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1.
J Vis Exp ; (168)2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33616107

RESUMO

Fetal tracheal occlusion (TO), an established treatment modality, promotes fetal lung growth and survival in severe congenital diaphragmatic hernia (CDH). Following TO, retention of the secreted epithelial fluid increases luminal pressure and induces lung growth. Various animal models have been defined to understand the pathophysiology of CDH and TO. All have their own advantages and disadvantages such as the difficulty of the technique, the size of the animal, cost, high mortality rates, and the availability of genetic tools. Herein, a novel transuterine model of murine fetal TO is described. Pregnant mice were anesthetized, and the uterus exposed via a midline laparotomy. The trachea of selected fetuses were ligated with a single transuterine suture placed behind the trachea, one carotid artery, and one jugular vein. The dam was closed and allowed to recover. Fetuses were collected just before parturition. Lung to body weight ratio in TO fetuses was higher than that in control fetuses. This model provides researchers with a new tool to study the impact of both TO and increased luminal pressure on lung development.


Assuntos
Embrião de Mamíferos/cirurgia , Fetoscopia/métodos , Feto/cirurgia , Hérnias Diafragmáticas Congênitas/cirurgia , Pulmão/crescimento & desenvolvimento , Modelos Animais , Traqueia/cirurgia , Animais , Feminino , Pulmão/embriologia , Camundongos , Gravidez
2.
Respir Res ; 22(1): 26, 2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33478486

RESUMO

BACKGROUND: The epithelial-mesenchymal signaling involving SHH-FOXF1, TBX4-FGF10, and TBX2 pathways is an essential transcriptional network operating during early lung organogenesis. However, precise regulatory interactions between different genes and proteins in this pathway are incompletely understood. METHODS: To identify TBX2 and TBX4 genome-wide binding sites, we performed chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq) in human fetal lung fibroblasts IMR-90. RESULTS: We identified 14,322 and 1,862 sites strongly-enriched for binding of TBX2 and TBX4, respectively, 43.95% and 18.79% of which are located in the gene promoter regions. Gene Ontology, pathway enrichment, and DNA binding motif analyses revealed a number of overrepresented cues and transcription factor binding motifs relevant for lung branching that can be transcriptionally regulated by TBX2 and/or TBX4. In addition, TBX2 and TBX4 binding sites were found enriched around and within FOXF1 and its antisense long noncoding RNA FENDRR, indicating that the TBX4-FGF10 cascade may directly interact with the SHH-FOXF1 signaling. CONCLUSIONS: We highlight the complexity of transcriptional network driven by TBX2 and TBX4 and show that disruption of this crosstalk during morphogenesis can play a substantial role in etiology of lung developmental disorders.


Assuntos
Sequenciamento de Cromatina por Imunoprecipitação/métodos , Fator 10 de Crescimento de Fibroblastos/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Proteínas Hedgehog/metabolismo , Pulmão/metabolismo , Proteínas com Domínio T/metabolismo , Desenvolvimento Fetal/fisiologia , Fator 10 de Crescimento de Fibroblastos/genética , Fatores de Transcrição Forkhead/genética , Proteínas Hedgehog/genética , Humanos , Pulmão/irrigação sanguínea , Pulmão/embriologia , Ligação Proteica/imunologia , Proteínas com Domínio T/genética
3.
Nucleic Acids Res ; 49(1): 322-339, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33330905

RESUMO

Many APOBEC cytidine deaminase members are known to induce 'off-target' cytidine deaminations in 5'TC motifs in genomic DNA that contribute to cancer evolution. In this report, we characterized APOBEC1, which is a possible cancer related APOBEC since APOBEC1 mRNA is highly expressed in certain types of tumors, such as lung adenocarcinoma. We found a low level of APOBEC1-induced DNA damage, as measured by γH2AX foci, in genomic DNA of a lung cancer cell line that correlated to its inability to compete in vitro with replication protein A (RPA) for ssDNA. This suggests that RPA can act as a defense against off-target deamination for some APOBEC enzymes. Overall, the data support the model that the ability of an APOBEC to compete with RPA can better predict genomic damage than combined analysis of mRNA expression levels in tumors and analysis of mutation signatures.


Assuntos
Desaminase APOBEC-1/antagonistas & inibidores , DNA de Cadeia Simples/metabolismo , Proteínas de Neoplasias/metabolismo , Proteína de Replicação A/metabolismo , Desaminase APOBEC-1/metabolismo , Ligação Competitiva , Linhagem Celular , Linhagem Celular Tumoral , Citidina/metabolismo , Dano ao DNA , Replicação do DNA , DNA de Neoplasias/química , DNA de Neoplasias/metabolismo , DNA de Cadeia Simples/química , Desaminação , Difusão Facilitada , Histonas/análise , Humanos , Pulmão/citologia , Pulmão/embriologia , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias/genética , Neoplasias/patologia , Especificidade de Órgãos , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Proteínas Recombinantes de Fusão/metabolismo , Proteína de Replicação A/genética
4.
Cochrane Database Syst Rev ; 12: CD004454, 2020 12 25.
Artigo em Inglês | MEDLINE | ID: mdl-33368142

RESUMO

BACKGROUND: Respiratory morbidity including respiratory distress syndrome (RDS) is a serious complication of preterm birth and the primary cause of early neonatal mortality and disability. Despite early evidence indicating a beneficial effect of antenatal corticosteroids on fetal lung maturation and widespread recommendations to use this treatment in women at risk of preterm delivery, some uncertainty remains about their effectiveness particularly with regard to their use in lower-resource settings, different gestational ages and high-risk obstetric groups such as women with hypertension or multiple pregnancies. This updated review (which supersedes an earlier review Crowley 1996) was first published in 2006 and subsequently updated in 2017. OBJECTIVES: To assess the effects of administering a course of corticosteroids to women prior to anticipated preterm birth (before 37 weeks of pregnancy) on fetal and neonatal morbidity and mortality, maternal mortality and morbidity, and on the child in later life. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (3 September 2020), ClinicalTrials.gov, the databases that contribute to the WHO International Clinical Trials Registry Platform (ICTRP) (3 September 2020), and reference lists of the retrieved studies. SELECTION CRITERIA: We considered all randomised controlled comparisons of antenatal corticosteroid administration with placebo, or with no treatment, given to women with a singleton or multiple pregnancy, prior to anticipated preterm delivery (elective, or following rupture of membranes or spontaneous labour), regardless of other co-morbidity, for inclusion in this review. DATA COLLECTION AND ANALYSIS: We used standard Cochrane Pregnancy and Childbirth methods for data collection and analysis. Two review authors independently assessed trials for inclusion, assessed risk of bias, evaluated trustworthiness based on predefined criteria developed by Cochrane Pregnancy and Childbirth, extracted data and checked them for accuracy, and assessed the certainty of the evidence using the GRADE approach. Primary outcomes included perinatal death, neonatal death, RDS, intraventricular haemorrhage (IVH), birthweight, developmental delay in childhood and maternal death. MAIN RESULTS: We included 27 studies (11,272 randomised women and 11,925 neonates) from 20 countries. Ten trials (4422 randomised women) took place in lower- or middle-resource settings. We removed six trials from the analysis that were included in the previous version of the review; this review only includes trials that meet our pre-defined trustworthiness criteria. In 19 trials the women received a single course of steroids. In the remaining eight trials repeated courses may have been prescribed. Fifteen trials were judged to be at low risk of bias, two had a high risk of bias in two or more domains and we ten trials had a high risk of bias due to lack of blinding (placebo was not used in the control arm. Overall, the certainty of evidence was moderate to high, but it was downgraded for IVH due to indirectness; for developmental delay due to risk of bias and for maternal adverse outcomes (death, chorioamnionitis and endometritis) due to imprecision. Neonatal/child outcomes Antenatal corticosteroids reduce the risk of: - perinatal death (risk ratio (RR) 0.85, 95% confidence interval (CI) 0.77 to 0.93; 9833 infants; 14 studies; high-certainty evidence; 2.3% fewer, 95% CI 1.1% to 3.6% fewer), - neonatal death (RR 0.78, 95% CI 0.70 to 0.87; 10,609 infants; 22 studies; high-certainty evidence; 2.6% fewer, 95% CI 1.5% to 3.6% fewer), - respiratory distress syndrome (RR 0.71, 95% CI 0.65 to 0.78; 11,183 infants; studies = 26; high-certainty evidence; 4.3% fewer, 95% CI 3.2% to 5.2% fewer). Antenatal corticosteroids probably reduce the risk of IVH (RR 0.58, 95% CI 0.45 to 0.75; 8475 infants; 12 studies; moderate-certainty evidence; 1.4% fewer, 95% CI 0.8% to1.8% fewer), and probably have little to no effect on birthweight (mean difference (MD) -14.02 g, 95% CI -33.79 to 5.76; 9551 infants; 19 studies; high-certainty evidence). Antenatal corticosteroids probably lead to a reduction in developmental delay in childhood (RR 0.51, 95% CI 0.27 to 0.97; 600 children; 3 studies; moderate-certainty evidence; 3.8% fewer, 95% CI 0.2% to 5.7% fewer). Maternal outcomes Antenatal corticosteroids probably result in little to no difference in maternal death (RR 1.19, 95% CI 0.36 to 3.89; 6244 women; 6 studies; moderate-certainty evidence; 0.0% fewer, 95% CI 0.1% fewer to 0.5% more), chorioamnionitis (RR 0.86, 95% CI 0.69 to 1.08; 8374 women; 15 studies; moderate-certainty evidence; 0.5% fewer, 95% CI 1.1% fewer to 0.3% more), and endometritis (RR 1.14, 95% CI 0.82 to 1.58; 6764 women; 10 studies; moderate-certainty; 0.3% more, 95% CI 0.3% fewer to 1.1% more) The wide 95% CIs in all of these outcomes include possible benefit and possible harm. AUTHORS' CONCLUSIONS: Evidence from this updated review supports the continued use of a single course of antenatal corticosteroids to accelerate fetal lung maturation in women at risk of preterm birth. Treatment with antenatal corticosteroids reduces the risk of perinatal death, neonatal death and RDS and probably reduces the risk of IVH. This evidence is robust, regardless of resource setting (high, middle or low). Further research should focus on variations in the treatment regimen, effectiveness of the intervention in specific understudied subgroups such as multiple pregnancies and other high-risk obstetric groups, and the risks and benefits in the very early or very late preterm periods. Additionally, outcomes from existing trials with follow-up into childhood and adulthood are needed in order to investigate any longer-term effects of antenatal corticosteroids. We encourage authors of previous studies to provide further information which may answer any remaining questions about the use of antenatal corticosteroids without the need for further randomised controlled trials. Individual patient data meta-analyses from published trials are likely to provide answers for most of the remaining clinical uncertainties.


Assuntos
Corticosteroides/administração & dosagem , Maturidade dos Órgãos Fetais/efeitos dos fármacos , Pulmão/embriologia , Nascimento Prematuro , Cuidado Pré-Natal/métodos , Síndrome do Desconforto Respiratório do Recém-Nascido/prevenção & controle , Betametasona/administração & dosagem , Viés , Hemorragia Cerebral Intraventricular/prevenção & controle , Deficiências do Desenvolvimento/epidemiologia , Dexametasona/administração & dosagem , Feminino , Humanos , Hidrocortisona/administração & dosagem , Recém-Nascido , Pulmão/efeitos dos fármacos , Morte Materna , Morte Perinatal , Gravidez , Ensaios Clínicos Controlados Aleatórios como Assunto
5.
Pediatrics ; 146(4)2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32938776

RESUMO

For healthy individuals, it is increasingly accepted that lung function follows along an individual percentile established early in life and that the level of maximal function reached as a young adult can affect the subsequent development of lung disease that occurs with the normal aging process. This emphasizes the need to maximize early lung function. The trajectories of lung function are at least partially established by perinatal factors, including prematurity and in utero exposures (tobacco exposure, nutrition, inflammation, etc), although they can also be affected by a variety of additional factors and exposures throughout the life span. Whether lung function trajectories can be impacted or reset if established under suboptimal conditions is an unanswered question, offering new avenues for research. In this review, we will summarize important articles outlining lung function trajectories and linking pediatric lung function tests to adult lung function tests decades later. We will focus on perinatal factors and outline progress and opportunities for further investigation into the potential ability to reset trajectories to impact long-term lung health.


Assuntos
Pneumopatias/fisiopatologia , Pulmão/fisiologia , Criança , Feminino , Humanos , Lactente , Recém-Nascido Prematuro , Doenças do Prematuro , Pulmão/embriologia , Pneumopatias/prevenção & controle , Assistência Perinatal , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Testes de Função Respiratória
6.
Ann Ist Super Sanita ; 56(3): 378-389, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32959805

RESUMO

INTRODUCTION: The study was implemented to provide guidance to decision-makers and clinicians by describing hospital care offered to women who gave birth with confirmed SARS-CoV-2 infection. MATERIALS AND METHODS: National population-based prospective cohort study involving all women with confirmed SARS-CoV-2 infection who gave birth between February 25 and April 22, 2020 in any Italian hospital. RESULTS: The incidence rate of confirmed SARS-CoV-2 infection in women who gave birth was 2.1 per 1000 maternities at a national level and 6.9/1000 in the Lombardy Region. Overall one third of the women developed a pneumonia and 49.7% assumed at least one drug against SARS-CoV-2 infection. Caesarean rate was 32.9%, no mothers nor newborns died. Six percent of the infants tested positive for SARS-CoV-2 at birth. CONCLUSIONS: Clinical features and outcomes of COVID-19 in women who gave birth are similar to those described for the general population, most women developing mild to moderate illness.


Assuntos
Betacoronavirus , Infecções por Coronavirus/epidemiologia , Pandemias , Pneumonia Viral/epidemiologia , Complicações Infecciosas na Gravidez/epidemiologia , Corticosteroides/uso terapêutico , Adulto , Cesárea/estatística & dados numéricos , Infecções por Coronavirus/congênito , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/terapia , Infecções por Coronavirus/transmissão , Emigrantes e Imigrantes/estatística & dados numéricos , Feminino , Maturidade dos Órgãos Fetais/efeitos dos fármacos , Humanos , Incidência , Recém-Nascido , Transmissão Vertical de Doença Infecciosa/estatística & dados numéricos , Itália/epidemiologia , Pulmão/embriologia , Pneumonia Viral/congênito , Pneumonia Viral/terapia , Pneumonia Viral/transmissão , Gravidez , Complicações Infecciosas na Gravidez/virologia , Resultado da Gravidez , Nascimento Prematuro/epidemiologia , Utilização de Procedimentos e Técnicas , Estudos Prospectivos , Natimorto/epidemiologia
7.
Toxicol Lett ; 333: 222-231, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32798538

RESUMO

Despite many hypothesized benefits of dietary isoflavone genistein (GEN) deriving from soy-based products, questions surrounding GEN's developmental effects are increasing. To understand if in utero GEN exposure modulated postnatal respiratory allergies in the middle age, we conducted a time course study in the B6C3F1 offspring (PND 240-330) using a common household allergen (house dust mites: HDM; 10 µg/mouse for PND 240 and 290, and 50 µg/mouse for PND 330, a middle age in mice) following intranasal instillation, a physiological route of allergen exposure. GEN was administered to dams by gavage from gestational day 14 to parturition at a physiologically relevant dose (20 mg/kg body weight). Female and male offspring were sensitized with HDM allergens beginning about one month prior to sacrifice followed by challenges with three weekly dosings of HDM extracts, and they were euthanized at day 3 following the final HDM exposure. In utero exposure to GEN decreased HDM allergen-induced respiratory allergy in male B6C3F1 offspring at PND 330 as reflected by decreases in airway hyperresponsiveness (e.g., Penh value), HDM-specific IgG1 (a Th2 type Ab) and the activity of eosinophil peroxidase in the lung (an indication of eosinophil recruitment to the lungs). However, in utero exposure to GEN had minimal effects on HDM allergen-induced respiratory allergy in the middle-aged female offspring. Changes in serum total IgE, HDM-specific IgE, and lung histopathology scores in both male and female offspring were not biologically significant. Overall, in utero GEN exposure exerted a protective effect on respiratory allergy in the middle-aged male, but not female, B6C3F1 offspring following later-life HDM exposures.


Assuntos
Envelhecimento/imunologia , Genisteína/farmacologia , Pulmão/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Hipersensibilidade Respiratória/prevenção & controle , Envelhecimento/sangue , Alérgenos/imunologia , Animais , Peroxidase de Eosinófilo/metabolismo , Eosinófilos/efeitos dos fármacos , Eosinófilos/enzimologia , Feminino , Genisteína/administração & dosagem , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Pulmão/embriologia , Pulmão/imunologia , Pulmão/patologia , Masculino , Exposição Materna , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Pyroglyphidae/imunologia , Hipersensibilidade Respiratória/sangue , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/patologia
8.
Nat Commun ; 11(1): 3822, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732898

RESUMO

Alveolar macrophages (AMs) derived from embryonic precursors seed the lung before birth and self-maintain locally throughout adulthood, but are regenerated by bone marrow (BM) under stress conditions. However, the regulation of AM development and maintenance remains poorly understood. Here, we show that histone deacetylase 3 (HDAC3) is a key epigenetic factor required for AM embryonic development, postnatal homeostasis, maturation, and regeneration from BM. Loss of HDAC3 in early embryonic development affects AM development starting at E14.5, while loss of HDAC3 after birth affects AM homeostasis and maturation. Single-cell RNA sequencing analyses reveal four distinct AM sub-clusters and a dysregulated cluster-specific pathway in the HDAC3-deficient AMs. Moreover, HDAC3-deficient AMs exhibit severe mitochondrial oxidative dysfunction and deteriorative cell death. Mechanistically, HDAC3 directly binds to Pparg enhancers, and HDAC3 deficiency impairs Pparg expression and its signaling pathway. Our findings identify HDAC3 as a key epigenetic regulator of lung AM development and homeostasis.


Assuntos
Histona Desacetilases/genética , Homeostase/genética , Pulmão/metabolismo , Macrófagos Alveolares/metabolismo , Animais , Apoptose/genética , Diferenciação Celular/genética , Linhagem Celular , Células Cultivadas , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica no Desenvolvimento , Ontologia Genética , Histona Desacetilases/deficiência , Histona Desacetilases/metabolismo , Pulmão/embriologia , Pulmão/crescimento & desenvolvimento , Macrófagos Alveolares/citologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos
9.
Am J Respir Crit Care Med ; 202(8): 1146-1158, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32551816

RESUMO

Rationale: Antenatal inflammation with placental dysfunction is strongly associated with high bronchopulmonary dysplasia (BPD) risk in preterm infants. Whether antenatal or postnatal HIF (hypoxia-inducible factor) augmentation can preserve lung structure and function and prevent pulmonary hypertension after intrauterine inflammation is controversial.Objectives: To determine whether antenatal or postnatal prolyl-hydroxylase inhibitor (PHi) therapy increases lung HIF expression, preserves lung growth and function, and prevents pulmonary hypertension in a rat model of chorioamnionitis-induced BPD caused by antenatal inflammation.Methods: Endotoxin (ETX) was administered to pregnant rats by intraamniotic injection at Embryonic Day 20, and pups were delivered by cesarean section at Embryonic Day 22. Selective PHi drugs, dimethyloxalylglycine or GSK360A, were administered into the amniotic space at Embryonic Day 20 or after birth by intraperitoneal injection for 2 weeks. Placentas and lung tissue were collected at birth for morphometric and Western blot measurements of HIF-1a, HIF-2a, VEGF (vascular endothelial growth factor), and eNOS (endothelial nitric oxide synthase) protein contents. At Day 14, lung function was assessed, and tissues were harvested to determine alveolarization by radial alveolar counts, pulmonary vessel density, and right ventricle hypertrophy (RVH).Measurements and Main Results: Antenatal PHi therapy preserves lung alveolar and vascular growth and lung function and prevents RVH after intrauterine ETX exposure. Antenatal administration of PHi markedly upregulates lung HIF-1a, HIF-2a, VEGF, and eNOS expression after ETX exposure.Conclusions: HIF augmentation improves lung structure and function, prevents RVH, and improves placental structure following antenatal ETX exposure. We speculate that antenatal or postnatal PHi therapy may provide novel strategies to prevent BPD due to antenatal inflammation.


Assuntos
Displasia Broncopulmonar/tratamento farmacológico , Fator 1 Induzível por Hipóxia/metabolismo , Pulmão/efeitos dos fármacos , Peptídeo PHI/farmacologia , Prenhez , Aminoácidos Dicarboxílicos/farmacologia , Animais , Animais Recém-Nascidos , Western Blotting , Displasia Broncopulmonar/metabolismo , Displasia Broncopulmonar/patologia , Modelos Animais de Doenças , Endotoxinas/efeitos adversos , Endotoxinas/farmacologia , Feminino , Fator 1 Induzível por Hipóxia/efeitos dos fármacos , Imuno-Histoquímica , Técnicas In Vitro , Injeções Intralesionais , Pulmão/embriologia , Gravidez , Cuidado Pré-Natal , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/crescimento & desenvolvimento , Circulação Pulmonar/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Valores de Referência , Testes de Função Respiratória , Técnicas de Cultura de Tecidos
10.
Life Sci ; 256: 117893, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32502539

RESUMO

AIMS: To investigate the effect and underlying mechanism of melittin and tripartite motif (TRIM) family in human embryonic lung fibroblast (HELF). MATERIALS AND METHODS: Lentiviral RNA interference vector and lentiviral overexpression vector were constructed and packaged by transfecting 293T cells; the proliferation of HELF was examined using Cell Counting Kit 8; Western blot and qRT-PCR were performed to examine protein and mRNA expression; the interaction with protein phosphatase magnesium-dependent 1A (PPM1A) was examined by Co-immunoprecipitation. KEY FINDINGS: Compared with the control group, the mRNA expression of the TRIM6, TRIM8 and TRIM47 in the IPF group significantly increased. Melittin inhibited the mRNA expression and protein expression levels of TRIM47, the HELF proliferation, the hydroxyproline levels, and the phosphorylation of Smad2/3; the interference of TRIM47 inhibited the protein expression of Vimentin, α-SMA, CTGF, the phosphorylation of Smad2/3 and the synthesis of hydroxyproline; TRIM47 overexpression elevated the phosphorylation of Smad2/3, induced ubiquitination of PPM1A and decreased the expression level of PPM1A, while TRIM47 RNA interference reversed this result. SIGNIFICANCE: Melittin has anti-fibrotic effect in HELF by directly reducing the phosphorylation of Smad2/3 or indirectly reducing the phosphorylation of Smad2/3 by decreasing the expression levels of TRIM47 whose overexpression induces ubiquitination of PPM1A.


Assuntos
Proteínas de Transporte/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patologia , Pulmão/embriologia , Meliteno/farmacologia , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Transdução de Sinais , Actinas/metabolismo , Proteínas de Transporte/sangue , Proliferação de Células/efeitos dos fármacos , Fator de Crescimento do Tecido Conjuntivo/genética , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Fibroblastos/efeitos dos fármacos , Fibrose , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hidroxiprolina/metabolismo , Proteínas de Neoplasias/sangue , Proteínas Nucleares/sangue , Fosforilação/efeitos dos fármacos , Proteína Fosfatase 2C/metabolismo , Interferência de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Ubiquitinação/efeitos dos fármacos , Vimentina/metabolismo
11.
Ecotoxicol Environ Saf ; 200: 110772, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32464444

RESUMO

Recently two-dimensional nanomaterials, such as graphene and molybdenum disulfide (MoS2), have received much attention as adsorbent materials for the effective removal of organic contaminants. MoS2 is attracting attention, not only for its chemical-physical properties, but also for its wide availability in nature as a constituent of molybdenite. The aim of this investigation was to assess the effects of different MoS2 concentrations (5 × 10-1, 5 × 10-2 and 5 × 10-3 mg/ml) on the embryonated eggs of Gallus gallus domesticus, according to Beck method. We evaluated the toxic effect of the MoS2 powder purchased at Sigma-Aldrich indicated as "received" and MoS2 powder treated via mechanical milling indicated as "ball mille". Subsequently, the embryos were sacrificed at different times of embryonic development (11th, 15th and 19th day after incubation) in order to evaluate their embryotoxic and teratogenic effects. The alterations of the embryonic development were studied by morphological and immunohistochemical analysis of the tissues. The results obtained have shown the toxicity of both powders of MoS2 with a high percentage of deaths and growth delays. Moreover, the immunohistochemical analysis performed on several tissue sections showed a strong positivity to the anti-metallothionein1 antibody only for the erythrocytes.


Assuntos
Dissulfetos/química , Dissulfetos/toxicidade , Desenvolvimento Embrionário/efeitos dos fármacos , Molibdênio/química , Molibdênio/toxicidade , Nanopartículas/química , Nanopartículas/toxicidade , Animais , Embrião de Galinha , Relação Dose-Resposta a Droga , Grafite/química , Coração/efeitos dos fármacos , Coração/embriologia , Fígado/efeitos dos fármacos , Fígado/embriologia , Fígado/patologia , Pulmão/efeitos dos fármacos , Pulmão/embriologia , Pulmão/patologia , Tamanho da Partícula , Propriedades de Superfície
12.
Med Hypotheses ; 140: 109751, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32344304

RESUMO

COVID-19 pandemic is a major challenge for global and national healthcare providers. Number of new cases is continuously increasing with an emerging trend showing worse prognosis in males in comparison to females. Based on this observation, our proposed hypothesis is that 5-alpha-reductase inhibitors, that are commonly used for BPH treatment, may be one of the factors contributing to poorer prognosis in males.


Assuntos
Inibidores de 5-alfa Redutase/efeitos adversos , Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Animais , Betacoronavirus , Finasterida/efeitos adversos , Humanos , Pulmão/efeitos dos fármacos , Pulmão/embriologia , Masculino , Pandemias , Prognóstico , Hiperplasia Prostática/complicações , Hiperplasia Prostática/tratamento farmacológico , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/embriologia , Fatores Sexuais
13.
J Comput Assist Tomogr ; 44(3): 328-333, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32345806

RESUMO

OBJECTIVE: To establish the normal parameters of fetal lung development at different gestational ages and to study their correlation with gestational age, thereby providing clinicians with a noninvasive method for assessing fetal lung maturity. METHODS: Two hundred eight cases with pregnancy of 22 to 39 weeks plus 6 days were divided into 18 groups according to gestational age. Ultrasound Doppler was used to measure the relevant parameters of fetal pulmonary development, including right pulmonary left and right diameter, right pulmonary upper and lower diameter, right pulmonary anterior and posterior diameter, right pulmonary area, thoracic area, inner diameter of fetal main pulmonary artery, and Doppler velocity curve parameters of main pulmonary artery: systolic acceleration time (AT), ejection time (ET), AT/ET. RESULTS: This study establishes normal parameters of lung development at different gestational weeks, draws scatter plots, correlation, and regression analysis of fetal main pulmonary artery AT, ET, AT/ET, and gestational weeks; selects the optimal equation; and analyzes the correlation among right pulmonary left and right diameter, right pulmonary upper and lower diameter, right pulmonary anterior and posterior diameter, right lung diameter, right lung area, thoracic area, and gestational weeks; and draw growth curve. The diameter of main pulmonary artery, AT, and AT/ET increased with the increase of gestational age and were positively correlated with gestational age (r = 0.948, 0.875, 0.810; P = 0.012). Ejection time had no correlation with gestational weeks. There were significant differences in the diameter of main pulmonary artery, AT, AT/ET between different gestational weeks (F = 240.67, 41.137, 23.067; P = 0.024); left and right diameter of right lung, anterior and posterior diameter of right lung, upper and lower diameter of right lung, chest area and right lung area were positively correlated with gestational weeks, and there were significant differences between different gestational weeks (F = 190.85, 105.74, 34.97, 172.33, 35.33, P = 0.018). CONCLUSIONS: Ultrasound Doppler can be used as a noninvasive detecting equipment to evaluate the growth of fetal lung, thus providing a basis for the evaluation of fetal lung maturity.


Assuntos
Pulmão , Artéria Pulmonar , Ultrassonografia Pré-Natal , Adulto , Feminino , Humanos , Pulmão/diagnóstico por imagem , Pulmão/embriologia , Valor Preditivo dos Testes , Gravidez , Terceiro Trimestre da Gravidez/fisiologia , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/embriologia , Adulto Jovem
14.
Am J Physiol Lung Cell Mol Physiol ; 318(6): L1165-L1171, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32292070

RESUMO

Bronchopulmonary dysplasia (BPD), a long-term respiratory morbidity of prematurity, is characterized by attenuated alveolar and vascular development. Supplemental oxygen and immature antioxidant defenses contribute to BPD development. Our group identified thioredoxin reductase-1 (TXNRD1) as a therapeutic target to prevent BPD. The present studies evaluated the impact of the TXNRD1 inhibitor aurothioglucose (ATG) on pulmonary responses and gene expression in newborn C57BL/6 pups treated with saline or ATG (25 mg/kg ip) within 12 h of birth and exposed to room air (21% O2) or hyperoxia (>95% O2) for 72 h. Purified RNA from lung tissues was sequenced, and differential expression was evaluated. Hyperoxic exposure altered ~2,000 genes, including pathways involved in glutathione metabolism, intrinsic apoptosis signaling, and cell cycle regulation. The isolated effect of ATG treatment was limited primarily to genes that regulate angiogenesis and vascularization. In separate studies, pups were treated as described above and returned to room air until 14 days. Vascular density analyses were performed, and ANOVA indicated an independent effect of hyperoxia on vascular density and alveolar architecture at 14 days. Consistent with RNA-seq analyses, ATG significantly increased vascular density in room air, but not in hyperoxia-exposed pups. These findings provide insights into the mechanisms by which TXNRD1 inhibitors may enhance lung development.


Assuntos
Ar , Aurotioglucose/farmacologia , Hiperóxia/patologia , Pulmão/irrigação sanguínea , Pulmão/patologia , Neovascularização Fisiológica/efeitos dos fármacos , Doença Aguda , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Apoptose/genética , DNA/biossíntese , Glutationa/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/embriologia , Camundongos Endogâmicos C57BL , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/embriologia , Alvéolos Pulmonares/patologia , Transdução de Sinais/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos , Transcriptoma/genética , Regulação para Cima/efeitos dos fármacos
15.
Am J Respir Cell Mol Biol ; 62(6): 692-698, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32208105

RESUMO

Type II alveolar epithelial cells (AEC2s) play an essential role in the function and maintenance of the pulmonary epithelium. Several transgenic mice have been developed to study the function of these cells in vivo by using the human SFTPC promoter to drive expression of Cre recombinase. The precise activity of each of these transgenic alleles has not been studied, and previous reports suggest that their activity can depend on breeding strategies. We bred mice with a conditional allele of the essential telomere capping protein TRF2 with two different SFTPC-Cre-transgenic strains and observed opposite phenotypes (100% lethality vs. 100% viability). We characterized the Cre recombinase activity in these two transgenic lines and found that the contrasting phenotypes were driven by difference in embryonic expression of the two transgenes, likely due to position effects or differences in the transgenic constructs. We also tested if SFTPC-Cre activity was dependent on maternal or paternal inheritance. When paternally inherited, both SFTPC-Cre alleles produced offspring with constitutive reporter activity independent of the inheritance of the Cre allele, suggesting that Cre recombinase was expressed in the male germline before meiosis. Immunohistochemical analysis of the testis showed reporter activity during spermatogenesis. Analysis of single-cell RNA sequencing data from murine and human testis demonstrated SFTPC expression uniquely during human spermatogenesis, suggesting that use of the human promoter in these constructs is responsible for male germline activity. Our data highlight the importance of careful analysis of transgenic allele activity and identify an SFTPC-Cre allele that is useful for panepithelial targeting in the mouse.


Assuntos
Integrases/genética , Regiões Promotoras Genéticas/genética , Proteína C Associada a Surfactante Pulmonar/genética , Transgenes , Alelos , Células Epiteliais Alveolares/metabolismo , Animais , Linhagem da Célula , Senescência Celular , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Genes Letais , Genes Reporter , Estudos de Associação Genética , Humanos , Integrases/biossíntese , Pulmão/embriologia , Pulmão/crescimento & desenvolvimento , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenótipo , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Proteínas Recombinantes/metabolismo , Análise de Célula Única , Espermatogênese , Homeostase do Telômero/genética , Proteína 2 de Ligação a Repetições Teloméricas/biossíntese , Proteína 2 de Ligação a Repetições Teloméricas/genética , Testículo/crescimento & desenvolvimento , Testículo/metabolismo
16.
N Engl J Med ; 382(6): 525-533, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32023372

RESUMO

BACKGROUND: We previously reported the results of a trial of prenatal vitamin D supplementation to prevent asthma and recurrent wheeze in young children, which suggested that supplementation provided a protective effect at the age of 3 years. We followed the children through the age of 6 years to determine the course of asthma and recurrent wheeze. METHODS: In this follow-up study, investigators and participants remained unaware of the treatment assignments through the children's sixth birthday. We aimed to determine whether, when maternal levels of 25-hydroxyvitamin D were taken into account, children born to mothers who had received 4400 IU of vitamin D3 per day during pregnancy (vitamin D group) would have a lower incidence of asthma and recurrent wheeze at the age of 6 years than would those born to mothers who had received 400 IU of vitamin D3 per day (control group). Time-to-event methods were used to compare the treatment groups with respect to time to the onset of asthma or recurrent wheeze. Multivariate methods were used to compare longitudinal measures of lung function between the treatment groups. RESULTS: There was no effect of maternal vitamin D supplementation on asthma and recurrent wheeze in either an intention-to-treat analysis or an analysis with stratification according to the maternal 25-hydroxyvitamin D level during pregnancy. There was no effect of prenatal vitamin D supplementation on most of the prespecified secondary outcomes. We found no effects of prenatal supplementation on spirometric indexes. Although there was a very small effect on airway resistance as measured by impulse oscillometry, this finding was of uncertain significance. CONCLUSIONS: Vitamin D supplementation during the prenatal period alone did not influence the 6-year incidence of asthma and recurrent wheeze among children who were at risk for asthma. (Funded by the National Heart, Lung, and Blood Institute; VDAART ClinicalTrials.gov number, NCT00920621.).


Assuntos
Resistência das Vias Respiratórias/efeitos dos fármacos , Asma/prevenção & controle , Suplementos Nutricionais , Cuidado Pré-Natal , Vitamina D/administração & dosagem , Vitaminas/administração & dosagem , Asma/epidemiologia , Criança , Feminino , Seguimentos , Humanos , Incidência , Análise de Intenção de Tratamento , Pulmão/efeitos dos fármacos , Pulmão/embriologia , Gravidez , Sons Respiratórios/efeitos dos fármacos , Espirometria , Vitamina D/análogos & derivados , Vitamina D/sangue
17.
Nat Commun ; 11(1): 635, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005814

RESUMO

Multipotent Nkx2-1-positive lung epithelial primordial progenitors of the foregut endoderm are thought to be the developmental precursors to all adult lung epithelial lineages. However, little is known about the global transcriptomic programs or gene networks that regulate these gateway progenitors in vivo. Here we use bulk RNA-sequencing to describe the unique genetic program of in vivo murine lung primordial progenitors and computationally identify signaling pathways, such as Wnt and Tgf-ß superfamily pathways, that are involved in their cell-fate determination from pre-specified embryonic foregut. We integrate this information in computational models to generate in vitro engineered lung primordial progenitors from mouse pluripotent stem cells, improving the fidelity of the resulting cells through unbiased, easy-to-interpret similarity scores and modulation of cell culture conditions, including substratum elastic modulus and extracellular matrix composition. The methodology proposed here can have wide applicability to the in vitro derivation of bona fide tissue progenitors of all germ layers.


Assuntos
Células Epiteliais/citologia , Pulmão/citologia , Camundongos/genética , Células-Tronco Pluripotentes/citologia , Animais , Técnicas de Cultura de Células , Diferenciação Celular , Células Epiteliais/metabolismo , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Feminino , Camadas Germinativas/embriologia , Camadas Germinativas/metabolismo , Pulmão/embriologia , Pulmão/metabolismo , Masculino , Camundongos/embriologia , Camundongos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células-Tronco Pluripotentes/metabolismo , Transdução de Sinais , Fator Nuclear 1 de Tireoide/genética , Fator Nuclear 1 de Tireoide/metabolismo , Transcriptoma , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
18.
J Surg Res ; 250: 23-38, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32014698

RESUMO

BACKGROUND: Fetal tracheal occlusion (TO) is an experimental therapeutic approach to stimulate lung growth in the most severe congenital diaphragmatic hernia (CDH) cases. We have previously demonstrated a heterogeneous response of normal fetal rabbit lungs after TO with the appearance of at least two distinct zones. The aim of this study was to examine the fetal lung response after TO in a left CDH fetal rabbit model. METHODS: Fetal rabbits at 25 d gestation underwent surgical creation of CDH followed by TO at 27 d and harvest on day 30. Morphometric analysis, global metabolomics, and fluorescence lifetime imaging microscopy (FLIM) were performed to evaluate structural and metabolic changes in control, CDH, and CDH + TO lungs. RESULTS: Right and left lungs were different at the baseline and had a heterogeneous pulmonary growth response in CDH and after TO. The relative percent growth of the right lungs in CDH + TO was higher than the left lungs. Morphometric analyses revealed heterogeneous tissue-to-airspace ratios, in addition to size and number of airspaces within and between the lungs in the different groups. Global metabolomics demonstrated a slower rate of metabolism in the CDH group with the left lungs being less metabolically active. TO stimulated metabolic activity in both lungs to different degrees. FLIM analysis demonstrated local heterogeneity in glycolysis, oxidative phosphorylation (OXPHOS), and FLIM "lipid-surfactant" signal within and between the right and left lungs in all groups. CONCLUSIONS: We demonstrate that TO leads to a heterogeneous morphologic and metabolic response within and between the right and left lungs in a left CDH rabbit model.


Assuntos
Terapias Fetais/métodos , Feto/embriologia , Hérnias Diafragmáticas Congênitas/cirurgia , Pulmão/embriologia , Oclusão Terapêutica/métodos , Animais , Modelos Animais de Doenças , Feminino , Feto/cirurgia , Glicólise , Humanos , Pulmão/metabolismo , Metabolômica , Fosforilação Oxidativa , Surfactantes Pulmonares/metabolismo , Coelhos , Traqueia/cirurgia
19.
J Leukoc Biol ; 108(1): 113-121, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32040236

RESUMO

Asthma is a chronic inflammatory airway disease characterized by airway hyperresponsiveness, inflammation, and remodeling. Asthma often develops during childhood and causes lifelong decrements in lung function and quality of life. Risk factors for childhood asthma are numerous and include genetic, epigenetic, developmental, and environmental factors. Uncontrolled maternal asthma during pregnancy exposes the developing fetus to inflammatory insults, which further increase the risk of childhood asthma independent of genetic predisposition. This review focuses on the role of maternal asthma in the development of asthma in offspring. We will present maternal asthma as a targetable and modifiable risk factor for childhood asthma and discuss the mechanisms by which maternal inflammation increases childhood asthma risk. Topics include how exposure to maternal asthma in utero shapes structural lung development with a special emphasis on airway nerves, how maternal type-2 cytokines such as IL-5 activate the fetal immune system, and how changes in lung and immune cell development inform responses to aero-allergens later in life. Finally, we highlight emerging evidence that maternal asthma establishes a unique "asthma signature" in the airways of children, leading to novel mechanisms of airway hyperreactivity and inflammatory cell responses.


Assuntos
Asma/sangue , Inflamação/sangue , Asma/fisiopatologia , Criança , Citocinas/metabolismo , Feminino , Humanos , Inflamação/fisiopatologia , Pulmão/embriologia , Pulmão/inervação , Pulmão/fisiopatologia , Terapia de Alvo Molecular , Gravidez , Fatores de Risco
20.
Development ; 147(4)2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-32001436

RESUMO

Proper organ development depends on coordinated communication between multiple cell types. Retinoic acid (RA) is an autocrine and paracrine signaling molecule essential for the development of most organs, including the lung. Despite extensive work detailing effects of RA deficiency in early lung morphogenesis, little is known about how RA regulates late gestational lung maturation. Here, we investigate the role of the RA catabolizing protein Cyp26b1 in the lung. Cyp26b1 is highly enriched in lung endothelial cells (ECs) throughout development. We find that loss of Cyp26b1 leads to reduction of alveolar type 1 cells, failure of alveolar inflation and early postnatal lethality in mouse. Furthermore, we observe expansion of distal epithelial progenitors, but no appreciable changes in proximal airways, ECs or stromal populations. Exogenous administration of RA during late gestation partially mimics these defects; however, transcriptional analyses comparing Cyp26b1-/- with RA-treated lungs reveal overlapping, but distinct, responses. These data suggest that defects observed in Cyp26b1-/- lungs are caused by both RA-dependent and RA-independent mechanisms. This work reports crucial cellular crosstalk during lung development involving Cyp26b1-expressing endothelium and identifies a novel RA modulator in lung development.


Assuntos
Epitélio/embriologia , Pulmão/embriologia , Alvéolos Pulmonares/embriologia , Ácido Retinoico 4 Hidroxilase/genética , Ácido Retinoico 4 Hidroxilase/fisiologia , Animais , Sistemas CRISPR-Cas , Diferenciação Celular , Células Endoteliais/citologia , Células Epiteliais/citologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Rim/embriologia , Camundongos , Camundongos Endogâmicos C57BL , Organogênese/efeitos dos fármacos , Gravidez , Prenhez , Transdução de Sinais , Células-Tronco/citologia , Tretinoína/farmacologia
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