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1.
Chem Biol Drug Des ; 103(4): e14520, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38570710

RESUMO

Quercetin, a bioactive natural compound renowned for its potent anti-inflammatory, antioxidant, and antiviral properties, has exhibited therapeutic potential in various diseases. Given that bronchopulmonary dysplasia (BPD) development is closely linked to inflammation and oxidative stress, and quercetin, a robust antioxidant known to activate NRF2 and influence the ferroptosis pathway, offers promise for a wide range of age groups. Nonetheless, the specific role of quercetin in BPD remains largely unexplored. This study aims to uncover the target role of quercetin in BPD through a combination of network pharmacology, molecular docking, computer analyses, and experimental evaluations.


Assuntos
Displasia Broncopulmonar , Ferroptose , Hiperóxia , Animais , Recém-Nascido , Humanos , Displasia Broncopulmonar/tratamento farmacológico , Displasia Broncopulmonar/metabolismo , Hiperóxia/tratamento farmacológico , Hiperóxia/metabolismo , Quercetina/farmacologia , Quercetina/uso terapêutico , Simulação de Acoplamento Molecular , Ciclo-Oxigenase 2 , Animais Recém-Nascidos , Antioxidantes , Farmacologia em Rede
2.
BMC Pediatr ; 24(1): 238, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38570780

RESUMO

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a major complication affecting the survival rate and long-term outcomes of preterm infants. A large, prospective, multicenter cohort study was conducted to evaluate early nutritional support during the first week of life for preterm infants with a gestational age < 32 weeks and to verify nutritional risk factors related to BPD development. METHODS: A prospective multicenter cohort study of very preterm infants was conducted in 40 tertiary neonatal intensive care units across mainland China between January 1, 2020, and December 31, 2021. Preterm infants who were born at a gestational age < 32 weeks, < 72 h after birth and had a respiratory score > 4 were enrolled. Antenatal and postnatal information focusing on nutritional parameters was collected through medical systems. Statistical analyses were also performed to identify BPD risk factors. RESULTS: The primary outcomes were BPD and severity at 36 weeks postmenstrual age. A total of 1410 preterm infants were enrolled in this study. After applying the exclusion criteria, the remaining 1286 infants were included in this analysis; 614 (47.7%) infants were in the BPD group, and 672 (52.3%) were in the non-BPD group. In multivariate logistic regression model, the following six factors were identified of BPD: birth weight (OR 0.99, 95% CI 0.99-0.99; p = 0.039), day of full enteral nutrition (OR 1.03, 95% CI 1.02-1.04; p < 0.001), parenteral protein > 3.5 g/kg/d during the first week (OR 1.65, 95% CI 1.25-2.17; p < 0.001), feeding type (formula: OR 3.48, 95% CI 2.21-5.49; p < 0.001, mixed feed: OR 1.92, 95% CI 1.36-2.70; p < 0.001; breast milk as reference), hsPDA (OR 1.98, 95% CI 1.44-2.73; p < 0.001), and EUGR ats 36 weeks (OR 1.40, 95% CI 1.02-1.91; p = 0.035). CONCLUSIONS: A longer duration to achieve full enteral nutrition in very preterm infants was associated with increased BPD development. Breastfeeding was demonstrated to have a protective effect against BPD. Early and rapidly progressive enteral nutrition and breastfeeding should be promoted in very preterm infants. TRIAL REGISTRATION: The trial was registered in the Chinese Clinical Trial Registry (No. ChiCTR2000030125 on 24/02/2020) and in www.ncrcch.org (No. ISRCTN84167642 on 25/02/2020).


Assuntos
Displasia Broncopulmonar , Doenças do Prematuro , Síndrome do Desconforto Respiratório , Lactente , Recém-Nascido , Humanos , Feminino , Gravidez , Recém-Nascido Prematuro , Displasia Broncopulmonar/terapia , Estudos de Coortes , Estudos Prospectivos , Idade Gestacional , Retardo do Crescimento Fetal , Nutrição Enteral
3.
J Clin Invest ; 134(6)2024 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-38488000

RESUMO

Premature birth disrupts normal lung development and places infants at risk for bronchopulmonary dysplasia (BPD), a disease disrupting lung health throughout the life of an individual and that is increasing in incidence. The TGF-ß superfamily has been implicated in BPD pathogenesis, however, what cell lineage it impacts remains unclear. We show that TGFbr2 is critical for alveolar epithelial (AT1) cell fate maintenance and function. Loss of TGFbr2 in AT1 cells during late lung development leads to AT1-AT2 cell reprogramming and altered pulmonary architecture, which persists into adulthood. Restriction of fetal lung stretch and associated AT1 cell spreading through a model of oligohydramnios enhances AT1-AT2 reprogramming. Transcriptomic and proteomic analyses reveal the necessity of TGFbr2 expression in AT1 cells for extracellular matrix production. Moreover, TGF-ß signaling regulates integrin transcription to alter AT1 cell morphology, which further impacts ECM expression through changes in mechanotransduction. These data reveal the cell intrinsic necessity of TGF-ß signaling in maintaining AT1 cell fate and reveal this cell lineage as a major orchestrator of the alveolar matrisome.


Assuntos
Displasia Broncopulmonar , Alvéolos Pulmonares , Humanos , Camundongos , Animais , Recém-Nascido , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/metabolismo , Alvéolos Pulmonares/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Mecanotransdução Celular , Proteômica , Células Epiteliais Alveolares , Pulmão/patologia , Diferenciação Celular , Matriz Extracelular/metabolismo , Displasia Broncopulmonar/patologia , Transcrição Gênica
4.
NPJ Biofilms Microbiomes ; 10(1): 32, 2024 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-38553470

RESUMO

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 , Biomarcadores
5.
Int J Mol Sci ; 25(5)2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38474125

RESUMO

Neonatal disorders, particularly those resulting from prematurity, pose a major challenge in health care and have a significant impact on infant mortality and long-term child health. The limitations of current therapeutic strategies emphasize the need for innovative treatments. New cell-free technologies utilizing extracellular vesicles (EVs) offer a compelling opportunity for neonatal therapy by harnessing the inherent regenerative capabilities of EVs. These nanoscale particles, secreted by a variety of organisms including animals, bacteria, fungi and plants, contain a repertoire of bioactive molecules with therapeutic potential. This review aims to provide a comprehensive assessment of the therapeutic effects of EVs and mechanistic insights into EVs from stem cells, biological fluids and non-animal sources, with a focus on common neonatal conditions such as hypoxic-ischemic encephalopathy, respiratory distress syndrome, bronchopulmonary dysplasia and necrotizing enterocolitis. This review summarizes evidence for the therapeutic potential of EVs, analyzes evidence of their mechanisms of action and discusses the challenges associated with the implementation of EV-based therapies in neonatal clinical practice.


Assuntos
Displasia Broncopulmonar , Vesículas Extracelulares , Doenças do Recém-Nascido , Humanos , Recém-Nascido , Lactente , Animais , Criança , Células-Tronco , Doenças do Recém-Nascido/terapia , Displasia Broncopulmonar/terapia , Recém-Nascido Prematuro
6.
Stem Cell Res Ther ; 15(1): 80, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38486338

RESUMO

BACKGROUND: Despite advances in neonatal care, the incidence of Bronchopulmonary Dysplasia (BPD) remains high among preterm infants. Human induced pluripotent stem cells (hiPSCs) have shown promise in repairing injury in animal BPD models. Evidence suggests they exert their effects via paracrine mechanisms. We aim herein to assess the effectiveness of extracellular vesicles (EVs) derived from hiPSCs and their alveolar progenies (diPSCs) in attenuating hyperoxic injury in a preterm lung explant model. METHODS: Murine lung lobes were harvested on embryonic day 17.5 and maintained in air-liquid interface. Following exposure to 95% O2 for 24 h, media was supplemented with 5 × 106 particles/mL of EVs isolated from hiPSCs or diPSCs by size-exclusion chromatography. On day 3, explants were assessed using Hematoxylin-Eosin staining with mean linear intercept (MLI) measurements, immunohistochemistry, VEGFa and antioxidant gene expression. Statistical analysis was conducted using one-way ANOVA and Multiple Comparison Test. EV proteomic profiling was performed, and annotations focused on alveolarization and angiogenesis signaling pathways, as well as anti-inflammatory, anti-oxidant, and regenerative pathways. RESULTS: Exposure of fetal lung explants to hyperoxia induced airspace enlargement, increased MLI, upregulation of anti-oxidants Prdx5 and Nfe2l2 with decreased VEGFa expression. Treatment with hiPSC-EVs improved parenchymal histologic changes. No overt changes in vasculature structure were observed on immunohistochemistry in our in vitro model. However, VEGFa and anti-oxidant genes were upregulated with diPSC-EVs, suggesting a pro-angiogenic and cytoprotective potential. EV proteomic analysis provided new insights in regard to potential pathways influencing lung regeneration. CONCLUSION: This proof-of-concept in vitro study reveals a potential role for hiPSC- and diPSC-EVs in attenuating lung changes associated with prematurity and oxygen exposure. Our findings pave the way for a novel cell free approach to prevent and/or treat BPD, and ultimately reduce the global burden of the disease.


Assuntos
Displasia Broncopulmonar , Vesículas Extracelulares , Hiperóxia , Células-Tronco Pluripotentes Induzidas , Lesão Pulmonar , Animais , Camundongos , Humanos , Recém-Nascido , Hiperóxia/complicações , Hiperóxia/metabolismo , Hiperóxia/patologia , Animais Recém-Nascidos , Células-Tronco Pluripotentes Induzidas/metabolismo , Lesão Pulmonar/terapia , Lesão Pulmonar/etiologia , Antioxidantes/metabolismo , Proteômica , Recém-Nascido Prematuro , Pulmão/patologia , Displasia Broncopulmonar/terapia , Displasia Broncopulmonar/patologia , Modelos Animais de Doenças , Vesículas Extracelulares/metabolismo
7.
J Clin Invest ; 134(6)2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38488005

RESUMO

Bronchopulmonary dysplasia (BPD) is a chronic lung disease common in extreme preterm infants and is characterized by alveolar simplification. Current BPD research mainly focuses on alveolar type 2 (AT2) cells, myofibroblasts, and the endothelium. However, a notable gap exists in the involvement of AT1 cells, which constitute a majority of the alveolar surface area. In this issue of the JCI, Callaway and colleagues explored the role of TGF-ß signaling in AT1 cells for managing the AT1-to-AT2 transition and its involvement in the integration of mechanical forces with the pulmonary matrisome during development. The findings implicate AT1 cells in the pathogenesis of BPD.


Assuntos
Displasia Broncopulmonar , Animais , Lactente , Recém-Nascido , Humanos , Displasia Broncopulmonar/genética , Displasia Broncopulmonar/patologia , Animais Recém-Nascidos , Recém-Nascido Prematuro , Pulmão/patologia , Fator de Crescimento Transformador beta
8.
J Biochem Mol Toxicol ; 38(4): e23680, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38511245

RESUMO

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/metabolismo
9.
Early Hum Dev ; 191: 105976, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38452632

RESUMO

BACKGROUND: Patent ductus arteriosus (PDA) in premature infants is associated with adverse clinical outcomes. Mode and timing of treatment are still controversial. Data are limited in the most extremely premature infants <26 weeks of gestational age (GA), where clinical problems are most significant and patients are most vulnerable. AIMS: To investigate whether different approaches to surgical closure of PDA in two large Swedish centers has an impact on clinical outcomes including mortality in extremely preterm infants born <26 weeks GA. STUDY DESIGN: Retrospective, two-center, cohort study. SUBJECTS: Infants born at 22+0-25+6 weeks GA between 2010 and 2016 at Uppsala University Children's Hospital (UUCH; n = 228) and Queen Silvia Children's Hospital Gothenburg (QSCHG; n = 220). MAIN OUTCOME MEASURES: Survival, bronchopulmonary dysplasia (BPD), and retinopathy of prematurity (ROP). RESULTS: Surgical closure of PDA was more common and performed earlier at QSCHG (50 % vs 16 %; median age 11 vs 44 days; p < 0.01). Survival was similar in both centres. There was a higher incidence of severe BPD and longer duration of mechanical ventilation at UUCH (p < 0.01). There was a higher incidence of ROP, IVH and sepsis at QSCH (p < 0.05, p < 0.01 and p < 0.01). A sub-group analysis matching all surgically treated infants at QSCHG with infants at UUCH with the same GA showed similar results as the total cohort. CONCLUSION: Earlier and higher rate of surgical PDA closure in this cohort of extremely preterms born <26 weeks GA did not impact mortality but was associated with lower rates of severe BPD and higher rates of severe ROP.


Assuntos
Displasia Broncopulmonar , Permeabilidade do Canal Arterial , Retinopatia da Prematuridade , Lactente , Feminino , Criança , Recém-Nascido , Humanos , Lactente Extremamente Prematuro , Permeabilidade do Canal Arterial/epidemiologia , Permeabilidade do Canal Arterial/cirurgia , Idade Gestacional , Estudos Retrospectivos , Estudos de Coortes , Displasia Broncopulmonar/epidemiologia , Displasia Broncopulmonar/complicações , Retinopatia da Prematuridade/epidemiologia , Retinopatia da Prematuridade/cirurgia
10.
Exp Cell Res ; 437(1): 113997, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38508328

RESUMO

Bronchopulmonary dysplasia (BPD) is characterized by shortened secondary septa and fewer, larger alveoli. Elastin deposition to the distal tips of the secondary septa is critical for elongation of the secondary septa. Alveolar myofibroblasts, which are thought to migrate to the septal tips during alveolarization, are mainly responsible for elastin production and deposition. Antenatal exposure to inflammation induces abnormal elastin deposition, thereby increasing the risk of developing BPD. Here, we found that lipopolysaccharide (LPS) significantly increased the expression of transforming growth factor-α (TGF-α) in an LPS-induced rat model of BPD and in LPS-treated human pulmonary epithelial cells (BEAS-2B). In addition, in vitro experiments suggested that LPS upregulated TGF-α expression via toll-like receptor 4 (TLR4)/tumor necrosis factor α-converting enzyme (TACE) signaling. Increased TGF-α levels via its receptor epidermal growth factor receptor (EGFR)-induced lysyl oxidase (LOX) overactivation and cell division cycle 42 (Cdc42) activity inhibition of myofibroblasts. Similarly, in vivo LOX overactivation and inhibition of Cdc42 activity were observed in the lungs of LPS-exposed pups. LOX overactivation led to abnormal elastin deposition, and inhibition of Cdc42 activity disturbed the directional migration of myofibroblasts and disrupted elastin localization. Most importantly, the EGFR inhibitor erlotinib partially rescued LOX overactivation and Cdc42 activity inhibition, and improved elastin deposition and alveolar development in antenatal LPS-treated rats. Taken together, our data suggest that TGF-α/EGFR signaling is critically involved in the regulation of elastin deposition and represents a novel therapeutic target.


Assuntos
Displasia Broncopulmonar , Lipopolissacarídeos , Gravidez , Recém-Nascido , Animais , Ratos , Feminino , Humanos , Lipopolissacarídeos/farmacologia , Fator de Crescimento Transformador alfa , Pulmão/metabolismo , Elastina , Displasia Broncopulmonar/induzido quimicamente , Displasia Broncopulmonar/metabolismo , Receptores ErbB/metabolismo
11.
Heart Lung ; 65: 109-115, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38471331

RESUMO

BACKGROUND: Bronchopulmonary dysplasia (BPD) is the most common pulmonary complication in preterm infants. OBJECTIVES: The study aimed to explore the effects of bradycardia, hypoxemia, and early intubation on BPD in very preterm infants. METHODS: This is a prospective observational cohort study. Preterm infants with a mean gestational age of 28.67 weeks were recruited from two level III neonatal intensive care units (NICUs) in Taiwan. Continuous electrocardiography was used to monitor heart rates and oxygen saturation (SpO2). Infants were monitored for heart rates of <100 beats per minute and SpO2 levels of <90 % lasting for 30 s. Generalized estimating equations were used to analyze the effects of bradycardia, hypoxemia, and early intubation on BPD in very preterm infants. Model fit was visually assessed using receiver operating characteristic curve analysis. RESULTS: Bradycardia, hypoxemia, and early intubation significantly increased the odds of BPD among the preterm infants (N = 39) during NICU stay; the odds ratios for bradycardia, hypoxemia, and early intubation for BPD versus non-BPD were 1.058, 1.013, and 29.631, respectively (all p < 0.05). A model combining bradycardia, hypoxemia, and early intubation accurately predicted BPD development (area under the curve = 0.919). CONCLUSIONS: Bradycardia, hypoxemia, and early intubation significantly increased the odds of BPD among very preterm infants during NICU stay. The model combining bradycardia, hypoxemia, and early intubation accurately predicted BPD development.


Assuntos
Displasia Broncopulmonar , Doenças do Prematuro , Lactente , Recém-Nascido , Humanos , Displasia Broncopulmonar/complicações , Displasia Broncopulmonar/epidemiologia , Recém-Nascido Prematuro , Bradicardia/epidemiologia , Bradicardia/etiologia , Estudos de Coortes , Hipóxia/etiologia
12.
Nutrients ; 16(6)2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38542769

RESUMO

INTRODUCTION: Breastfeeding is one of the strategies that has been shown to be effective in preventing severe forms of bronchopulmonary dysplasia (BPD). When mother's own milk (MOM) is not available, pasteurized donor milk (DM) is the best alternative. However, the evidence is inconclusive on the difference in the incidence of bronchopulmonary dysplasia (BPD) between patients fed MOM and those fed with DM. As standard DM is usually mature pooled milk donated by mothers who have delivered their babies at term, the potential benefits of preterm milk may be lost. MATERIALS AND METHODS: An observational, retrospective, single-center study was conducted in the neonatology department of a high-complexity hospital. The study included newborns <32 weeks of gestational age born between January 2020 and December 2022. When supplemental milk was needed, non-pooled preterm pasteurized donor milk (PDM) matched for gestational age and moment of lactation was used in this study, classifying preterm infants in two groups: mainly MOM (>50% of the milk) or mainly PDM (>50% of the milk). Two groups were established: those who received >50% MOM and those who received >50% PDM. They were also classified according to the diagnosis of DBP: one group included no BPD or grade 1 BPD (noBPD/1), while the other included grade 2 or 3 BPD (BPD 2-3). The objectives of this study were, firstly, to evaluate the incidence of BPD 2-3 among patients who predominantly received PDM versus MOM. Secondly, to analyze differences in the type of human milk received and its nutritional components, as well as to study the growth in patients with or without BPD. RESULTS: One hundred ninety-nine patients were included in the study. A comparison of noBPD/1 versus BPD 2-3 groups between those receiving mainly MOM versus PDM showed no significant differences (19% vs. 20%, p 0.95). PDM colostrum in BPD 2-3 compared to noBPD/1 was higher in protein content (2.24 g/100 mL (SD 0.37) vs. 2.02 g/100 mL (SD 0.29) p < 0.01), although the statistical significance decreased after adjustment for gestational age and birth weight z-score (OR 3.53 (0.86-14.51)). No differences were found in the macronutrients in the mature milk of patients feeding more than 50% PDM in both study groups. Growth of BPD 2-3 showed a greater decrease in the difference in z-scores for height at birth and at discharge compared to noBPD/1 (-1.64 vs. -0.43, p 0.03). CONCLUSIONS: The use of mainly MOM or PDM demonstrates a similar incidence of noBPD/1 or BPD 2-3. Non-pooled and matched by gestational age and time of lactation preterm donor milk can probably be an alternative when mother's own milk is not available, with a similar protective effect in the prevention of severe BPD.


Assuntos
Displasia Broncopulmonar , Nascimento Prematuro , Lactente , Feminino , Recém-Nascido , Humanos , Recém-Nascido Prematuro , Displasia Broncopulmonar/epidemiologia , Displasia Broncopulmonar/prevenção & controle , Recém-Nascido de muito Baixo Peso , Estudos Retrospectivos , Leite Humano/metabolismo , Aleitamento Materno
13.
Gene ; 910: 148337, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38432533

RESUMO

Bronchopulmonary dysplasia (BPD) is a serious chronic lung disease affecting extremely preterm infants. While mitochondrial dysfunction has been investigated in various medical conditions, limited research has explored mitochondrial DNA (mtDNA) gene mutations, specifically in BPD. This study aimed to evaluate mitochondrial mtDNA gene mutations in extremely preterm infants with BPD. In this prospective observational study, we enrolled a cohort of extremely preterm infants diagnosed with BPD. Clinical data were collected to provide comprehensive patient profiles. Peripheral blood mononuclear cells were isolated from whole-blood samples obtained within a defined timeframe. Subsequently, mtDNA extraction and sequencing using next-generation sequencing technology were performed to identify mtDNA gene mutations. Among the cohort of ten extremely preterm infants with BPD, mtDNA sequencing revealed the presence of mutations in seven patients, resulting in a total of twenty-one point mutations. Notably, many of these mutations were identified in loci associated with critical components of the respiratory chain complexes, vital for proper mitochondrial function and cellular energy production. This pilot study provides evidence of mtDNA point mutations in a subset of extremely preterm infants with BPD. These findings suggest a potential association between mitochondrial dysfunction and the pathogenesis of BPD. Further extensive investigations are warranted to unravel the mechanisms underlying mtDNA mutations in BPD.


Assuntos
Displasia Broncopulmonar , Doenças Mitocondriais , Lactente , Humanos , Recém-Nascido , Lactente Extremamente Prematuro , Displasia Broncopulmonar/genética , Leucócitos Mononucleares , Projetos Piloto , Mutação , DNA Mitocondrial/genética
14.
BMC Pulm Med ; 24(1): 130, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38491484

RESUMO

Bronchopulmonary dysplasia (BPD) is characterized by alveolar dysplasia, and evidence indicates that interferon regulatory factor 4 (IRF4) is involved in the pathogenesis of various inflammatory lung diseases. Nonetheless, the significance and mechanism of IRF4 in BPD remain unelucidated. Consequently, we established a mouse model of BPD through hyperoxia exposure, and ELISA was employed to measure interleukin-17 A (IL-17 A) and interleukin-6 (IL-6) expression levels in lung tissues. Western blotting was adopted to determine the expression of IRF4, surfactant protein C (SP-C), and podoplanin (T1α) in lung tissues. Flow cytometry was utilized for analyzing the percentages of FOXP3+ regulatory T cells (Tregs) and FOXP3+RORγt+ Tregs in CD4+ T cells in lung tissues to clarify the underlying mechanism. Our findings revealed that BPD mice exhibited disordered lung tissue structure, elevated IRF4 expression, decreased SP-C and T1α expression, increased IL-17 A and IL-6 levels, reduced proportion of FOXP3+ Tregs, and increased proportion of FOXP3+RORγt+ Tregs. For the purpose of further elucidating the effect of IRF4 on Treg phenotype switching induced by hyperoxia in lung tissues, we exposed neonatal mice with IRF4 knockout to hyperoxia. These mice exhibited regular lung tissue structure, increased proportion of FOXP3+ Tregs, reduced proportion of FOXP3+RORγt+ Tregs, elevated SP-C and T1α expression, and decreased IL-17 A and IL-6 levels. In conclusion, our findings demonstrate that IRF4-mediated Treg phenotype switching in lung tissues exacerbates alveolar epithelial cell injury under hyperoxia exposure.


Assuntos
Displasia Broncopulmonar , Hiperóxia , Animais , Camundongos , Células Epiteliais Alveolares/patologia , Linfócitos T Reguladores/metabolismo , Interleucina-17/metabolismo , Interleucina-6/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Hiperóxia/complicações , Displasia Broncopulmonar/metabolismo , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Fenótipo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo
15.
J Matern Fetal Neonatal Med ; 37(1): 2332914, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38522947

RESUMO

BACKGROUND: Bronchopulmonary dysplasia (BPD) has a lasting effect on the respiratory function of infants, imposing chronic health burdens. BPD is influenced by various prenatal, postnatal, and genetic factors. This study explored the connection between BPD and home oxygen therapy (HOT), and then we examined the association between HOT and a specific single-nucleotide polymorphism (SNP) in the hyaluronan and proteoglycan link protein 1 (HAPLN1) gene among premature Japanese infants. MATERIALS AND METHODS: Prenatal and postnatal data from 212 premature infants were collected and analyzed by four SNPs (rs975563, rs10942332, rs179851, and rs4703570) around HAPLN1 using the TaqMan polymerase chain reaction method. The clinical characteristics and genotype frequencies of HAPLN1 were assessed and compared between HOT and non-HOT groups. RESULTS: Individuals with AA/AC genotypes in the rs4703570 SNP exhibited significantly higher HOT rates at discharge than those with CC homozygotes (odds ratio, 1.20, 95% confidence interval, 1.07-1.35, p = .038). A logistic regression analysis determined that CC homozygotes in the rs4703570 SNP did not show a statistically significant independent association with HOT at discharge. CONCLUSIONS: Although our study did not reveal a correlation between HAPLN1 and the onset of BPD, we observed that individuals with CC homozygosity at the rs4703570 SNP exhibit a reduced risk of HOT.


Assuntos
Displasia Broncopulmonar , Proteínas da Matriz Extracelular , Ácido Hialurônico , Recém-Nascido , Lactente , Feminino , Humanos , Gravidez , Displasia Broncopulmonar/genética , Displasia Broncopulmonar/terapia , Japão , Recém-Nascido Prematuro , Proteoglicanas/genética , Oxigênio
16.
Ital J Pediatr ; 50(1): 56, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38528568

RESUMO

BACKGROUND: Respiratory Syncytial Virus (RSV) infections may lead to severe consequences in infants born preterm with breathing problems (such as bronchopulmonary dysplasia (BPD) and respiratory distress syndrome (RDS)) or congenital heart diseases (CHD). Since studies investigating the influence of different gestational age (WGA) and concomitant specific comorbidities on the burden of RSV infections are scarce, the present study aimed to better characterize these high-risk populations in the Italian context. METHODS: This retrospective, longitudinal and record-linkage cohort study involved infants born between 2017 and 2019 in Lazio Region (Italy) and is based on data extracted from administrative databases. Each infant was exclusively included in one of the following cohorts: (1) BPD-RDS (WGA ≤35 with or without CHD) or (2) CHD (without BPD and/or RDS) or (3) Preterm (WGA ≤35 without BPD (and/or RDS) or CHD). Each cohort was followed for 12 months from birth. Information related to sociodemographic at birth, and RSV and Undetermined Respiratory Agents (URA) hospitalizations and drug consumption at follow-up were retrieved and described. RESULTS: A total of 8,196 infants were selected and classified as 1,084 BPD-RDS, 3,286 CHD and 3,826 Preterm. More than 30% of the BPD-RDS cohort was composed by early preterm infants (WGA ≤ 29) in contrast to the Preterm cohort predominantly constitute by moderate preterm infants (98.2%), while CHD infants were primarily born at term (83.9%). At follow-up, despite the cohorts showed similar proportions of RSV hospitalizations, in BPD-RDS cohort hospitalizations were more frequently severe compared to those occurred in the Preterm cohort (p<0.01), in the BPD-RDS cohort was also found the highest proportion of URA hospitalizations (p<0.0001). In addition, BPD-RDS infants, compared to those of the remaining cohorts, received more frequently prophylaxis with palivizumab (p<0.0001) and were more frequently treated with adrenergics inhalants, and glucocorticoids for systemic use. CONCLUSIONS: The assessment of the study clinical outcomes highlighted that, the demographic and clinical characteristics at birth of the study cohorts influence their level of vulnerability to RSV and URA infections. As such, continuous monitoring of these populations is necessary in order to ensure a timely organization of health care system able to respond to their needs in the future.


Assuntos
Displasia Broncopulmonar , Cardiopatias Congênitas , Infecções por Vírus Respiratório Sincicial , Lactente , Recém-Nascido , Humanos , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Recém-Nascido Prematuro , Estudos Retrospectivos , Estudos de Coortes , Palivizumab/uso terapêutico , Hospitalização , Cardiopatias Congênitas/epidemiologia , Displasia Broncopulmonar/epidemiologia , Antivirais/uso terapêutico
17.
PLoS One ; 19(3): e0300817, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38536822

RESUMO

INTRODUCTION: Bronchopulmonary dysplasia (BPD) poses a substantial global health burden. Individualized treatment strategies based on early prediction of the development of BPD can mitigate preterm birth complications; however, previously suggested predictive models lack early postnatal applicability. We aimed to develop predictive models for BPD and mortality based on immediate postnatal clinical data. METHODS: Clinical information on very preterm and very low birth weight infants born between 2008 and 2018 was extracted from a nationwide Japanese database. The gradient boosting decision trees (GBDT) algorithm was adopted to predict BPD and mortality, using predictors within the first 6 h postpartum. We assessed the temporal validity and evaluated model adequacy using Shapley additive explanations (SHAP) values. RESULTS: We developed three predictive models using data from 39,488, 39,096, and 40,291 infants to predict "death or BPD," "death or severe BPD," and "death before discharge," respectively. These well-calibrated models achieved areas under the receiver operating characteristic curve of 0.828 (95% CI: 0.828-0.828), 0.873 (0.873-0.873), and 0.887 (0.887-0.888), respectively, outperforming the multivariable logistic regression models. SHAP value analysis identified predictors of BPD, including gestational age, size at birth, male sex, and persistent pulmonary hypertension. In SHAP value-based case clustering, the "death or BPD" prediction model stratified infants by gestational age and persistent pulmonary hypertension, whereas the other models for "death or severe BPD" and "death before discharge" commonly formed clusters of low mortality, extreme prematurity, low Apgar scores, and persistent pulmonary hypertension of the newborn. CONCLUSIONS: GBDT models for predicting BPD and mortality, designed for use within 6 h postpartum, demonstrated superior prognostic performance. SHAP value-based clustering, a data-driven approach, formed clusters of clinical relevance. These findings suggest the efficacy of a GBDT algorithm for the early postnatal prediction of BPD.


Assuntos
Displasia Broncopulmonar , Hipertensão Pulmonar , Nascimento Prematuro , Lactente , Feminino , Humanos , Recém-Nascido , Gravidez , Displasia Broncopulmonar/diagnóstico , Displasia Broncopulmonar/epidemiologia , Displasia Broncopulmonar/complicações , Japão/epidemiologia , Lactente Extremamente Prematuro , Hipertensão Pulmonar/complicações , Recém-Nascido de muito Baixo Peso , Idade Gestacional , Árvores de Decisões
18.
BMC Pediatr ; 24(1): 157, 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38443865

RESUMO

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/etiologia
19.
J Neonatal Perinatal Med ; 17(1): 21-30, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38393924

RESUMO

BACKGROUND: Few studies characterize feeding performance in the NICU when predicting neurodevelopmental outcomes. Our objective was to investigate the relationship between time to full oral feeds (FULL-PO) and neurodevelopmental and feeding outcomes in the first 2 years in preterm infants admitted to the NICU. METHODS: This retrospective study included infants born between 01/01/2014-07/31/2017, gestational age < 32 weeks and/or birth weight < 1500 g. We examined feeding difficulties, cerebral palsy, and Bayley scores for those reaching FULL-PO at a post menstrual age (PMA)≤38.0 weeks (EARLY) vs.>38.0 weeks (LATE). Additionally, the oral feeding achieved at various timepoints between 36- and 42-weeks postmenstrual age (PMA) was measured to construct a timeline of oral feeding acquisition. RESULTS: Of 192 infants, 147(77%) achieved FULL-PO EARLY and 45(23%) LATE. Comorbidities and length of stay were higher and unadjusted Bayley scores were lower at 12 months corrected age (CA) and 24 months chronological age (CH) in the LATE group. Feeding difficulties were higher in the LATE group at 24 months CH. Infants born < 27-28 weeks GA were more likely to achieve oral feeding at a later PMA. Infants with bronchopulmonary dysplasia (BPD) had significant feeding and developmental delays. CONCLUSIONS: Establishing full oral feeds by 38.0 weeks PMA may be used as a predictor for feeding difficulties at 24 months CH. Infants born < 27-28 weeks GA and those with BPD are more likely to take extended amounts of time to achieve full oral feeding and need additional feeding support. Infants with BPD are high risk for neurodevelopmental delays.


Assuntos
Displasia Broncopulmonar , Recém-Nascido Prematuro , Lactente , Recém-Nascido , Humanos , Pré-Escolar , Estudos Retrospectivos , Seguimentos , Idade Gestacional , Peso ao Nascer , Displasia Broncopulmonar/epidemiologia , Recém-Nascido de muito Baixo Peso
20.
Early Hum Dev ; 190: 105950, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38301336

RESUMO

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 Gestacional
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