Antenatal vitamin A administration attenuates lung hypoplasia by interfering with early instead of late determinants of lung underdevelopment in congenital diaphragmatic hernia

Baptista, Maria João; Melo-Rocha, Gustavo; Pedrosa, Carla; Gonzaga, Sílvia; Teles, Antónia; Estevão‐Costa, José; Areias, José Carlos; Flake, Alan W.; Leite‐Moreira, Adelino F.; Correia‐Pinto, Jorge

doi:10.1016/j.jpedsurg.2005.01.034

Cited by 36 publications

(36 citation statements)

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“…Regarding the nitrofen-induced CDH model, it was already demonstrated that nitrofen inhibits retinal dehydrogenase 2 (RALDH2), a key enzyme responsible for the conversion of retinal to retinoic acid (47). Moreover, the co-administration of retinoids (Vitamin A or retinoic acid) in nitrofeninduced CDH induces lung growth and reduces the incidence of CDH (9,10,48). Interestingly, some studies have described an inhibitory interaction between retinoid acid pathway and RAS, namely in adult cardiac remodeling (49,50).…”

Section: Discussionmentioning

confidence: 99%

“…However, fetal surgical interventions, such as fetal tracheal occlusion, are invasive, technically demanding, limited by the maternal and fetal risks, and their efficacy is still not determined, with controversial results in survival and morbidity rates (5,6). Therefore, less invasive approaches such as antenatal pharmacological treatment to stimulate lung growth before birth and to treat PH are also under investigation (3,(7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

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

Nogueira‐Silva

Carvalho-Dias

Piairo

et al. 2011

Mol Med

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Antenatal stimulation of lung growth is a reasonable approach to treat congenital diaphragmatic hernia (CDH), a disease characterized by pulmonary hypoplasia and hypertension. Several evidences from the literature demonstrated a possible involvement of renin-angiotensin system (RAS) during fetal lung development. Thus, the expression pattern of renin, angiotensin-converting enzyme, angiotensinogen, type 1 (AT 1 ) and type 2 (AT 2 ) receptors of angiotensin II (ANGII) was assessed by immunohistochemistry throughout gestation, whereas the function of RAS in the fetal lung was evaluated using fetal rat lung explants. These were morphometrically analyzed and intracellular pathway alterations assessed by Western blot. In nitrofen-induced CDH model, pregnant rats were treated with saline or PD-123319. In pups, lung growth, protein/DNA ratio, radial saccular count, epithelial differentiation and lung maturation, vascular morphometry, right ventricular hypertrophy and overload molecular markers, gasometry and survival time were evaluated. Results demonstrated that all RAS components were constitutively expressed in the lung during gestation and that ANGII had a stimulatory effect on lung branching, mediated by AT 1 receptor, through p44/42 and Akt phosphorylation. This stimulatory effect on lung growth was mimicked by AT 2 -antagonist (PD-123319) treatment. In vivo antenatal PD-123319 treatment increased lung growth, ameliorated indirect parameters of pulmonary hypertension, improved lung function and survival time in nonventilated CDH pups, without maternal or fetal deleterious effects. Therefore, this study demonstrated a local and physiologically active RAS during lung morphogenesis. Moreover, selective inhibition of AT 2 receptor is presented as a putative antenatal therapy for CDH.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Nogueira‐Silva

Carvalho-Dias

Piairo

et al. 2011

Mol Med

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“…Reversing lung hypoplasia surgically during the prenatal development has been attempted; however, this intervention is invasive, technically demanding and limited by the maternal and fetal risk (2). Thus, antenatal therapies that promote lung growth remain an appealing approach for fetuses with severe CDH (3,4).…”

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Ghrelin Expression in Human and Rat Fetal Lungs and the Effect of Ghrelin Administration in Nitrofen-Induced Congenital Diaphragmatic Hernia

et al. 2006

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ABSTRACT:Ghrelin is a strong physiologic growth hormone secretagogue that exhibits endocrine and non-endocrine actions. In this study, ghrelin expression in humans and rats was evaluated throughout development of normal and hypoplastic lungs associated with congenital diaphragmatic hernia (CDH). Additionally, the effect of antenatal treatment with ghrelin in the nitrofen-induced CDH rat model was tested. In normal lungs, ghrelin was expressed in the primitive epithelium at early stages of development and decreased in levels of expression with gestational age. In hypoplastic lungs ghrelin was overexpressed in both human and rat CDH fetuses when compared with controls. Exogenous administration of ghrelin to nitrofentreated dams led to an attenuation of pulmonary hypoplasia of CDH pups. Furthermore, the growth hormone, secretagogue receptor (GHSR1a), could not be amplified from human or rat fetal lungs by RT-PCR. In conclusion, of all the lungs studied so far, the fetal lung is one of the first to express ghrelin during development and might be considered a new source of circulating fetal ghrelin. Overexpression of ghrelin in hypoplastic lungs and the effect of exogenous administration of ghrelin to nitrofen-treated dams strongly suggest a role for ghrelin in mechanisms involved in attenuation of fetal lung hypoplasia, most likely through a GHSR1a-independent pathway. (Pediatr Res 59: 531-537, 2006)

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“…While antioxidant vitamins did not rescue the nitrofen-induced perturbations of retinoid signaling in this study, they have been shown to alleviate nitrofen-induced effects in other systems. This includes partial rescue of nitrofen-induced lung hypoplasia (8,26,29,49) defects in neural crest-derived tissue (26, 71), transcription in pneumocyte cell lines, and embryonic rat lung (29,30,71). However, there have been no reports of antioxidant treatment decreasing the incidence of CDH.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of action of the congenital diaphragmatic hernia-inducing teratogen nitrofen

Noble

Babiuk²,

Clugston³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

110

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Congenital diaphragmatic hernia (CDH) is a developmental anomaly that results in significant mortality and morbidity. The underlying etiology is poorly understood. Insights will arise from an understanding of the mechanisms by which the teratogen nitrofen induces CDH in rodent models. In this study, we use in vitro cell assays in conjunction with whole animal rodent studies to test hypotheses regarding nitrofen's mechanism of action. The first component examined the interaction of nitrofen with various aspects of the retinoid signaling pathway including uptake proteins, binding proteins, receptors, conversion, and degradation enzymes. The second component examined the interactions of nitrofen and vitamins A, C, and E to test the hypothesis that nitrofen was functioning as an antioxidant to interfere with retinoid signaling. Third, we performed a series of experiments examining the interaction of nitrofen and thyroid signaling. Collectively, the data suggest that the primary aspect of retinoid signaling affected by nitrofen is via inhibition of the rate-limiting enzymes controlling retinoic acid synthesis. Retinoid signaling perturbations do not appear to involve oxidative effects of nitrofen. Any substantial roles of nitrofen-induced perturbations of thyroid hormone signaling or receptor function are not supported. retinoid signaling CONGENITAL DIAPHRAGMATIC HERNIA (CDH) is a serious developmental abnormality that occurs in ϳ1 in 2,500 live births (41). The most commonly observed type of this anomaly is the Bochdalek hernia, characterized by incomplete formation of the posterolateral diaphragm and the invasion of the thoracic cavity by abdominal viscera. The ensuing abnormal fetal breathing movements and physical constraints on the developing lungs and heart contribute to pulmonary and left ventricular hypoplasia and pulmonary hypertension (20,35,37). Despite improved treatment strategies, CDH continues to have significant morbidity and mortality (50,69). Insights into the pathogenesis of the diaphragm defect have arisen from teratogenic, dietary, and genetic rodent models of Bochdalek CDH in conjunction with examination of human postmortem tissue (17). Specifically, the initial diaphragmatic defect appears to occur early (before week 5) during the embryogenesis of the amuscular component of the primordial diaphragm, the pleuroperitoneal fold. Much less is known about the etiology of CDH. However, considering the partial similarities between the pathologies observed in the teratogenic nitrofen-induced rat model and infants with CDH (1, 19, 40), the possibility that a common underlying etiology exists has received consideration. There have been a number of hypotheses put forth to explain the teratogenic effects of nitrofen. The retinoid hypothesis suggests that abnormalities in retinoid signaling, or regulation of the retinoid pathway, lead to the development of the primary diaphragm defect and potentially to direct effects on lung development (reviewed in Ref. 33). Other studies have suggested that nitrofen alte...

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Antenatal vitamin A administration attenuates lung hypoplasia by interfering with early instead of late determinants of lung underdevelopment in congenital diaphragmatic hernia

Cited by 36 publications

References 38 publications

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

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

Ghrelin Expression in Human and Rat Fetal Lungs and the Effect of Ghrelin Administration in Nitrofen-Induced Congenital Diaphragmatic Hernia

Mechanisms of action of the congenital diaphragmatic hernia-inducing teratogen nitrofen

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