RESUMO
OBJECTIVES: To investigate the clinical characteristics of Ureaplasma urealyticum (UU) infection and colonization in extremely preterm infants and its impact on the incidence of bronchopulmonary dysplasia (BPD). METHODS: A retrospective analysis was conducted on 258 extremely preterm infants who were admitted to the Department of Neonatology, Shenzhen Maternity and Child Healthcare Hospital, from September 2018 to September 2022. According to the results of UU nucleic acid testing and the evaluation criteria for UU infection and colonization, the subjects were divided into three groups: UU-negative group (155 infants), UU infection group (70 infants), and UU colonization group (33 infants). The three groups were compared in terms of general information and primary and secondary clinical outcomes. RESULTS: Compared with the UU-negative group, the UU infection group had significant increases in the incidence rate of BPD, total oxygen supply time, and the length of hospital stay (P<0.05), while there were no significant differences in the incidence rates of BPD and moderate/severe BPD between the UU colonization group and the UU-negative group (P>0.05). CONCLUSIONS: The impact of UU on the incidence of BPD in extremely preterm infants is associated with the pathogenic state of UU (i.e., infection or colonization), and there are significant increases in the incidence rate of BPD, total oxygen supply time, and the length of hospital stay in extremely preterm infants with UU infection. UU colonization is not associated with the incidence of BPD and moderate/severe BPD in extremely preterm infants.
Assuntos
Displasia Broncopulmonar , Lactente Extremamente Prematuro , Infecções por Ureaplasma , Ureaplasma urealyticum , Humanos , Infecções por Ureaplasma/epidemiologia , Infecções por Ureaplasma/complicações , Ureaplasma urealyticum/isolamento & purificação , Recém-Nascido , Estudos Retrospectivos , Feminino , Masculino , Displasia Broncopulmonar/epidemiologia , Displasia Broncopulmonar/microbiologia , Displasia Broncopulmonar/etiologia , Tempo de InternaçãoRESUMO
OBJECTIVES: To investigate the role and mechanism of epithelial-mesenchymal transition (EMT) in a rat model of bronchopulmonary dysplasia (BPD). METHODS: The experiment consisted of two parts. (1) Forty-eight preterm rats were randomly divided into a normoxia group and a hyperoxia group, with 24 rats in each group. The hyperoxia group was exposed to 85% oxygen to establish a BPD model, while the normoxia group was kept in room air at normal pressure. Lung tissue samples were collected on days 1, 4, 7, and 14 of the experiment. (2) Rat type II alveolar epithelial cells (RLE-6TN) were randomly divided into a normoxia group (cultured in air) and a hyperoxia group (cultured in 95% oxygen), and cell samples were collected 12, 24, and 48 hours after hyperoxia exposure. Hematoxylin-eosin staining was used to observe alveolarization in preterm rat lungs, and immunofluorescence was used to detect the co-localization of surfactant protein C (SPC) and α-smooth muscle actin (α-SMA) in preterm rat lung tissue and RLE-6TN cells. Quantitative real-time polymerase chain reaction and protein immunoblotting were used to detect the expression levels of EMT-related mRNA and proteins in preterm rat lung tissue and RLE-6TN cells. RESULTS: (1) Compared with the normoxia group, the hyperoxia group showed blocked alveolarization and simplified alveolar structure after 7 days of hyperoxia exposure. Co-localization of SPC and α-SMA was observed in lung tissue, with decreased SPC expression and increased α-SMA expression in the hyperoxia group at 7 and 14 days of hyperoxia exposure compared to the normoxia group. In the hyperoxia group, the mRNA and protein levels of TGF-ß1, α-SMA, and N-cadherin were increased, while the mRNA and protein levels of SPC and E-cadherin were decreased at 7 and 14 days of hyperoxia exposure compared to the normoxia group (P<0.05). (2) SPC and α-SMA was observed in RLE-6TN cells, with decreased SPC expression and increased α-SMA expression in the hyperoxia group at 24 and 48 hours of hyperoxia exposure compared to the normoxia group. Compared to the normoxia group, the mRNA and protein levels of SPC and E-cadherin in the hyperoxia group were decreased, while the mRNA and protein levels of TGF-ß1, α-SMA, and E-cadherin in the hyperoxia group increased at 48 hours of hyperoxia exposure (P<0.05). CONCLUSIONS: EMT disrupts the tight connections between alveolar epithelial cells in a preterm rat model of BPD, leading to simplified alveolar structure and abnormal development, and is involved in the development of BPD. Citation:Chinese Journal of Contemporary Pediatrics, 2024, 26(7): 765-773.
Assuntos
Displasia Broncopulmonar , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal , Hiperóxia , Ratos Sprague-Dawley , Animais , Displasia Broncopulmonar/etiologia , Displasia Broncopulmonar/patologia , Displasia Broncopulmonar/metabolismo , Hiperóxia/complicações , Ratos , Actinas/análise , Actinas/metabolismo , Actinas/genética , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/análise , Animais Recém-Nascidos , Feminino , Proteína C Associada a Surfactante Pulmonar/genética , Pulmão/patologia , Pulmão/metabolismo , MasculinoRESUMO
BACKGROUND: Airway injuries are reported among preterm infants with bronchopulmonary dysplasia. We hypothesized that prolonged ventilation in preterm infants is associated with subglottic dilatation that can be reliably evaluated by point of care ultrasonography (POCUS). METHODS: All preterm infants (<29-weeks) admitted to the neonatal ICU at the Advent-Health from January-2020 to June-2022 were eligible if they required invasive ventilation for ≤7 days in the first 28 days of life (control) or remained intubated for ≥28 days (prolonged ventilation). Sonography was performed by one technician and all images were reviewed by the pediatric radiologist. The trachea size was measured 3 times by randomly selecting three images. The first 20 scans were also independently reported by a different pediatric radiologist. Intra and inter-observer variability was estimated. Mean trachea size and weight at the time of imaging were compared. RESULTS: Out of 417 eligible infants; 11 died before 28 days and 163 required ventilation for 8-27 days. Consent missed for 80 infants during COVID-19 pandemic. We enrolled 23 and 28 infants in the control & prolonged ventilation groups, respectively. Inter and intra-observer correlations were 0.83 and 0.97 respectively. Infants in the control group had higher gestation and birth weight. Infants on prolonged ventilation were at higher risk for infections, BPD, longer hospital stay and significant subglottic dilation (4.51 ± 0.04 vs 4.17 ± 0.02 mm, p < 0.01) despite smaller body weight at the time of imaging (884 ± 102 vs 1059 ± 123g, p < 0.01). CONCLUSION: Extremely preterm infants on prolonged ventilation are at risk for sub-glottic dilatation that can be reliably measured by POCUS.
Assuntos
Displasia Broncopulmonar , Lactente Extremamente Prematuro , Respiração Artificial , Traqueia , Ultrassonografia , Humanos , Recém-Nascido , Respiração Artificial/efeitos adversos , Respiração Artificial/métodos , Masculino , Feminino , Traqueia/diagnóstico por imagem , Displasia Broncopulmonar/diagnóstico por imagem , Displasia Broncopulmonar/etiologia , Ultrassonografia/métodos , Dilatação Patológica/diagnóstico por imagem , Glote/diagnóstico por imagem , COVID-19/complicações , Fatores de TempoRESUMO
OBJECTIVES: To investigate the risk factors for bronchopulmonary dysplasia (BPD) in twin preterm infants with a gestational age of <34 weeks, and to provide a basis for early identification of BPD in twin preterm infants in clinical practice. METHODS: A retrospective analysis was performed for the twin preterm infants with a gestational age of <34 weeks who were admitted to 22 hospitals nationwide from January 2018 to December 2020. According to their conditions, they were divided into group A (both twins had BPD), group B (only one twin had BPD), and group C (neither twin had BPD). The risk factors for BPD in twin preterm infants were analyzed. Further analysis was conducted on group B to investigate the postnatal risk factors for BPD within twins. RESULTS: A total of 904 pairs of twins with a gestational age of <34 weeks were included in this study. The multivariate logistic regression analysis showed that compared with group C, birth weight discordance of >25% between the twins was an independent risk factor for BPD in one of the twins (OR=3.370, 95%CI: 1.500-7.568, P<0.05), and high gestational age at birth was a protective factor against BPD (P<0.05). The conditional logistic regression analysis of group B showed that small-for-gestational-age (SGA) birth was an independent risk factor for BPD in individual twins (OR=5.017, 95%CI: 1.040-24.190, P<0.05). CONCLUSIONS: The development of BPD in twin preterm infants is associated with gestational age, birth weight discordance between the twins, and SGA birth.
Assuntos
Displasia Broncopulmonar , Recém-Nascido Prematuro , Gêmeos , Humanos , Displasia Broncopulmonar/etiologia , Displasia Broncopulmonar/epidemiologia , Fatores de Risco , Recém-Nascido , Feminino , Estudos Retrospectivos , Masculino , Idade Gestacional , Peso ao Nascer , Modelos LogísticosRESUMO
In infants with severe bronchopulmonary dysplasia (sBPD), severe pulmonary lobar emphysema may occur as a complication, contributing to significant impairment in ventilation. Clinical management of these infants is extremely challenging and some may require lobectomy to improve ventilation. However, prior to the lobectomy, it is very difficult to assess whether the remaining lung parenchyma would be able to sustain adequate ventilation postoperatively. In addition, preoperative planning and perioperative management are also quite challenging in these patients. This paper reports the utility of selective bronchial occlusion in assessing the safety and efficacy of lobectomy in a case of sBPD complicated by severe right upper lobar emphysema. Since infants with sBPD already have poor lung development and significant lung injury, lobectomy should be viewed as a non-traditional therapy and be carried out with extreme caution. Selective bronchial occlusion test can be an effective tool in assessing the risks and benefits of lobectomy in cases with sBPD and lobar emphysema. However, given the technical difficulty, successful application of this technique requires close collaboration of an experienced interdisciplinary team.
Assuntos
Displasia Broncopulmonar , Recém-Nascido Prematuro , Enfisema Pulmonar , Humanos , Enfisema Pulmonar/cirurgia , Displasia Broncopulmonar/etiologia , Recém-Nascido , Brônquios , Masculino , Pneumonectomia , FemininoRESUMO
Bronchopulmonary dysplasia (BPD) remains a significant challenge in neonatal care, the pathogenesis of which potentially involves altered lipid metabolism. Given the critical role of lipids in lung development and the injury response, we hypothesized that specific lipid species could serve as therapeutic agents in BPD. This study aimed to investigate the role of the lipid Phosphatidylcholine (PC) (16:0/14:0) in modulating BPD pathology and to elucidate its underlying mechanisms of action. Our approach integrated in vitro and in vivo methodologies to assess the effects of PC (16:0/14:0) on the histopathology, cellular proliferation, apoptosis, and molecular markers in lung tissue. In a hyperoxia-induced BPD rat model, we observed a reduction in alveolar number and an enlargement in alveolar size, which were ameliorated by PC (16:0/14:0) treatment. Correspondingly, in BPD cell models, PC (16:0/14:0) intervention led to increased cell viability, enhanced proliferation, reduced apoptosis, and elevated surfactant protein C (SPC) expression. RNA sequencing revealed significant gene expression differences between BPD and PC (16:0/14:0) treated groups, with a particular focus on Cldn1 (encoding claudin 1), which was significantly enriched in our analysis. Our findings suggest that PC (16:0/14:0) might protect against hyperoxia-induced alveolar type II cell damage by upregulating CLDN1 expression, potentially serving as a novel therapeutic target for BPD. This study not only advances our understanding of the role of lipids in BPD pathogenesis, but also highlights the significance of PC (16:0/14:0) in the prevention and treatment of BPD, offering new avenues for future research and therapeutic development.
Assuntos
Células Epiteliais Alveolares , Displasia Broncopulmonar , Claudina-1 , Hiperóxia , Fosfatidilcolinas , Regulação para Cima , Animais , Displasia Broncopulmonar/metabolismo , Displasia Broncopulmonar/patologia , Displasia Broncopulmonar/etiologia , Hiperóxia/metabolismo , Hiperóxia/complicações , Hiperóxia/patologia , Ratos , Claudina-1/metabolismo , Claudina-1/genética , Fosfatidilcolinas/metabolismo , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Ratos Sprague-Dawley , Apoptose , Proliferação de Células , Humanos , Alvéolos Pulmonares/patologia , Alvéolos Pulmonares/metabolismo , Animais Recém-Nascidos , Modelos Animais de DoençasRESUMO
OBJECTIVES: To investigate the effects of different angles of pulmonary surfactant (PS) administration on the incidence of bronchopulmonary dysplasia and intracranial hemorrhage in preterm infants. METHODS: A prospective study was conducted on 146 preterm infants (gestational age <32 weeks) admitted to the Department of Neonatology, Provincial Hospital Affiliated to Anhui Medical University from January 2019 to May 2023. The infants were randomly assigned to different angles for injection of pulmonary surfactant groups: 0° group (34 cases), 30° group (36 cases), 45° group (38 cases), and 60° group (38 cases). Clinical indicators and outcomes were compared among the groups. RESULTS: The oxygenation index was lower in the 60° group compared with the other three groups, with shorter invasive ventilation time and oxygen use time, and a lower incidence of bronchopulmonary dysplasia than the other three groups (P<0.05). The incidence of intracranial hemorrhage was lower in the 60° group compared to the 0° group (P<0.05). The cure rate in the 60° group was higher than that in the 0° group and the 30° group (P<0.05). CONCLUSIONS: The clinical efficacy of injection of pulmonary surfactant at a 60° angle is higher than other angles, reducing the incidence of intracranial hemorrhage and bronchopulmonary dysplasia in preterm infants.
Assuntos
Displasia Broncopulmonar , Recém-Nascido Prematuro , Hemorragias Intracranianas , Surfactantes Pulmonares , Humanos , Surfactantes Pulmonares/administração & dosagem , Recém-Nascido , Estudos Prospectivos , Displasia Broncopulmonar/prevenção & controle , Displasia Broncopulmonar/tratamento farmacológico , Displasia Broncopulmonar/etiologia , Masculino , Feminino , Hemorragias Intracranianas/prevenção & controle , Hemorragias Intracranianas/induzido quimicamenteRESUMO
BACKGROUND: Chorioamnionitis (CA) can cause multiple organ injuries in premature neonates, particularly to the lungs. Different opinions exist regarding the impact of intrauterine inflammation on neonatal respiratory distress syndrome (NRDS) and bronchopulmonary dysplasia (BPD). We aim to systematically review the relationship between CA or Funisitis (FV) and lung injury among preterm infants. METHODS: We electronically searched PubMed, EMbase, the Cochrane library, CNKI, and CMB for cohort studies from their inception to March 15, 2023. Two reviewers independently screened literature, gathered data, and did NOS scale of included studies. The meta-analysis was performed using RevMan 5.3. RESULTS: Sixteen observational studies including 68,397 patients were collected. Meta-analysis showed CA or FV increased the lung injury risk (OR = 1.43, 95%CI: 1.06-1.92). Except for histological chorioamnionitis (HCA) (OR = 0.72, 95%CI: 0.57-0.90), neither clinical chorioamnionitis (CCA) (OR = 1.86, 95%CI: 0.93-3.72) nor FV (OR = 1.23, 95%CI: 0.48-3.15) nor HCA with FV (OR = 1.85, 95%CI: 0.15-22.63) had statistical significance in NRDS incidence. As a result of stratification by grade of HCA, HCA (II) has a significant association with decreased incidence of NRDS (OR = 0.48, 95%CI: 0.35-0.65). In terms of BPD, there is a positive correlation between BPD and CA/FV (CA: OR = 3.18, 95%CI: 1.68-6.03; FV: OR = 6.36, 95%CI: 2.45-16.52). Among CA, HCA was positively associated with BPD (OR = 2.70, 95%CI: 2.38-3.07), whereas CCA was not associated with BPD (OR = 2.77, 95%CI: 0.68-11.21). HCA and moderate to severe BPD (OR = 25.38, 95%CI: 7.13-90.32) showed a positive correlation, while mild BPD (OR = 2.29, 95%CI: 0.99-5.31) did not. CONCLUSION: Currently, evidence suggests that CA or FV increases the lung injury incidence in premature infants. For different types of CA and FV, HCA can increase the incidence of BPD while decreasing the incidence of NRDS. And this "protective effect" only applies to infants under 32 weeks of age. Regarding lung injury severity, only moderate to severe cases of BPD were positively correlated with CA.
Assuntos
Displasia Broncopulmonar , Corioamnionite , Lesão Pulmonar , Síndrome do Desconforto Respiratório do Recém-Nascido , Recém-Nascido , Feminino , Gravidez , Lactente , Humanos , Corioamnionite/epidemiologia , Recém-Nascido Prematuro , Inflamação , Displasia Broncopulmonar/epidemiologia , Displasia Broncopulmonar/etiologia , Síndrome do Desconforto Respiratório do Recém-Nascido/epidemiologia , Síndrome do Desconforto Respiratório do Recém-Nascido/etiologiaRESUMO
Bronchopulmonary dysplasia (BPD) is a chronic respiratory disease in newborns, which severely influences the health of infants and lacks effective clinical treatment strategies. The pathogenesis of BPD is correlated to enhanced inflammation and activated oxidative stress (OS). The application of antioxidants and anti-inflammatory treatment could be hot spots for BPD treatment. Nesfatin-1, a peptide with a suppressive property against inflammation, was tested herein for its potential therapeutic value in BPD. Neonatal SD rats were stimulated with hyperoxia, followed by being intraperitoneally administered with 20 µg/kg/day Nesfatin-1 for 2 weeks. Decreased RAC value in lung tissues, increased wet weight/dry weight (W/D) pulmonary ratio and bronchoalveolar lavage fluid (BALF) proteins, elevated cytokine release in BALF, increased malondialdehyde (MDA) content, and declined superoxide dismutase (SOD) activity were observed in BPD rats, all of which were sharply mitigated by Nesfatin-1. Rat epithelial type II cells (AECIIs) were handled with hyperoxia, and then cultured with 1 and 10 nM Nesfatin-1. Reduced cell viability, elevated lactate dehydrogenase production, elevated cytokine secretion, elevated MDA content, and decreased SOD activity were observed in hyperoxia-handled AECIIs, all of which were markedly alleviated by Nesfatin-1. Furthermore, activated nuclear factor-κB (NF-κB) signaling observed in both BPD rats and hyperoxia-handled AECIIs were notably repressed by Nesfatin-1. Collectively, Nesfatin-1 alleviated hyperoxia-triggered BPD by repressing inflammation and OS via the NF-κB signaling pathway.
Assuntos
Displasia Broncopulmonar , Hiperóxia , Animais , Humanos , Recém-Nascido , Ratos , Animais Recém-Nascidos , Displasia Broncopulmonar/tratamento farmacológico , Displasia Broncopulmonar/etiologia , Displasia Broncopulmonar/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Hiperóxia/metabolismo , Inflamação/metabolismo , Pulmão/metabolismo , NF-kappa B/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais , Superóxido Dismutase/metabolismoRESUMO
OBJECTIVE: To examine nutritional intake profiles and growth trajectories of extremely low birth weight (ELBW) infants who develop severe bronchopulmonary dysplasia (BPD). STUDY DESIGN: Case-control study using multiple logistic regression analysis with generalized estimating equations (GEE) to adjust for matching. RESULTS: Cumulative and mean fluid intakes were higher (p = 0.003) and caloric intakes lower (p < 0.0001) through week two in infants who developed severe BPD (n = 120) versus those without severe BPD (n = 104). Mean caloric intake through week 12 was lower in infants who developed severe BPD (102 ± 10.1 vs. 107 ± 8.5 kcal/kg/day, p < 0.0001). In the logistic regression models, lower mean caloric intake through week 12 was associated with increased risk of developing severe BPD. Linear growth reduced the odds of BPD by ~30% for each Z-score point. CONCLUSIONS: Higher fluid and lower total caloric intakes and reductions in linear growth were independently associated with an increased risk of developing severe BPD in ELBW infants.
Assuntos
Displasia Broncopulmonar , Ingestão de Energia , Recém-Nascido de Peso Extremamente Baixo ao Nascer , Humanos , Displasia Broncopulmonar/etiologia , Recém-Nascido , Masculino , Feminino , Estudos de Casos e Controles , Modelos Logísticos , Fatores de RiscoRESUMO
Alteration of gut microbiota can affect chronic lung diseases, such as asthma and chronic obstructive pulmonary disease, through abnormal immune and inflammatory responses. Previous studies have shown a feasible connection between gut microbiota and bronchopulmonary dysplasia (BPD) in preterm infants. However, whether BPD can be ameliorated by restoring the gut microbiota remains unclear. In preterm infants with BPD, we found variance in the diversity and structure of gut microbiota. Similarly, BPD rats showed gut dysbiosis, characterized by a deficiency of Lactobacillus, which was abundant in normal rats. We therefore explored the effect and potential mechanism of action of a probiotic strain, Lactobacillus plantarum L168, in improving BPD. The BPD rats were treated with L. plantarum L168 by gavage for 2 weeks, and the effect was evaluated by lung histopathology, lung function, and serum inflammatory markers. Subsequently, we observed reduced lung injury and improved lung development in BPD rats exposed to L. plantarum L168. Further evaluation revealed that L. plantarum L168 improved intestinal permeability in BPD rats. Serum metabolomics showed altered inflammation-associated metabolites following L. plantarum L168 intervention, notably a marked increase in anti-inflammatory metabolites. In agreement with the metabolites analysis, RNA-seq analysis of the intestine and lung showed that inflammation and immune-related genes were down-regulated. Based on the information from RNA-seq, we validated that L. plantarum L168 might improve BPD relating to down-regulation of TLR4 /NF-κB /CCL4 pathway. Together, our findings suggest the potential of L. plantarum L168 to provide probiotic-based therapeutic strategies for BPD.
Assuntos
Displasia Broncopulmonar , Hiperóxia , Lactobacillus plantarum , Pneumonia , Humanos , Recém-Nascido , Animais , Ratos , Displasia Broncopulmonar/tratamento farmacológico , Displasia Broncopulmonar/etiologia , Hiperóxia/complicações , Hiperóxia/metabolismo , Recém-Nascido Prematuro , Inflamação/tratamento farmacológico , Inflamação/metabolismo , BiomarcadoresRESUMO
BACKGROUND: Premature infants often require oxygen supplementation, which can elicit bronchopulmonary dysplasia (BPD) and lead to mitochondrial dysfunction. Mitochondria play important roles in lung development, in both normal metabolism and apoptosis. Enhancing our comprehension of the underlying mechanisms in BPD development can facilitate the effective treatments. METHODS: Plasma samples from BPD and non-BPD infants were collected at 36 weeks post-menstrual age and used for metabolomic analysis. Based on hyperoxia-induced animal and cell models, changes in mitophagy and apoptosis were evaluated following treatment with itaconic acid (ITA). Finally, the mechanism of action of ITA in lung development was comprehensively demonstrated through rescue strategies and administration of corresponding inhibitors. RESULTS: An imbalance in the tricarboxylic acid (TCA) cycle significantly affected lung development, with ITA serving as a significant metabolic marker for the outcomes of lung development. ITA improved the morphological changes in BPD rats, promoted SP-C expression, and inhibited the degree of alveolar type II epithelial cells (AEC II) apoptosis. Mechanistically, ITA mainly promotes the nuclear translocation of transcription factor EB (TFEB) to facilitate dysfunctional mitochondrial clearance and reduces apoptosis in AEC II cells by regulating autophagic flux. CONCLUSION: The metabolic imbalance in the TCA cycle is closely related to lung development. ITA can improve lung development by regulating autophagic flux and promote the nuclear translocation of TFEB, implying its potential therapeutic utility in the treatment of BPD.
Assuntos
Autofagia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Displasia Broncopulmonar , Hiperóxia , Succinatos , Succinatos/farmacologia , Animais , Autofagia/efeitos dos fármacos , Displasia Broncopulmonar/metabolismo , Displasia Broncopulmonar/etiologia , Displasia Broncopulmonar/patologia , Ratos , Humanos , Hiperóxia/metabolismo , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Apoptose/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Ciclo do Ácido Cítrico/efeitos dos fármacos , Feminino , Mitofagia/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Recém-NascidoRESUMO
BACKGROUND: Bronchopulmonary dysplasia (BPD), a common complication of premature birth, exerts considerable impact on the respiratory health of infants. This study aimed to identify the role of plasma metabolites in predicting respiratory outcomes in BPD-afflicted infants. METHODS: This was a case-control study including 15 BPD premature infants and 15 gestational age and birth weight matched no-BPD preterm infants. Plasma samples, obtained at 36 weeks postmenstrual age (PMA), were subjected to a comprehensive analysis of over 300 metabolites using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The respiratory outcomes of the infants were collected with the first 2 years of corrected postnatal age. RESULTS: The analysis revealed a significant upregulation of urea and downregulation of nine metabolites in BPD infants, including oxalacetic acid, cis-aconitic acid, itaconic acid, betaine, L-asparagine, L-alanine, picolinic acid, inositol, and purine (p < 0.05). These metabolites primarily pertained to the citrate cycle (TCA cycle), glyoxylate and dicarboxylate metabolism, and alanine, aspartate, and glutamate metabolism. Furthermore, seven metabolites demonstrated substantial predictive capacity for respiratory readmissions within the first two years of corrected postnatal age, achieving an area under curve (AUC) exceeding or equal to 0.8. These included chenodeoxycholic acid, dehydrolithocholic acid, glucaric acid, D-glucuronic acid, gamma-glutamylvaline, mevalonic acid, and 3-ureidopropionic acid. CONCLUSIONS: This study identified ten distinct plasma metabolites at 36 weeks PMA that differentiate BPD infants from their non-BPD counterparts, implicating three major metabolic pathways. Additionally, seven metabolites showed strong predictive value for heightened risk of respiratory readmission within two years, underscoring their potential utility in clinical prognostication and management strategies for BPD.
Assuntos
Displasia Broncopulmonar , Recém-Nascido Prematuro , Lactente , Feminino , Gravidez , Recém-Nascido , Humanos , Displasia Broncopulmonar/etiologia , Estudos de Casos e Controles , Cromatografia Líquida , Espectrometria de Massas em Tandem , Idade GestacionalRESUMO
BACKGROUND: The transcriptional repressor B-cell lymphoma 6 (BCL6) has been reported to inhibit inflammation. So far, experimental evidence for the role of BCL6 in bronchopulmonary dysplasia (BPD) is lacking. Our study investigated the roles of BCL6 in the progression of BPD and its downstream mechanisms. METHODS: Hyperoxia or lipopolysaccharide (LPS) was used to mimic the BPD mouse model. To investigate the effects of BCL6 on BPD, recombination adeno-associated virus serotype 9 expressing BCL6 (rAAV9-BCL6) and BCL6 inhibitor FX1 were administered in mice. The pulmonary pathological changes, inflammatory chemokines and NLRP3-related protein were observed. Meanwhile, BCL6 overexpression plasmid was used in human pulmonary microvascular endothelial cells (HPMECs). Cell proliferation, apoptosis, and NLRP3-related protein were detected. RESULTS: Either hyperoxia or LPS suppressed pulmonary BCL6 mRNA expression. rAAV9-BCL6 administration significantly inhibited hyperoxia-induced NLRP3 upregulation and inflammation, attenuated alveolar simplification and dysregulated angiogenesis in BPD mice, which were characterized by decreased mean linear intercept, increased radical alveolar count and alveoli numbers, and the upregulated CD31 expression. Meanwhile, BCL6 overexpression promoted proliferation and angiogenesis, inhibited apoptosis and inflammation in hyperoxia-stimulated HPMECs. Moreover, administration of BCL6 inhibitor FX1 arrested growth and development. FX1-treated BPD mice exhibited exacerbation of alveolar pathological changes and pulmonary vessel permeability, with upregulated mRNA levels of pro-inflammatory cytokines and pro-fibrogenic factors. Furthermore, both rAAV9-BCL6 and FX1 administration exerted a long-lasting effect on hyperoxia-induced lung injury (≥4 wk). CONCLUSIONS: BCL6 inhibits NLRP3-mediated inflammation, attenuates alveolar simplification and dysregulated pulmonary vessel development in hyperoxia-induced BPD mice. Hence, BCL6 may be a target in treating BPD and neonatal diseases.
Assuntos
Displasia Broncopulmonar , Hiperóxia , Lesão Pulmonar , Animais , Humanos , Recém-Nascido , Camundongos , Animais Recém-Nascidos , Displasia Broncopulmonar/etiologia , Displasia Broncopulmonar/metabolismo , Modelos Animais de Doenças , Células Endoteliais/patologia , Hiperóxia/metabolismo , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Pulmão/metabolismo , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/etiologia , Lesão Pulmonar/prevenção & controle , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , RNA Mensageiro/metabolismoRESUMO
BACKGROUND: The cyclooxygenase inhibitor ibuprofen may be used to treat patent ductus arteriosus (PDA) in preterm infants. Whether selective early treatment of large PDAs with ibuprofen would improve short-term outcomes is not known. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled trial evaluating early treatment (≤72 hours after birth) with ibuprofen for a large PDA (diameter of ≥1.5 mm with pulsatile flow) in extremely preterm infants (born between 23 weeks 0 days' and 28 weeks 6 days' gestation). The primary outcome was a composite of death or moderate or severe bronchopulmonary dysplasia evaluated at 36 weeks of postmenstrual age. RESULTS: A total of 326 infants were assigned to receive ibuprofen and 327 to receive placebo; 324 and 322, respectively, had data available for outcome analyses. A primary-outcome event occurred in 220 of 318 infants (69.2%) in the ibuprofen group and 202 of 318 infants (63.5%) in the placebo group (adjusted risk ratio, 1.09; 95% confidence interval [CI], 0.98 to 1.20; P = 0.10). A total of 44 of 323 infants (13.6%) in the ibuprofen group and 33 of 321 infants (10.3%) in the placebo group died (adjusted risk ratio, 1.32; 95% CI, 0.92 to 1.90). Among the infants who survived to 36 weeks of postmenstrual age, moderate or severe bronchopulmonary dysplasia occurred in 176 of 274 (64.2%) in the ibuprofen group and 169 of 285 (59.3%) in the placebo group (adjusted risk ratio, 1.09; 95% CI, 0.96 to 1.23). Two unforeseeable serious adverse events occurred that were possibly related to ibuprofen. CONCLUSIONS: The risk of death or moderate or severe bronchopulmonary dysplasia at 36 weeks of postmenstrual age was not significantly lower among infants who received early treatment with ibuprofen than among those who received placebo. (Funded by the National Institute for Health Research Health Technology Assessment Programme; Baby-OSCAR ISRCTN Registry number, ISRCTN84264977.).
Assuntos
Inibidores de Ciclo-Oxigenase , Permeabilidade do Canal Arterial , Ibuprofeno , Humanos , Recém-Nascido , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Displasia Broncopulmonar/etiologia , Displasia Broncopulmonar/mortalidade , Permeabilidade do Canal Arterial/complicações , Permeabilidade do Canal Arterial/tratamento farmacológico , Permeabilidade do Canal Arterial/mortalidade , Ibuprofeno/administração & dosagem , Ibuprofeno/efeitos adversos , Ibuprofeno/uso terapêutico , Lactente Extremamente Prematuro , Inibidores de Ciclo-Oxigenase/administração & dosagem , Inibidores de Ciclo-Oxigenase/efeitos adversos , Inibidores de Ciclo-Oxigenase/uso terapêutico , Método Duplo-Cego , Fatores de Tempo , Resultado do TratamentoRESUMO
Mechanisms underlying hyperoxia-induced airflow restriction in the pediatric lung disease Bronchopulmonary dysplasia (BPD) are unclear. We hypothesized a role for Renin-Angiotensin System (RAS) activity in BPD. RAS is comprised of a pro-developmental pathway consisting of angiotensin converting enzyme-2 (ACE2) and angiotensin II receptor type 2 (AT2), and a pro-fibrotic pathway mediated by angiotensin II receptor type 1 (AT1). We investigated associations between neonatal hyperoxia, airflow restriction, and RAS activity in a BPD mouse model. C57 mouse pups were randomized to normoxic (FiO2 = 0.21) or hyperoxic (FiO2 = 0.75) conditions for 15 days (P1-P15). At P15, P20, and P30, we measured airflow restriction using plethysmography and ACE2, AT1, and AT2 mRNA and protein expression via polymerase chain reaction and Western Blot. Hyperoxia increased airflow restriction P15 and P20, decreased ACE2 and AT2 mRNA, decreased AT2 protein, and increased AT1 protein expression. ACE2 mRNA and protein remained suppressed at P20. By P30, airflow restriction and RAS expression did not differ between groups. Hyperoxia caused high airflow restriction, increased pulmonary expression of the pro-fibrotic RAS pathway, and decreased expression of the pro-developmental in our BPD mouse model. These associated findings may point to a causal role for RAS in hyperoxia-induced airflow restriction.
Assuntos
Displasia Broncopulmonar , Hiperóxia , Animais , Camundongos , Enzima de Conversão de Angiotensina 2/metabolismo , Animais Recém-Nascidos , Displasia Broncopulmonar/etiologia , Displasia Broncopulmonar/metabolismo , Modelos Animais de Doenças , Fibrose , Hiperóxia/metabolismo , Pulmão/metabolismo , Sistema Renina-Angiotensina/genética , RNA Mensageiro/genéticaRESUMO
OBJECTIVES@#To study the effect of sex on the clinical outcome of extremely preterm infants (EPIs)/extremely low birth weight infants (ELBWIs) by propensity score matching.@*METHODS@#A retrospective analysis was performed for the medical data of 731 EPIs or ELBWIs who were admitted from January 1, 2011 to December 31, 2020. These infants were divided into two groups: male and female. A propensity score matching analysis was performed at a ratio of 1:1. The matching variables included gestational age, birth weight, percentage of withdrawal from active treatment, percentage of small-for-gestational-age infant, percentage of use of pulmonary surfactant, percentage of 1-minute Apgar score ≤3, percentage of mechanical ventilation, duration of mechanical ventilation, percentage of antenatal use of inadequate glucocorticoids, and percentage of hypertensive disorders in pregnancy. The two groups were compared in the incidence rate of main complications during hospitalization and the rate of survival at discharge.@*RESULTS@#Before matching, compared with the female group, the male group had significantly higher incidence rates of neonatal respiratory distress syndrome, bronchopulmonary dysplasia (BPD), severe intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, and patent ductus arteriosus (P<0.05), while after matching, the male group only had a significantly higher incidence rate of BPD than the female group (P<0.05). There was no significant difference in the rate of survival at discharge between the two groups before and after matching (P>0.05).@*CONCLUSIONS@#Male EPIs/ELBWIs have a higher risk of BPD than female EPIs/ELBWIs, but male and female EPIs/ELBWIs tend to have similar outcomes.
Assuntos
Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Gravidez , Displasia Broncopulmonar/etiologia , Recém-Nascido de Peso Extremamente Baixo ao Nascer , Lactente Extremamente Prematuro , Pontuação de Propensão , Estudos Retrospectivos , Caracteres SexuaisRESUMO
OBJECTIVE@#To systematically evaluate the association of early nutrition intake with the risk of bronchopulmonary dysplasia (BPD).@*METHODS@#PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, Wanfang Data, and Weipu Periodical Database were searched for the observational studies on the association between early nutrition intake and BPD. RevMan 5.3 software was used to perform a Meta analysis of eligible studies.@*RESULTS@#Eight observational studies were included, with 548 infants with BPD and 522 infants without BPD. The Meta analysis showed that the BPD group had a significantly lower caloric intake than the non-BPD group within the first week after birth and in the first 2 weeks after birth (@*CONCLUSIONS@#Early nutrition deficiency may be associated with the development of BPD, and more attention should be paid to enteral feeding of infants at a high risk of BPD to achieve total enteral feeding as soon as possible.
Assuntos
Humanos , Lactente , Recém-Nascido , Displasia Broncopulmonar/etiologia , China , Recém-Nascido Prematuro , Desnutrição , Nutrição ParenteralRESUMO
Bronchopulmonary dysplasia (BPD) has the main manifestations of pulmonary edema in the early stage and characteristic alveolar obstruction and microvascular dysplasia in the late stage, which may be caused by structural and functional destruction of the lung epithelial barrier. The Claudin family is the main component of tight junction and plays an important role in regulating the permeability of paracellular ions and solutes. Claudin-18 is the only known tight junction protein solely expressed in the lung. The lack of Claudin-18 can lead to barrier dysfunction and impaired alveolar development, and the knockout of Claudin-18 can cause characteristic histopathological changes of BPD. This article elaborates on the important role of Claudin-18 in the development and progression of BPD from the aspects of lung epithelial permeability, alveolar development, and progenitor cell homeostasis, so as to provide new ideas for the pathogenesis and clinical treatment of BPD.