ; 47(4): 470-477, 2019 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-30789824

RESUMO

Background The pathogenesis of bronchopulmonary dysplasia (BPD) includes arrest of alveolar septation and enhanced fibrosis. We hypothesized that mesenchymal stromal cells (MSC) and transforming growth factor-ß1 (TGF-ß1) in tracheal aspirates of mechanically ventilated premature infants differ in BPD and non-BPD infants. Methods Tracheal aspirates were collected during the first week of life. Mononuclear cells were separated, cultured and immunophenotyped by flow cytometry. MSCs colony/cluster ratio was calculated as an index for dysplastic potentials. TGF-ß1 was assessed by enzyme-linked immunosorbent assay (ELISA). Setting: Neonatal intensive care unit. Patients Premature infants at risk for BPD. Results A total of 121 preterm infants were enrolled; 27 of them died and among the 94 survivors 23 infants had BPD. MSCs were identified in younger [gestational age (GA): 30.9±1.7 vs. 31.8±1.8, P=0.025] and smaller [birth weight (BW): 1.3±0.28 vs. 1.44±0.37 kg, P=0.04] infants with lower Apgar scores. The recovery rate of MSCs in BPD and non-BPD groups did not differ. BPD group had significantly smaller colony/cluster ratio compared to non-BPD (0.97 vs. 4.25, P=0.002). TGF-ß1 was significantly greater in BPD infants (4173.9±864.3 vs. 3705.8±540.5 pg/mL, P=0.021). Conclusion Infants with BPD had different MSCs morphology and greater TGF-ß1 expression. The pathogenesis for these morphological changes of resident lung MSCs needs further studying.


Assuntos
Displasia Broncopulmonar/diagnóstico , Células-Tronco Mesenquimais/patologia , Fator de Crescimento Transformador beta1/metabolismo , Displasia Broncopulmonar/metabolismo , Displasia Broncopulmonar/patologia , Estudos Transversais , Diagnóstico Precoce , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Células-Tronco Mesenquimais/metabolismo , Traqueia/metabolismo , Traqueia/patologia
8.
Oxid Med Cell Longev ; 2019: 7945983, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30805084

RESUMO

Background: Aurothioglucose- (ATG-) mediated inhibition of thioredoxin reductase-1 (TXNRD1) improves alveolarization in experimental murine bronchopulmonary dysplasia (BPD). Glutathione (GSH) mediates susceptibility to neonatal and adult oxidative lung injury. We have previously shown that ATG attenuates hyperoxic lung injury and enhances glutathione- (GSH-) dependent antioxidant defenses in adult mice. Hypothesis: The present studies evaluated the effects of TXNRD1 inhibition on GSH-dependent antioxidant defenses in newborn mice in vivo and lung epithelia in vitro. Methods: Newborn mice received intraperitoneal ATG or saline prior to room air or 85% hyperoxia exposure. Glutamate-cysteine ligase (GCL) catalytic (Gclc) and modifier (Gclm) mRNA levels, total GSH levels, total GSH peroxidase (GPx) activity, and Gpx2 expression were determined in lung homogenates. In vitro, murine transformed club cells (mtCCs) were treated with the TXNRD1 inhibitor auranofin (AFN) or vehicle in the presence or absence of the GCL inhibitor buthionine sulfoximine (BSO). Results: In vivo, ATG enhanced hyperoxia-induced increases in Gclc mRNA levels, total GSH contents, and GPx activity. In vitro, AFN increased Gclm mRNA levels, intracellular and extracellular GSH levels, and GPx activity. BSO prevented AFN-induced increases in GSH levels. Conclusions: Our data are consistent with a model in which TXNRD1 inhibition augments hyperoxia-induced GSH-dependent antioxidant responses in neonatal mice. Discrepancies between in vivo and in vitro results highlight the need for methodologies that permit accurate assessments of the GSH system at the single-cell level.


Assuntos
Antioxidantes/metabolismo , Displasia Broncopulmonar/enzimologia , Displasia Broncopulmonar/patologia , Glutationa/metabolismo , Tiorredoxina Redutase 1/antagonistas & inibidores , Animais , Animais Recém-Nascidos , Aurotioglucose , Displasia Broncopulmonar/genética , Células Epiteliais/metabolismo , Glutamato-Cisteína Ligase/genética , Glutamato-Cisteína Ligase/metabolismo , Glutationa Peroxidase/metabolismo , Hiperóxia/genética , Hiperóxia/patologia , Pulmão/metabolismo , Pulmão/patologia , Camundongos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Tiorredoxina Redutase 1/metabolismo
9.
Am J Pathol ; 189(5): 999-1014, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30794808

RESUMO

Bronchopulmonary dysplasia (BPD) is a disease prevalent in preterm babies with a need for supplemental oxygen, resulting in impaired lung development and dysregulated vascularization. Epidemiologic studies have shown that males are more prone to BPD and have a delayed recovery compared with females, for reasons unknown. Herein, we tried to recapitulate mild, moderate, and severe BPD, using two different strains of mice, in males and females: CD1 (outbred) and C57BL/6 (inbred). Aside from higher body weight in the CD1 strain, there were no other gross morphologic differences with respect to alveolar development between the two strains. With respect to lung morphology after oxygen exposure, females had less injury with better preservation of alveolar chord length and decreased alveolar protein leak and inflammatory cells in the bronchoalveolar lavage fluid. In addition, housekeeping genes, which are routinely used as loading controls, were expressed differently in males and females. In the BPD mouse model, gonadotropin-releasing hormone was increased in females compared with males. Specific miRNAs (miR-146 and miR-34a) were expressed differently in the sexes. In the severe BPD mouse model, administering miR-146 mimic to males attenuated lung damage, whereas administering miR-146 inhibitor to females increased pulmonary injury.


Assuntos
Displasia Broncopulmonar/patologia , Modelos Animais de Doenças , Hiperóxia/complicações , Lesão Pulmonar/patologia , Índice de Gravidade de Doença , Animais , Displasia Broncopulmonar/etiologia , Feminino , Lesão Pulmonar/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores Sexuais , Especificidade da Espécie
10.
Am J Physiol Lung Cell Mol Physiol ; 316(3): L506-L518, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30652496

RESUMO

Infants born very prematurely (<28 wk gestation) have immature lungs and often require supplemental oxygen. However, long-term hyperoxia exposure can arrest lung development, leading to bronchopulmonary dysplasia (BPD), which increases acute and long-term respiratory morbidity and mortality. The neural mechanisms controlling breathing are highly plastic during development. Whether the ventilatory control system adapts to pulmonary disease associated with hyperoxia exposure in infancy remains unclear. Here, we assessed potential age-dependent adaptations in the control of breathing in an established rat model of BPD associated with hyperoxia. Hyperoxia exposure ( FIO2 ; 0.9 from 0 to 10 days of life) led to a BPD-like lung phenotype, including sustained reductions in alveolar surface area and counts, and modest increases in airway resistance. Hyperoxia exposure also led to chronic increases in room air and acute hypoxic minute ventilation (V̇e) and age-dependent changes in breath-to-breath variability. Hyperoxia-exposed rats had normal oxygen saturation ( SpO2 ) in room air but greater reductions in SpO2 during acute hypoxia (12% O2) that were likely due to lung injury. Moreover, acute ventilatory sensitivity was reduced at P12 to P14. Perinatal hyperoxia led to greater glial fibrillary acidic protein expression and an increase in neuron counts within six of eight or one of eight key brainstem regions, respectively, controlling breathing, suggesting astrocytic expansion. In conclusion, perinatal hyperoxia in rats induced a BPD-like phenotype and age-dependent adaptations in V̇e that may be mediated through changes to the neural architecture of the ventilatory control system. Our results suggest chronically altered ventilatory control in BPD.


Assuntos
Displasia Broncopulmonar/metabolismo , Hiperóxia/metabolismo , Hipóxia/metabolismo , Lesão Pulmonar/metabolismo , Fatores Etários , Animais , Displasia Broncopulmonar/patologia , Modelos Animais de Doenças , Hiperóxia/patologia , Hipertensão Pulmonar/metabolismo , Hipóxia/patologia , Pulmão/metabolismo , Pulmão/patologia , Lesão Pulmonar/patologia , Ratos
11.
Zhonghua Er Ke Za Zhi ; 57(1): 33-39, 2019 Jan 02.
Artigo em Chinês | MEDLINE | ID: mdl-30630229

RESUMO

Objective: To analyze clinical characteristics and risk factors of very low birth weight and extremely low birth weight infants with bronchopulmonary dysplasia (BPD). Methods: A retrospective epidemiological study was performed in 768 neonates (376 males) with birth weights<1 500 g and gestational age ≤ 34 weeks who survived ≥28 days. Clinical data were obtained from the multi-center clinical database of neonatal intensive care units (NICU) in 19 hospitals of Jiangsu Province between January 1, 2017 and December 31, 2017. These infants were divided into non-BPD group and BPD group according to BPD diagnositic criteria. Clinical features and potential risk factors were compared between groups with Chi-square test or nonparametric test. Risk factors for BPD were analyzed with Logistic regression analysis. Results: Among the total of 768 eligible neonates, 577 without BPD, 191 with BPD (24.9%). Mild, moderate and severe BPD accounted for 73.3% (140/191), 23.6% (45/191) and 3.1% (6/191) of all BPD cases respectively. There were significant differences in the average gestational age (29 (28, 30) vs. 30 (29, 31) weeks) or the average birth weight (1 170 (990, 1 300) vs. 1 300 (1 160, 1 400) g) between BPD group and non-BPD group (Z=-9.959,-7.202, both P=0.000). The incidences of BPD in the infants with gestational age of<28 weeks, 28-31 weeks and 32-34 weeks were 51.7% (46/89), 24.8% (139/561), 5.1% (6/118) respectively. The incidences of BPD in infants with birth weight<1 000 g, 1 000- 1 249 g and 1 250-1 500 g were 62.3% (48/77), 25.9% (70/270) and 17.3% (73/421) respectively. Proportion of male (55.5% (106/191) vs. 46.8% (270/577)), rate and length of conventional mechanical ventilation (48.7% (93/191) vs. 14.9% (86/577), 120 (72, 259) vs. 80 (29, 144)h), initial inhaled oxygen concentration and maximum inhaled oxygen concentration (0.35 (0.30, 0.40) vs. 0.30(0.25, 0.40), 0.40 (0.30, 0.50) vs. 0.30 (0.30, 0.40)) and volume of red blood cell transfusion (53(30, 90) vs.38(28, 55) ml) were higher in BPD group than in non-BPD group (χ(2)=4.350, 91.640, Z=-3.557, -2.848, -3.776, -4.677, all P<0.05). Rate of continuous positive airway pressure (12.6%(24/191) vs. 19.4%(112/577)) during neonatal resuscitation in delivery room was lower in BPD group than that in non-BPD group (χ(2)=4.614, P=0.032). The incidences of complications in BPD group including severe asphyxia, neonatal respiratory distress syndrome (NRDS), persistent pulmonary hypertension in newborns (PPHN), patent ductus arteriosus, anemia of prematurity, early onset sepsis, clinical sepsis and ventilator associated pneumonia were higher than that in non-BPD group (15.2%(29/191) vs. 4.5% (26/577), 91.1% (174/191) vs. 56.7% (327/577), 2.6% (5/191) vs. 0.2% (1/577), 43.5% (83/191) vs. 34.2% (197/577), 88.0% (168/191) vs. 58.8% (339/577), 15.7% (30/191) vs. 9.9% (57/577), 42.9% (82/191) vs. 18.6% (107/577), 14.1% (27/191) vs. 2.3% (13/577); χ(2)=24.605, 74.993, 9.167, 5.373, 61.866, 4.557, 43.149, 34.315, all P<0.05). Multivariate logistic regression analysis showed that NRDS (OR=4.651, 95%CI: 1.860-11.625), clinical sepsis (OR=1.989, 95%CI: 1.067-3.708), ventilator associated pneumonia (OR=3.155, 95%CI: 1.060-9.388), conventional mechanical ventilation (OR=2.298, 95%CI: 1.152-4.586), and volume of red blood cell transfusion (OR=1.013, 95%CI: 1.002-1.024) were risk factors of BPD. Conclusions: BPD is more common in very low birth weight infants of male with gestational age less than 32 weeks. Using CPAP in the delivery room, active treatment of NRDS, preventing nosocomial infection, and reducing invasive ventilation and red blood cell transfusion may decrease the incidence of BPD.


Assuntos
Displasia Broncopulmonar , Recém-Nascido de Peso Extremamente Baixo ao Nascer , Recém-Nascido de muito Baixo Peso , Peso ao Nascer , Displasia Broncopulmonar/complicações , Displasia Broncopulmonar/epidemiologia , Displasia Broncopulmonar/patologia , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Masculino , Síndrome do Desconforto Respiratório do Recém-Nascido , Estudos Retrospectivos , Fatores de Risco
12.
Am J Physiol Lung Cell Mol Physiol ; 316(1): L144-L156, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30382766

RESUMO

Premature male neonates are at a greater risk of developing bronchopulmonary dysplasia (BPD). The reasons underlying sexually dimorphic outcomes in premature neonates are not known. The role of miRNAs in mediating sex biases in BPD is understudied. Analysis of the pulmonary transcriptome revealed that a large percentage of angiogenesis-related differentially expressed genes are miR-30a targets. We tested the hypothesis that there is differential expression of miR-30a in vivo and in vitro in neonatal human pulmonary microvascular endothelial cells (HPMECs) upon exposure to hyperoxia. Neonatal male and female mice (C57BL/6) were exposed to hyperoxia [95% fraction of inspired oxygen (FiO2), postnatal day ( PND) 1-5] and euthanized on PND 7 and 21. HPMECs (18-24-wk gestation donors) were subjected to hyperoxia (95% O2 and 5% CO2) or normoxia (air and 5% CO2) up to 72 h. miR-30a expression was increased in both males and females in the acute phase ( PND 7) after hyperoxia exposure. However, at PND 21 (recovery phase), female mice showed significantly higher miR-30a expression in the lungs compared with male mice. Female HPMECs showed greater expression of miR-30a in vitro upon exposure to hyperoxia. Delta-like ligand 4 (Dll4) was an miR-30a target in HPMECs and showed sex-specific differential expression. miR-30a increased angiogenic sprouting in vitro in female HPMECs. Lastly, we show decreased expression of miR-30a and increased expression of DLL4 in human BPD lung samples compared with controls. These results support the hypothesis that miR-30a could, in part, contribute to the sex-specific molecular mechanisms in play that lead to the sexual dimorphism in BPD.


Assuntos
Displasia Broncopulmonar/metabolismo , Regulação da Expressão Gênica , Hiperóxia/metabolismo , Lesão Pulmonar/metabolismo , MicroRNAs/biossíntese , Caracteres Sexuais , Animais , Animais Recém-Nascidos , Displasia Broncopulmonar/patologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Hiperóxia/patologia , Lesão Pulmonar/patologia , Masculino , Camundongos
13.
Semin Perinatol ; 42(7): 425-431, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30487069

RESUMO

Bronchopulmonary Dysplasia (BPD) is a disorder with a multifactorial etiology and highly variable clinical phenotype. Several traditional biomarkers have been identified, but due to the complex disease phenotype, these biomarkers have low predictive accuracy for BPD. In recent years, newer technologies have facilitated the in-depth and unbiased analysis of 'big data' in delineating the diagnosis, pathogenesis, and mechanisms of diseases. Novel systems-biology based 'omic' approaches, including but not limited to genomics, microbiomics, proteomics, and metabolomics may help define the multiple cellular and humoral interactions that regulate normal as well as abnormal lung development and response to injury that are the hallmarks of BPD.


Assuntos
Displasia Broncopulmonar/patologia , Genômica , Pulmão/patologia , Metabolômica , Neonatologia , Proteômica , Mucosa Respiratória/metabolismo , Biomarcadores/sangue , Displasia Broncopulmonar/sangue , Displasia Broncopulmonar/fisiopatologia , Feminino , Humanos , Recém-Nascido , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Pulmão/fisiologia , Neonatologia/tendências , Valor Preditivo dos Testes , Gravidez , Mucosa Respiratória/fisiopatologia
14.
Respir Res ; 19(1): 229, 2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30463566

RESUMO

BACKGROUND: Hyperoxia is a frequently employed therapy for prematurely born infants, induces lung injury and contributes to development of bronchopulmonary dysplasia (BPD). BPD is characterized by decreased cellular proliferation, cellular migration, and failure of injury repair systems. Actin binding proteins (ABPs) such as VASP, cofilin1, and profilin1 regulate cell proliferation and migration via modulation of actin dynamics. Lung mesenchymal stem cells (L-MSCs) initiate repair processes by proliferating, migrating, and localizing to sites of injury. These processes have not been extensively explored in hyperoxia induced lung injury and repair. METHODS: ABPs and CD146+ L-MSCs were analyzed by immunofluorescence in human lung autopsy tissues from infants with and without BPD and by western blot in lung tissue homogenates obtained from our murine model of newborn hyperoxic lung injury. RESULTS: Decreased F-actin content, ratio of VASPpS157/VASPpS239, and profilin 1 expression were observed in human lung tissues but this same pattern was not observed in lungs from hyperoxia-exposed newborn mice. Increases in cofilin1 expression were observed in both human and mouse tissues at 7d indicating a dysregulation in actin dynamics which may be related to altered growth. CD146 levels were elevated in human and newborn mice tissues (7d). CONCLUSION: Altered phosphorylation of VASP and expression of profilin 1 and cofilin 1 in human tissues indicate that the pathophysiology of BPD involves dysregulation of actin binding proteins. Lack of similar changes in a mouse model of hyperoxia exposure imply that disruption in actin binding protein expression may be linked to interventions or morbidities other than hyperoxia alone.


Assuntos
Displasia Broncopulmonar/metabolismo , Moléculas de Adesão Celular/metabolismo , Cofilina 1/biossíntese , Hiperóxia/metabolismo , Lesão Pulmonar/metabolismo , Proteínas dos Microfilamentos/metabolismo , Fosfoproteínas/metabolismo , Profilinas/biossíntese , Animais , Animais Recém-Nascidos , Displasia Broncopulmonar/patologia , Cofilina 1/genética , Feminino , Expressão Gênica , Humanos , Hiperóxia/patologia , Recém-Nascido , Lesão Pulmonar/patologia , Camundongos , Camundongos Endogâmicos C3H , Fosforilação/fisiologia , Gravidez , Profilinas/genética , Distribuição Aleatória
15.
Semin Perinatol ; 42(7): 404-412, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30384986

RESUMO

Bronchopulmonary dysplasia (BPD) continues to be one of the most common complications of preterm birth and is characterized histopathologically by impaired lung alveolarization. Extremely preterm born infants remain at high risk for the development of BPD, highlighting a pressing need for continued efforts to understand the pathomechanisms at play in affected infants. This brief review summarizes recent progress in our understanding of the how the development of the newborn lung is stunted, highlighting recent reports on roles for growth factor signaling, oxidative stress, inflammation, the extracellular matrix and proteolysis, non-coding RNA, and fibroblast and epithelial cell plasticity. Additionally, some concerns about modeling BPD in experimental animals are reviewed, as are new developments in the in vitro modeling of pathophysiological processes relevant to impaired lung alveolarization in BPD.


Assuntos
Displasia Broncopulmonar/fisiopatologia , Inflamação/fisiopatologia , Pulmão/patologia , Fator de Crescimento Transformador beta1/metabolismo , Animais , Animais Recém-Nascidos , Displasia Broncopulmonar/patologia , Modelos Animais de Doenças , Humanos , Lactente Extremamente Prematuro , Recém-Nascido , Inflamação/patologia , Transdução de Sinais/fisiologia
16.
Physiol Genomics ; 50(11): 940-946, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30169132

RESUMO

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of the neonate characterized by impaired alveolarization and vascular growth. BPD is more common in premature male infants, but the reasons underlying sexually dimorphic outcomes are not known. It is thought that alterations in fibroblast phenotype in response to environmental stress such as hyperoxia contribute to BPD. Notch signaling creates a profibrotic environment in the lung. However, the role of hyperoxia on differential Notch pathway activation in male vs. female neonatal lung fibroblasts is not known. Primary murine lung fibroblasts from 10-day-old male and female mice were exposed to room air (21% O2, 5% CO2) or hyperoxia (95% O2, 5% CO2), and changes in cell proliferation, viability and expression of fibrosis-related genes and Notch pathway mediators were measured. Upon exposure to hyperoxia, cell proliferation was arrested in male and female fibroblasts, but cell viability was preserved. Increased Notch pathway activation was noted in male fibroblasts along with differential sex-specific modulation of key Notch pathway mediators in response to hyperoxia. α-Smooth muscle actin expression was increased in both male and female fibroblasts upon exposure to hyperoxia. Male and female fibroblasts further demonstrated distinct changes in expression of key fibrosis-related genes upon exposure to hyperoxia. Differential Notch pathway activation and distinct differences in the expression of key fibrosis-related genes might contribute to the sex-specific differences seen in hyperoxia-induced fibrosis and inhibition of lung development in BPD, with more severe implications in male neonates.


Assuntos
Displasia Broncopulmonar/etiologia , Fibroblastos/fisiologia , Expressão Gênica , Hiperóxia , Pulmão/patologia , Actinas/genética , Actinas/metabolismo , Animais , Displasia Broncopulmonar/patologia , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , Feminino , Fibroblastos/patologia , Masculino , Camundongos , Receptores Notch/genética , Receptores Notch/metabolismo , Fatores Sexuais
17.
Am J Physiol Lung Cell Mol Physiol ; 315(5): L816-L833, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30211655

RESUMO

Preterm birth and mechanical ventilation (MV) frequently lead to bronchopulmonary dysplasia, the histopathological hallmark of which is alveolar simplification. How developmental immaturity and ongoing injury, repair, and remodeling impact completion of alveolar formation later in life is not known, in part because of lack of suitable animal models. We report a new model, using former-preterm lambs, to test the hypothesis that they will have persistent alveolar simplification later in life. Moderately preterm lambs (~85% gestation) were supported by MV for ~6 days before being transitioned from all respiratory support to become former-preterm lambs. Results are compared with term control lambs that were not ventilated, and between males (M) and females (F). Alveolar simplification was quantified morphometrically and stereologically at 2 mo (4 M, 4 F) or 5 mo (4 M, 6 F) corrected postnatal age (cPNA) compared with unventilated, age-matched term control lambs (4 M, 4 F per control group). These postnatal ages in sheep are equivalent to human postnatal ages of 1-2 yr and ~6 yr, respectively. Multivariable linear regression results showed that former-preterm lambs at 2 or 5 mo cPNA had significantly thicker distal airspace walls ( P < 0.001 and P < 0.009, respectively), lower volume density of secondary septa ( P < 0.007 and P < 0.001, respectively), and lower radial alveolar count ( P < 0.003 and P < 0.020, respectively) compared with term control lambs. Sex-specific differences were not detected. We conclude that moderate preterm birth and MV for ~6 days impedes completion of alveolarization in former-preterm lambs. This new model provides the opportunity to identify underlying pathogenic mechanisms that may reveal treatment approaches.


Assuntos
Displasia Broncopulmonar/patologia , Pulmão/patologia , Animais , Animais Recém-Nascidos , Feminino , Idade Gestacional , Masculino , Modelos Animais , Respiração Artificial/métodos , Ovinos
18.
Trans Am Clin Climatol Assoc ; 129: 195-201, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30166714

RESUMO

In premature neonates, hyperoxic exposure contributes to lung injury characterized by simplified alveolarization and arrested vascularization. These are the hallmarks of bronchopulmonary dysplasia, a disease with long-term consequences on pulmonary and neurodevelopmental function. Lung vascular development and endothelial cell signals are synergistically important for normal alveolarization. It has been shown that metabolism of nutrients such as glucose, fatty acid, and glutamine is key in controlling proliferation, differentiation, apoptosis, autophagy, senescence, and inflammatory responses, which contribute to the pathogenesis of chronic lung diseases, including bronchopulmonary dysplasia. Recent studies show that metabolic reprogramming occurs in vitro in cells and in vivo in animal models and more importantly in patients with bronchopulmonary dysplasia, suggesting that metabolic dysregulation may participate in the pathogenesis and progression of these diseases. Although endothelial cells rely mainly on glycolysis for bioenergetics, they have the metabolic flexibility to maintain cell function under stress or nutrient deprivation. Others have shown that hyperoxia decreases glycolysis and oxidative phosphorylation in epithelial cells. Nevertheless, endothelial cells show enhanced mitochondrial fatty acid use after exposure to hyperoxia. This may serve to preserve endothelial cell proliferation and alveolarization, and thereby mitigate neonatal hyperoxic lung injury.


Assuntos
Displasia Broncopulmonar/metabolismo , Células Endoteliais/metabolismo , Metabolismo Energético , Ácidos Graxos/metabolismo , Lesão Pulmonar/metabolismo , Pulmão/metabolismo , Mitocôndrias/metabolismo , Regeneração , Animais , Displasia Broncopulmonar/etiologia , Displasia Broncopulmonar/patologia , Displasia Broncopulmonar/fisiopatologia , Proliferação de Células , Células Endoteliais/patologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Idade Gestacional , Humanos , Hiperóxia/complicações , Hiperóxia/metabolismo , Hiperóxia/patologia , Hiperóxia/fisiopatologia , Recém-Nascido , Recém-Nascido Prematuro , Pulmão/patologia , Pulmão/fisiopatologia , Lesão Pulmonar/etiologia , Lesão Pulmonar/patologia , Lesão Pulmonar/fisiopatologia , Nascimento Prematuro , Fatores de Risco
19.
J Cell Mol Med ; 22(11): 5759-5763, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30160360

RESUMO

The aim of this study is to optimize the timing of erythropoietin gene modified mesenchymal stem cells (EPO-MSCs) transplantation for bronchopulmonary dysplasia (BPD). Three weeks post-operation, the results indicated that the damage of airway structure and apoptosis were significantly decreased, the proliferation was increased in three EPO-MSCs transplantation groups as compared with BPD mice. Moreover, the inflammation cytokines were improvement in early EPO-MSCs injection mice than in BPD mice, but there was no significant difference between late injection and BPD groups. Furthermore, the protein expression ratio of p-p38/p38MAPK was down-regulation in early mice but not in late transplantation mice. Our findings suggest that EPO-MSCs maybe attenuate BPD injury in early than in late administration by inhibiting inflammation response through down-regulation of the p38MAPK signalling pathway.


Assuntos
Displasia Broncopulmonar/terapia , Eritropoetina/genética , Transplante de Células-Tronco Mesenquimais , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Animais , Apoptose/genética , Displasia Broncopulmonar/genética , Displasia Broncopulmonar/patologia , Proliferação de Células/genética , Modelos Animais de Doenças , Eritropoetina/administração & dosagem , Regulação da Expressão Gênica/genética , Humanos , Recém-Nascido , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Transdução de Sinais/genética
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