Local Fetal Lung Renin-Angiotensin System as a Target to Treat Congenital Diaphragmatic Hernia

Nogueira‐Silva, Cristina; Carvalho-Dias, Emanuel; Piairo, Paulina; Nunes, Susana; Baptista, Maria João; Moura, Rute S.; Correia‐Pinto, Jorge

doi:10.2119/molmed.2011.00210

Cited by 24 publications

(33 citation statements)

References 62 publications

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“…Many factors that regulate fetal lung branching morphogenesis activate signaling pathways that culminate with MAPK, PI3K/Akt and p38 cascades [30,31,40,41,42]. In the present study, ephrin-B1 was found not to modify the phosphorylated levels of these proteins.…”

Section: Discussioncontrasting

confidence: 53%

The Role of Ephrins-B1 and -B2 During Fetal Rat Lung Development

Peixoto

Pereira-Terra

Moura

et al. 2015

Cell Physiol Biochem

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Background/ Aims: The knowledge of the molecular network that governs fetal lung branching is an essential step towards the discovery of novel therapeutic targets against pulmonary pathologies. Lung consists of two highly branched systems: airways and vasculature. Ephrins and its receptors, Eph, have been implicated in cardiovascular development, angiogenesis and vascular remodeling. This study aims to clarify the role of these factors during lung morphogenesis. Methods: Ephrins-B1, -B2 and receptor EphB4 expression pattern was assessed in fetal rat lungs between 15.5 and 21.5 days post-conception, by immunohistochemistry. Fetal rat lungs were harvested at 13.5 dpc, cultured during 4 days and treated with increasing doses of ephrins-B1 and -B2 and the activity of key signaling pathways was assessed. Results: Ephrin-B1 presents mesenchymal expression, whereas ephrin-B2 and its receptor EphB4 were expressed by the epithelium. Both ephrins stimulated pulmonary branching. Moreover, while ephrin-B1 did not affect the pathways studied, ephrin-B2 supplementation decreased activity of JNK, ERK and STAT. This study characterizes the expression pattern of ephrins-B1, -B2 and EphB4 receptor throughout rat lung development. Conclusion: Our data highlight a possible role of ephrins as molecular stimulators of lung morphogenesis. Moreover, it supports the idea that classical vascular factors might play a role as airway growth promoters.

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Section: Discussioncontrasting

confidence: 53%

The Role of Ephrins-B1 and -B2 During Fetal Rat Lung Development

Peixoto

Pereira-Terra

Moura

et al. 2015

Cell Physiol Biochem

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“…According to the nitrofen‐induced CDH rat model, randomly selected pregnant rats received 100 mg of nitrofen (2,4‐dichlorophenyl‐ p ‐nitrophenylether) dissolved in 1 ml of olive oil via gavage on 9.5 dpc (days postconception) (hypoplastic group) (Nogueira‐Silva et al . ). Control animals only received only olive oil (control group).…”

Section: Methodsmentioning

confidence: 97%

“…; Nogueira‐Silva et al . ). This congenital anomaly is characterised by a diaphragmatic defect that allows intra‐thoracic herniation of abdominal organs and maldevelopment of the alveoli and pulmonary vessels (van Loenhout et al .…”

Section: Introductionmentioning

confidence: 97%

Neuroendocrine factors regulate retinoic acid receptors in normal and hypoplastic lung development

Pereira-Terra

Moura

Nogueira‐Silva

et al. 2015

The Journal of Physiology

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Key pointsr Retinoic acid (RA) and ghrelin levels are altered in human hypoplastic lungs when compared to healthy lungs. Although considerable data have been obtained about RA, ghrelin and bombesin in the congenital diaphragmatic hernia (CDH) rat model, neuroendocrine factors have never been associated with the RA signalling pathway in this animal model. r In this study, the interaction between neuroendocrine factors and RA was explored in the CDH rat model. r The authors found that normal fetal lung explants treated with RA, bombesin and ghrelin showed an increase in lung growth. Hypoplastic lungs presented higher expression levels of the RA receptors α and γ. Moreover bombesin and ghrelin supplementation, in vitro, to normal lungs increased RA receptor α/γ expression whereas administration of bombesin and ghrelin antagonists to normal and hypoplastic lungs decreased it.r These data reveal for the first time that there is a link between neuroendocrine factors and RA, and that neuroendocrine factors sensitise the lung to the RA action through RA receptor modulation.Abstract Congenital diaphragmatic hernia (CDH) is characterised by a spectrum of lung hypoplasia and consequent pulmonary hypertension, leading to high morbidity and mortality rates. Moreover, CDH has been associated with an increase in the levels of pulmonary neuroendocrine factors, such as bombesin and ghrelin, and a decrease in the action of retinoic acid (RA). The present study aimed to elucidate the interaction between neuroendocrine factors and RA. In vitro analyses were performed on Sprague-Dawley rat embryos. Normal lung explants were treated with bombesin, ghrelin, a bombesin antagonist, a ghrelin antagonist, dimethylsulfoxide (DMSO), RA dissolved in DMSO, bombesin plus RA and ghrelin plus RA. Hypoplastic lung explants (nitrofen model) were cultured with bombesin, ghrelin, bombesin antagonist or ghrelin antagonist. The lung explants were analysed morphometrically, and retinoic acid receptor (RAR) α, β and γ expression levels were assessed via Western blotting. Immunohistochemistry analysis of RAR was performed in normal and hypoplastic lungs 17.5 days post-conception (dpc). Compared with the controls, hypoplastic lungs exhibited significantly higher RARα/γ expression levels. Furthermore considering hypoplastic lungs, bombesin and ghrelin antagonists decreased RARα/γ expression. Normal lung explants (13.5 dpc) treated with RA, bombesin plus RA, ghrelin plus RA, bombesin or ghrelin exhibited increased lung growth. Moreover, bombesin and ghrelin increased RARα/γ expression levels, whereas the bombesin and ghrelin antagonists decreased RARα/γ expression. This study demonstrates for the first time that neuroendocrine factors function as lung growth regulators, sensitising the lung to the action of RA through up-regulation of RARα and RARγ.

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“…The majority of preclinical studies have focused on vitamin or steroid administration [8,9]. Isolated studies on transplacental therapies in the nitrofen rat model have been published, including sildenafil (VEGF agonist), CGS-26303 (endothelin-converting enzyme-1 activator), PR-123319 (angiotensin 2 receptor antagonist), epidermal growth factor, ghrelin, estrogen, and tetrandrine (a Chinese herbal remedy) [10,11,12,13,14,15,16]. Only tadalafil has been used transplacentally in the sheep model [17].…”

Section: Introductionmentioning

confidence: 99%

The Effect of Transplacental Administration of Glucagon-Like Peptide-1 on Fetal Lung Development in the Rabbit Model of Congenital Diaphragmatic Hernia

et al. 2015

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Objective: Glucagon-like peptide-1 (GLP-1) increases surfactant protein expression in type 2 pneumocytes. Herein, we determine if transplacental GLP-1 treatment accelerates lung growth in the fetal rabbit model of congenital diaphragmatic hernia (DH). Methods: Time-mated does had an induction of DH on day 23 followed by daily GLP-1 or placebo injection until term. At that time, the does were weighed, fetal blood was obtained for GLP-1 assay, and the lungs were dissected. Fetal outcome measures were lung-to-body-weight ratio (LBWR), morphometry, and Ki67 and surfactant protein B (SPB) expression. Results: Maternal weight loss in the GLP-1 group was 7.1%. Fetal survival was lower in GLP-1 fetuses compared to placebo controls (27/85, 32% vs. 35/57, 61%; p < 0.05). Fetal GLP-1 levels were increased 3.6-fold. The LBWR of GLP-1 DH fetuses fell within the range of DH placebo fetuses (1.166 ± 0.207% vs. 1.312 ± 0.418%), being significantly lower than that of placebo-exposed unoperated fetuses (2.280 ± 0.522%; p < 0.001). GLP-1 did not improve airway morphometry. GLP-1 DH lungs had a reduced adventitial and medial thickness within the range of controls, and lesser muscularization of vessels measuring 30-60 µm. There were no differences in Ki67 and SPB expression. Conclusion: GLP-1 at this dosage improves peripheric pulmonary vessel morphology in intra-acinar vessels with no effect on airway morphometry but with significant maternal and fetal side effects. Thus, it is an unlikely medical strategy.

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Local Fetal Lung Renin-Angiotensin System as a Target to Treat Congenital Diaphragmatic Hernia

Cited by 24 publications

References 62 publications

The Role of Ephrins-B1 and -B2 During Fetal Rat Lung Development

The Role of Ephrins-B1 and -B2 During Fetal Rat Lung Development

Neuroendocrine factors regulate retinoic acid receptors in normal and hypoplastic lung development

The Effect of Transplacental Administration of Glucagon-Like Peptide-1 on Fetal Lung Development in the Rabbit Model of Congenital Diaphragmatic Hernia

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