Retinal Dehydrogenase-2 Is Inhibited by Compounds that Induce Congenital Diaphragmatic Hernias in Rodents

Mey, Jörg; Babiuk, Randal P.; Clugston, Robin D.; Zhang, Wei; Greer, John J.

doi:10.1016/s0002-9440(10)63861-8

Cited by 123 publications

(130 citation statements)

References 44 publications

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“…Indeed, one clinical study demonstrated the presence of decreased levels of retinol and retinol-binding protein in human CDH, suggesting a possible deterioration of retinol transport across the placenta (46). 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).…”

Section: Discussionmentioning

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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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%

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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“…The data derived from the study clearly demonstrated that all four CDH-inducing compounds inhibit RALDH-2 in a dose-dependent manner. Further, the most potent inhibitor of RALDH-2, bisdiamine, was also the most effective at inducing diaphragmatic defects in embryonic rats (13).…”

Section: Retinoid Signaling and Cdhmentioning

confidence: 91%

“…The similarities hold true with regard to the specific location and extent of diaphragmatic defects as well as the periodic occurrence of associated anomalies affecting cardiac, pulmonary and skeletal tissues. More recently, three additional compounds that cause diaphragmatic defects in rats have been characterized (13). Biphenyl carboxylic acid (BPCA), bisdiamine [N,N'-octamethylenebis (dichloroacetamide)] and SB-210661, all induce diaphragmatic as well as cardiopulmonary, dermal and skeletal defects in the fetuses isolated from treated pregnant rats.…”

Section: Insights Into the Pathogenesis Of Cdh From Animal Modelsmentioning

confidence: 99%

“…The developing diaphragm strongly expresses proteins associated with the metabolism and binding of retinoids (13,31). Studies of retinoid receptor double null-mutant mice, lacking both ␣ and ␤ subtypes of retinoic acid receptors (RAR), have demonstrated that some offspring have diaphragmatic hernias similar to those observed with nitrofen exposure or CDH (32,33).…”

Section: Retinoid Signaling and Cdhmentioning

confidence: 99%

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Etiology of Congenital Diaphragmatic Hernia: The Retinoid Hypothesis

2003

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Congenital diaphragmatic hernia (CDH) is a major lifethreatening cause of respiratory failure in the newborn. Although significant efforts have been undertaken to unravel the pathophysiology of CDH, our current understanding of the etiology remains spare. Here we outline recent evidence suggesting that abnormalities linked with the retinoid signaling pathway early in gestation may contribute to the etiology of CDH. These studies include 1) the effect of altering the retinoid system in vitamin A deficient and transgenic animals; 2) disruption of the retinoid system in teratogen-induced CDH in rodents, 3) the effect of co-administration of retinoids in nitrofen-induced CDH on lung and diaphragm development, and 4) clinical evidence suggesting decreased markers of vitamin A status in human CDH. Given the substantial mortality and morbidity associated with this serious developmental anomaly, advancements in this area will be critical. We feel that there is now sufficient circumstantial and direct experimental evidence to warrant further testing of the retinoid-CDH etiology hypothesis, including examination of retinoidregulated target genes that could be candidates for involvement in CDH. Severe respiratory failure in the newborn remains a main cause of neonatal death (1). Among the causes of severe respiratory failure in the newborn, congenital diaphragmatic hernia (CDH) remains the most life threatening (2, 3). Despite improvements in survival, the mortality rate is still high in many centers, and morbidity remains significant, with chronic oxygen dependence, gastroesophageal reflux, poor growth and developmental delay, and prolonged postoperative hospitalization of affected neonates (4). A major factor limiting survival in CDH is the degree of lung hypoplasia. Although tremendous efforts have been undertaken to unravel the pathophysiology of CDH, our current understanding of the pathogenesis and etiology remains spare. In this perspective, we review evidence linking abnormalities of the retinoid system and the occurrence of CDH. From the outset, it should be emphasized that a direct linkage between the etiology of CDH and retinoids has not been established. However, we summarize data from a variety of studies that provide a firm foundation for establishing the hypothesis that abnormalities within the retinoid signaling pathway during the early gestation contribute to the etiology of CDH. CONGENITAL DIAPHRAGMATIC HERNIA: THE CLINICAL DILEMMACDH occurs in 1/2500 live births (5). This malformation was first described in 1848 by Bochdalek, and for many years was thought to be a simple hole in the diaphragm, potentially curable by surgical closure of the defect after birth. However, unlike other causes of respiratory failure in the newborn, infants with CDH do not respond to our modern therapeutic armamentarium, including exogenous surfactant, high frequency oscillatory ventilation and inhaled nitric oxide (6). When conventional therapy fails, extra-corporeal membrane oxygenation (ECMO), a highly invasive, labor-intens...

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“…Abnormalities in the vitamin A status and/or metabolism may also play a role in the genesis of congenital diaphragmatic hernia (CDH). CDH can be induced in rodent by either maternal retinol deficiency during pregnancy (Anderson, 1941 and1949;Warkany and Wilson, 1948;Wilson et al, 1953;Mendelsohn et al, 1994;Lohnes et al, 1995), or administration of nitrofen, a retinal dehydrogenase type 2 (RalDH2) inhibitor reducing the RA production (Nakao and Ueki, 1987;Kluth et al, 1990;Mey et al, 2003). Therefore maternal administration of retinol or RA was recently proposed as a potential therapeutic measure to decrease foetal lung abnormalities in the rodent 'nitrofen-toxic' CDH (Thebaud et al, 1999;Babiuk et al, 2004;Oshiro et al, 2005).…”

mentioning

confidence: 99%

Expression of retinoid receptors during rabbit lung development

Coste

Gallot²,

Marceau³

et al. 2007

Animal

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Rabbit lung is often used to study the pathophysiology of some congenital anomalies affecting the lung because its development is very comparable with that of human. Retinoids and the molecular transducers of the retinoic signal play a crucial role in mammalian lung development. In the rabbit, the molecular retinoic pathway has so far been poorly studied. As a first step in elucidating this process, we aimed to identify the retinoic acid receptors (RARs) and retinoid X receptors (RXRs). We cloned a part of the nuclear receptors (RARs and RXRs), and we used reverse transcription -polymerase chain reaction (RT-PCR) and immunohistochemistry assays to demonstrate the presence of RAR (a,b) and RXR (a, b) at all stages of rabbit lung development. Our results initiate further analysis into the molecular and genetic functions of retinoids during normal and pathological rabbit lung development including the surgical model of congenital diaphragmatic hernia.Keywords: lung development, rabbits, retinoids, retinoic acid receptor, retinoid X receptor IntroductionMany factors including hormonal, biochemical and physical factors have been identified that modulate growth and development of the lung (Keijzer et al., 2000;Cardoso, 2001;Copland and Post, 2004;Rajatapiti et al., 2005). Among the variety of biochemical agents identified so far, retinoids (active derivatives of vitamin A) play a clearly defined role in lung development at its different stages (Gallot et al., 2005;Maden, 2004). Vitamin A (retinol) exerts important effects upon a vast number of development processes via signalling through heterodimerization complexes comprising retinoic acid receptors (RARs) and retinoid X receptors (RXRs) (Chambon, 1996). These receptors belong to the steroid/thyroid hormone receptor super family of ligand-inducible transcription regulators known to control the expression of target genes. All members of this family share a strongly conserved modular structure with discrete functional domains for ligand binding, DNA binding and transactivation. There are three RAR isotypes (RARa, b, g) activated by both all-trans and 9-cis retinoic acid (RA) and three retinoid X receptors (RXRa, b, g) only activated by 9-cis RA (Bastien and Rochette-Egly, 2004).The RAR and RXR proteins interact with each other to form RAR/RXR heterodimers which are able to bind to specific DNA sequences called RA responsive elements usually located within the 5 0 -regulatory region of retinoid-regulated genes.The importance of vitamin A in vertebrate lung development was first demonstrated by the observation that foetuses from pregnant rats which were fed a vitamin Adeficient diet had either agenesis of the left lung or rudimentary lung buds (Warkany and Wilson, 1948;Chazaud et al., 2003). Double mutant mice RARa, b 2/2 revealed defects comparable with the consequences of vitamin A deficiency including hypoplastic lungs (Mendelsohn et al., 1994;Kastner et al., 1997;Mascrez et al., 1998). Abnormalities in the vitamin A status and/or metabolism may also play a role in t...

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Retinal Dehydrogenase-2 Is Inhibited by Compounds that Induce Congenital Diaphragmatic Hernias in Rodents

Cited by 123 publications

References 44 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

Etiology of Congenital Diaphragmatic Hernia: The Retinoid Hypothesis

Expression of retinoid receptors during rabbit lung development

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