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BACKGROUND: Postnatal systemic corticosteroids reduce the risk of bronchopulmonary dysplasia but the effect depends on timing, dosing, and type of corticosteroids. Animal studies may provide valuable information on these variable effects. This systematic review summarizes the effects of postnatal systemic corticosteroids on lung development in newborn animals. METHODS: A systematic search was performed in PubMed and Embase in December 2022. The protocol was published on PROSPERO (CRD42021177701). RESULTS: Of the 202 eligible studies, 51 were included. Only newborn rodent studies met the inclusion criteria. Most studies used dexamethasone (98%). There was huge heterogeneity in study outcome measures and corticosteroid treatment regimens. Reporting of study quality indicators was mediocre and risk of bias was unclear due to poor reporting of study methodology. Meta-analysis showed that postnatal corticosteroids caused a decrease in body weight as well as persistent alveolar simplification. Subgroup analyses revealed that healthy animals were most affected. CONCLUSION: In newborn rodents, postnatal systemic corticosteroids have a persistent negative effect on body weight and lung development. There was huge heterogeneity in experimental models, mediocre study quality, unclear risk of bias, and very small subgroups for meta-analysis which limited firm conclusions. IMPACT: Postnatal corticosteroids reduce the risk of bronchopulmonary dysplasia but the effect depends on timing, dosing, and type of corticosteroids while the underlying mechanism of this variable effect is unknown. This is the first systematic review and meta-analysis of preclinical newborn animal studies reviewing the effect of postnatal systemic corticosteroids on lung development. In newborn rodent models, postnatal corticosteroids have a persistent negative effect on body weight and lung alveolarization, especially in healthy animals.
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Targeted therapies have drastically changed the management of metastatic melanoma and have shown encouraging results on tumour progression but are also known for their high rates of adverse reactions. In general, targeted therapies are contraindicated during pregnancy due to concerns about teratogenesis. For the BRAF V600 inhibitor vemurafenib, the available literature about the effects on human pregnancy is limited to a single case report. In patients with metastatic melanoma that wish to continue their pregnancy, targeted therapies like vemurafenib offer the only possibility of improving maternal outcome. In this article, we report on a pregnant woman with metastatic melanoma who was treated with vemurafenib during pregnancy and experienced a fatal adverse reaction.
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This study investigated whether hypoxia-inducible factor (HIF)-1 influences postnatal vascularization and alveologenesis in mice and whether stable (constitutive-active) HIF could prevent hyperoxia-induced lung injury. We assessed postnatal vessel and alveolar formation in transgenic mice, expressing a stable, constitutive-active, HIF1α-subunit (HIF-1αΔODD) in the distal lung epithelium. In addition, we compared lung function, histology, and morphometry of neonatal transgenic and wild-type mice subjected to hyperoxia. We found that postnatal lungs of HIF-1αΔODD mice had a greater peripheral vessel density and displayed advanced alveolarization compared with control lungs. Stable HIF-1α expression was associated with increased postnatal expression of angiogenic factors, including vascular endothelial growth factor, angiopoietins 1 and 2, Tie2, and Ephrin B2 and B4. Hyperoxia-exposed neonatal HIF-1αΔODD mice exhibited worse lung function but had similar histological and surfactant abnormalities compared with hyperoxia-exposed wild-type controls. In conclusion, expression of constitutive-active HIF-1α in the lung epithelium was associated with increased postnatal vessel growth via up-regulation of angiogenic factors. The increase in postnatal vasculature was accompanied by enhanced alveolar formation. However, stable HIF-1α expression in the distal lung did not prevent hyperoxia-induced lung injury in neonates but instead worsened lung function.
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Hiperóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Pulmão/metabolismo , Alvéolos Pulmonares/patologia , Animais , Células HEK293 , Humanos , Hiperóxia/patologia , Pulmão/patologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Alvéolos Pulmonares/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
CONTEXT: Apoptosis of lung epithelial cells is implicated in the pathogenesis of acute lung injury. Most research on this subject has focused on adults. Very little is known about a potential interaction of this process with lung development in children. OBJECTIVE: To summarize the current literature on lung epithelial cell apoptosis and common causes of acute lung injury in infants and young children and to identify new areas of research. DESIGN: A Medline-based literature search. RESULTS AND CONCLUSIONS: Few studies have focused on lung epithelial cell apoptosis during common causes of acute lung injury in children. Nevertheless, the limited literature suggests that this may be an important mechanism during respiratory distress syndrome of infants and viral respiratory tract infection. Apoptosis is an essential process during lung development and maturation. Insufficient attention has been paid to potential consequences of this for the short- and long-term outcomes of acute lung injury.
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Apoptose/fisiologia , Células Epiteliais/patologia , Pulmão/citologia , Síndrome do Desconforto Respiratório do Recém-Nascido/patologia , Síndrome do Desconforto Respiratório/patologia , Doença Aguda , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Pulmão/patologiaRESUMO
Sonic Hedgehog (Shh)-deficient mice have a severe lung branching defect. Recent studies have shown that hedgehog signaling is involved in vascular development and it is possible that the diminished airway branching in Shh-deficient mice is due to abnormal pulmonary vasculature formation. Therefore, we investigated the role of Shh in pulmonary vascular development using Shh/Tie2lacZ compound mice, which exhibit endothelial cell-specific LacZ expression, and Pecam-1 immunohistochemistry. In E11.5-13.5 Shh-deficient mice, the pulmonary vascular bed is decreased, but appropriate to the decrease in airway branching. However, when E12.5 Shh-deficient lungs were cultured for 4-6 days, the vascular network deteriorated compared to wild-type lungs. The expression of vascular endothelial growth factor (Vegf) or its receptor Vegfr2 (KDR/Flk-1) was not different between E12.5-13.5 Shh-deficient and wild-type lungs. In contrast, angiopoietin-1 (Ang1), but not Ang2 or the angiopoietin receptor Tie2, mRNA expression was downregulated in E12.5-E13.5 lungs of Shh null mutants. Recombinant Ang1 alone was unable to restore in vitro branching morphogenesis in Shh-deficient lungs. Conversely, the angiogenic factor fibroblast growth factor (Fgf)-2 alone or in combination with Ang1, increased vascularization and tubular growth and branching of Shh-deficient lungs in vitro. The angiogenic factors did not overcome the reduced smooth muscle cell differentiation in the Shh null lungs. These data indicate that early vascular development, mediated by Vegf/Vegfr2 signaling proceeds normally in Shh-deficient mice, while later vascular development and stabilization of the primitive network mediated by the Ang/Tie2 signaling pathway are defective, resulting in an abnormal vascular network. Stimulation of vascularization with angiogenic factors such as Fgf2 and Ang1 partially restored tubular growth and branching in Shh-deficient lungs, suggesting that vascularization is required for branching morphogenesis.
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Proteínas Angiogênicas/metabolismo , Proteínas Hedgehog/deficiência , Pulmão/embriologia , Pulmão/metabolismo , Proteínas Angiogênicas/genética , Animais , Proteínas Hedgehog/genética , Fatores de Transcrição Kruppel-Like/deficiência , Fatores de Transcrição Kruppel-Like/genética , Óperon Lac , Pulmão/irrigação sanguínea , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Morfogênese , Neovascularização Fisiológica/genética , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Proteína GLI1 em Dedos de Zinco , Proteína Gli2 com Dedos de ZincoRESUMO
Groucho proteins are transcriptional corepressors that are recruited to gene regulatory regions by numerous transcription factors. Long isoforms, such as Grg1, have all the domains of the prototype Drosophila Groucho. Short Groucho proteins, such as Grg5, have only the amino-terminal Q and G/P domains. We generated Grg1 and Grg5 transgenic mice and found that Grg1 overexpression induces lung adenocarcinoma, whereas Grg5 overexpression does not. Coexpression of Grg5 with Grg1 reduces tumor burden. Grg1 and Grg5 both diminish p53 protein levels; however, only Grg1 overexpression induces elevated levels of ErbB1 and ErbB2 receptor tyrosine kinases. The molecular and biological changes that accompany tumor progression in Grg1 transgenic mice closely reiterate events seen in human lung cancer. We also found that within a human lung tumor tissue array, a significant number of carcinomas overexpress Grg1/TLE1. Our data suggest that Grg1 overexpression contributes to malignancy in human lung cancers.
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Adenocarcinoma/genética , Neoplasias Pulmonares/genética , Oncogenes , Proteínas Repressoras/genética , Adenocarcinoma/metabolismo , Animais , Proteínas Correpressoras , Receptores ErbB/biossíntese , Receptores ErbB/genética , Vetores Genéticos/genética , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Transgênicos , Células NIH 3T3 , Receptor ErbB-2/biossíntese , Receptor ErbB-2/genética , Proteínas Repressoras/biossíntese , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima , Proteínas ras/metabolismoRESUMO
Lung development is a highly regulated process directed by mesenchymal-epithelial interactions, which coordinate the temporal and spatial expression of multiple regulatory factors required for proper lung formation. The Iroquois homeobox (Irx) genes have been implicated in the patterning and specification of several Drosophila and vertebrate organs, including the heart. Herein, we investigated whether the Irx genes play a role in lung morphogenesis. We found that Irx1-3 and Irx5 expression was confined to the branching lung epithelium, whereas Irx4 was not expressed in the developing lung. Antisense knockdown of all pulmonary Irx genes together dramatically decreased distal branching morphogenesis and increased distention of the proximal tubules in vitro, which was accompanied by a reduction in surfactant protein C-positive epithelial cells and an increase in beta-tubulin IV and Clara cell secretory protein positive epithelial structures. Transmission electron microscopy confirmed the proximal phenotype of the epithelial structures. Furthermore, antisense Irx knockdown resulted in loss of lung mesenchyme and abnormal smooth muscle cell formation. Expression of fibroblast growth factors (FGF) 1, 7, and 10, FGF receptor 2, bone morphogenetic protein 4, and Sonic hedgehog (Shh) were not altered in lung explants treated with antisense Irx oligonucleotides. All four Irx genes were expressed in Shh- and Gli(2)-deficient murine lungs. Collectively, these results suggest that Irx genes are involved in the regulation of proximo-distal morphogenesis of the developing lung but are likely not linked to the FGF, BMP, or Shh signaling pathways.
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Proteínas de Homeodomínio/genética , Pulmão/embriologia , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Proteína Morfogenética Óssea 4 , Proteínas Morfogenéticas Ósseas/metabolismo , Proliferação de Células/efeitos dos fármacos , Embrião de Mamíferos/citologia , Embrião de Mamíferos/metabolismo , Embrião de Mamíferos/fisiologia , Desenvolvimento Embrionário/efeitos dos fármacos , Desenvolvimento Embrionário/genética , Células Epiteliais/metabolismo , Feminino , Fatores de Crescimento de Fibroblastos/metabolismo , Expressão Gênica , Proteínas Hedgehog , Técnicas In Vitro , Fatores de Transcrição Kruppel-Like/deficiência , Fatores de Transcrição Kruppel-Like/genética , Pulmão/anormalidades , Masculino , Mesoderma/metabolismo , Camundongos , Camundongos Mutantes , Mutação , Oligonucleotídeos Antissenso/farmacologia , Ratos , Ratos Wistar , Transativadores/deficiência , Transativadores/genética , Proteína Gli2 com Dedos de ZincoRESUMO
The Notch/Notch-ligand pathway regulates cell fate decisions and patterning in various tissues. Several of its components are expressed in the developing lung, suggesting that this pathway is important for airway cellular patterning. Fringe proteins, which modulate Notch signaling, are crucial for defining morphogenic borders in several organs. Their role in controlling cellular differentiation along anterior-posterior axis of the airways is unknown. Herein, we report the temporal-spatial expression patterns of Lunatic fringe (Lfng) and Notch-regulated basic helix-loop-helix factors, Hes1 and Mash-1, during murine lung development. Lfng was only expressed during early development in epithelial cells lining the larger airways. Those epithelial cells also expressed Hes1, but at later gestation Hes1 expression was confined to epithelium lining the terminal bronchioles. Mash-1 displayed a very characteristic expression pattern. It followed neural crest migration in the early lung, whereas at later stages Mash-1 was expressed in lung neuroendocrine cells. To clarify whether Lfng influences airway cell differentiation, Lfng was overexpressed in distal epithelial cells of the developing mouse lung. Overexpression of Lfng did not affect spatial or temporal expression of Hes1 and Mash-1. Neuroendocrine CGRP and protein gene product 9.5 expression was not altered by Lfng overexpression. Expression of proximal ciliated (beta-tubulin IV), nonciliated (CCSP), and distal epithelial cell (SP-C, T1alpha) markers also was not influenced by Lfng excess. Overexpression of Lfng had no effect on mesenchymal cell marker (alpha-sma, vWF, PECAM-1) expression. Collectively, the data suggest that Lunatic fringe does not play a significant role in determining cell fate in fetal airway epithelium.
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Diferenciação Celular , Células Epiteliais/citologia , Regulação da Expressão Gênica no Desenvolvimento , Glicosiltransferases/genética , Pulmão/embriologia , Transdução de Sinais , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Brônquios/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Glicosiltransferases/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Hibridização In Situ , Ligantes , Proteínas de Membrana/metabolismo , Mesoderma/metabolismo , Camundongos , Camundongos Transgênicos , Sistemas Neurossecretores/metabolismo , Receptores Notch , Fatores de Transcrição HES-1 , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Recent investigations have suggested an active role for endothelial cells in organ development, including the lung. Herein, we investigated some of the molecular mechanisms underlying normal pulmonary vascular development and their influence on epithelial branching morphogenesis. Because the lung in utero develops in a relative hypoxic environment, we first investigated the influence of low oxygen on epithelial and vascular branching morphogenesis. Two transgenic mouse models, the C101-LacZ (epithelial-LacZ marker) and the Tie2-LacZ (endothelial-LacZ marker), were used. At embryonic day 11.5, primitive lung buds were dissected and cultured at either 20 or 3% oxygen. At 24-h intervals, epithelial and endothelial LacZ gene expression was visualized by X-galactosidase staining. The rate of branching of both tissue elements was increased in explants cultured at 3% oxygen compared with 20% oxygen. Low oxygen increased expression of VEGF, but not that of the VEGF receptor (Flk-1). Expression of two crucial epithelial branching factors, fibroblast growth factor-10 and bone morphogenetic protein-4, were not affected by low oxygen. Epithelial differentiation was maintained at low oxygen as shown by surfactant protein C in situ hybridization. To explore epithelial-vascular interactions, we inhibited vascular development with antisense oligonucleotides targeted against either hypoxia inducible factor-1 alpha or VEGF. Epithelial branching morphogenesis in vitro was dramatically abrogated when pulmonary vascular development was inhibited. Collectively, the in vitro data show that a low-oxygen environment enhances branching of both distal lung epithelium and vascular tissue and that pulmonary vascular development appears to be rate limiting for epithelial branching morphogenesis.
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Vasos Sanguíneos/embriologia , Pulmão/embriologia , Morfogênese/fisiologia , Oxigênio/fisiologia , Animais , Embrião de Mamíferos/irrigação sanguínea , Embrião de Mamíferos/metabolismo , Desenvolvimento Embrionário/fisiologia , Epitélio/embriologia , Camundongos , Camundongos Transgênicos , Técnicas de Cultura de Órgãos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Maternal hypothyroxinemia during early pregnancy poses an increased risk for poor neuropsychological development of the fetus. We tested the hypothesis that maternal hypothyroidism before the onset of fetal thyroid function also affects postnatal development of heart and lungs. This question was addressed in transgenic mice that express herpes simplex virus thymidine kinase in their thyroidal follicle cells. Treatment with ganciclovir rendered these mice severely hypothyroid because viral thymidine kinase converts ganciclovir into a cytotoxic nucleoside analog. Since ganciclovir crosses the placenta, it also destroyed the thyroid of transgenic embryos while leaving the thyroids of nontransgenic littermates unaffected. Hypothyroidism of both mother and fetus did not affect prenatal heart and lung development. However, the postnatal switch from beta- to alpha-myosin heavy chain (beta- and alpha-MHC, respectively) gene expression and the increase of SERCA-2a mRNA expression did not occur in the ventricular myocardium of either the transgenic (thyroid destroyed) or nontransgenic (intact thyroid) offspring of hypothyroid mothers. Similarly, postnatal animals of the latter two groups retained elevated surfactant protein (SP) A, B, and C mRNA levels in their alveolar epithelium. In hypothyroid pups from hypothyroid mothers, these changes were accompanied by decreased alveolar septation. Our study shows that these effects of maternal hypothyroidism become manifest after birth and are aggravated by the concomitant existence of neonatal hypothyroidism.
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Coração/crescimento & desenvolvimento , Pulmão/crescimento & desenvolvimento , Hormônios Tireóideos/fisiologia , Animais , Proteínas de Ligação ao Cálcio/genética , ATPases Transportadoras de Cálcio , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Hipotireoidismo/metabolismo , Pulmão/patologia , Camundongos , Camundongos Transgênicos , Miocárdio/metabolismo , Miocárdio/patologia , Cadeias Pesadas de Miosina/genética , Miosina não Muscular Tipo IIB , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Proteína A Associada a Surfactante Pulmonar/genética , Proteína B Associada a Surfactante Pulmonar/genética , Proteína C Associada a Surfactante Pulmonar/genética , Valores de Referência , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático , Tireoglobulina/genética , Hormônios Tireóideos/farmacologiaRESUMO
Neonates with congenital diaphragmatic hernia (CDH) suffer from a diaphragmatic defect, lung hypoplasia, and pulmonary hypertension, with poor lung function forming the major clinical challenge. Despite prenatal diagnosis and advanced postnatal treatment strategies, the mortality rate of CDH is still high. CDH has been subject of extensive research over the past decades, but its etiology remains unknown. A major problem with CDH is the failure to predict the individual response to treatment modalities like high-frequency ventilation, inhaled nitric oxide, and extracorporeal membrane oxygenation. In this study, we tested the possibility that CDH lungs are surfactant protein deficient, which could explain the respiratory failure and difficulties in treating CDH infants. We investigated this hypothesis in the nitrofen-induced CDH rat model and assessed the cellular concentrations of surfactant protein (SP)-A, -B, and -C mRNA with a quantitative radioactive in situ hybridization technique. No differences were observed between control and CDH lungs for SP mRNA expression patterns. The cellular concentration (mean OD) of SP-A and SP-B mRNA was similar at all stages whereas the mean OD of SP-C mRNA and the volume fraction of cells (% Area) expressing SP mRNA was higher in CDH lungs at term. Immunohistochemical analysis revealed no differences between control and CDH lungs for SP protein expression. No differences in the mean OD or % Area for the SP mRNAs were found between the ipsi- and contralateral side of CDH lungs. We conclude that there is no primary deficiency of surfactant proteins in the nitrofen-induced CDH rat model.