Congenital diaphragmatic hernia: searching for answers

Gosche, John R.; Islam, Saleem; Boulanger, Scott C.

doi:10.1016/j.amjsurg.2005.05.035

Cited by 65 publications

(70 citation statements)

References 78 publications

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“…Pulmonary hypoplasia and persistent pulmonary hypertension are the primary causes of morbidity and mortality in infants with congenital diaphragmatic hernia (CDH) [1]. Much of the current understanding of pathogenesis of CDH originates from experimental studies.…”

Section: Introductionmentioning

confidence: 99%

Altered regulation of retinoic acid synthesis in nitrofen-induced hypoplastic lung

et al. 2007

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Retinoids are a group of molecules derived from vitamin A, which play an important role in lung development. Within the cell, retinol can either be oxidized to retinal or esterified to retinyl esters by lecithin : retinol acyltransferase (LRAT) for storage. Retinal is then oxidized to an active metabolite of vitamin A, retinoic acid (RA) by retinal dehydrogenase (RALDH). RA is the active metabolite of vitamin A. Cyp26 (a1,b1, and c1), which is a member of the cytochrome P450 family, acts by reducing the activity of RA. Cyp26 type b1 is the predominant subtype expressed in the murine lung. Several studies have suggested that nitrofen may interfere with the retinoid pathway resulting in congenital diaphragmatic hernia (CDH) and pulmonary hypoplasia. Recently, it was reported that nitrofen may act by inhibiting RALDH2. The aim of this study was to examine the pulmonary expression of Cyp26b1, LRAT, and RALDH2, the key enzymes involved in the synthesis of RA, in order to understand the mechanisms underlying pulmonary hypoplasia in the nitrofen CDH model. Pregnant rats were exposed to either olive oil or 100 mg of nitrofen on day 9 of gestation (D9). Fetal lungs were harvested at D15, D17, D19, and D21. D17, D19, and D21 lungs were divided into three groups: control, nitrofen without CDH and nitrofen with CDH, whereas D15 lungs were divided into only two groups; control and nitrofen as the diaphragm is not fully formed yet at this stage. Real- time PCR was performed to evaluate the relative level of Cyp26b1, LRAT, and RALDH2 expression in the lung. Relative levels of Cyp26b1 mRNA were significantly decreased in the lungs of nitrofen with CDH (D17;0.19 +/- 0.09, D19;0.70 +/- 0.20, D21;0.40 +/- 0.36) and nitrofen without CDH (D17;0.14 +/- 0.06, D19;0.54 +/- 0.42, D21;0.51 +/- 0.56) compared to controls (D17;0.35 +/- 0.16, D19;1.15 +/- 0.48, D21;1.28 +/- 0.78) (P < 0.05). LRAT expression was also significantly decreased in nitrofen with CDH (D17; 19.3 +/- 7.8, D19; 4.3 +/- 1.1, D21; 3.3 +/- 1.6) and nitrofen without CDH (D17; 21.2 +/- 11.1, D19; 4.5 +/- 3.6, D21; 4.1 +/- 1.6) compared to controls (D17; 153.7 +/- 29.8, D19; 26.8 +/- 16.8 D21; 10.1 +/- 3.8) (P < 0.05). There was no significant difference in the relative levels of Cyp26b1 and LRAT between nitrofen with CDH and nitrofen without CDH. There were no significant differences in RALDH2 expression among the groups at any stages. Down-regulation of Cryp26b1 and LRAT demonstrates that RA content is decreased in nitrofen induced hypoplastic lungs compared to controls. The finding that RALDH2 expression in the hypoplastic lung is not altered suggests that nitrofen may act by interfering with the retinoid metabolism during the early stage of the retinoid signaling pathway.

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Section: Introductionmentioning

confidence: 99%

Altered regulation of retinoic acid synthesis in nitrofen-induced hypoplastic lung

et al. 2007

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“…Regarding the most popular pathogenetic theory, CDH could result from a failed closure of pleuroperitoneal canals [17,19]. In the nitrofen rat model Kluth et al observed a cluster of abnormal liver cells (endoderm), adjacent to the lower border of the posthepatic mesenchymal plate (PHMP), to invade the thoracic cavity and a failure of the phrenic nerve (ectoderm) to penetrate into the PHMP, supporting the crucial role of an abnormal pattern of cell-cell interactions of different origin in the diaphragm closure.…”

Section: Case Reportmentioning

confidence: 99%

Congenital diaphragmatic hernia in CHARGE syndrome

et al. 2007

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Congenital diaphragmatic hernia (CDH) has been rarely described in CHARGE syndrome. We report a patient affected by CHARGE syndrome presenting with a right-sided Bochdalek-type diaphragmatic hernia, and collect the pertinent literature. Furthermore, we review the embryogenesis of the diaphragm and the pathogenesis of CDH to highlight if this malformation could be explained by a developmental anomaly of CHARGE. On the basis of our study, we suggest that patients affected by CDH, facial asymmetry and cardiovascular or urogenital malformations, should be actively screened for CHARGE syndrome findings.

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“…Pulmonary hypoplasia and hypertension are the primary causes of morbidity and mortality in infants with congenital diaphragmatic hernia (CDH) [1]. The association of pulmonary hypoplasia and disturbance of foetal renal function suggests that there may be a relationship between lung and kidney development [2,3].…”

Section: Introductionmentioning

confidence: 99%

Altered renin–angiotensin system gene expression causes renal hypoplasia in the rats with nitrofen-induced diaphragmatic hernia

et al. 2005

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The association between renal hypoplasia and pulmonary hypoplasia in congenital diaphragmatic hernia (CDH) has become recently appreciated. However, the underlying mechanisms responsible for this association are still unknown. Renin-angiotensin system (RAS) plays an important role in renal and somatic growth, angiogenesis and reproduction. We hypothesized that abnormal expression of RAS components may be responsible for renal hypoplasia in CDH. We therefore designed this study to examine the gene expression of main components of RAS in the kidney of nitrofen-induced CDH in the rat. Pregnant rats were exposed to either olive oil or 100 mg of nitrofen on day 9.5 of gestation. Foetuses were recovered at term and divided into three groups: control (n=8), nitrofen without CDH (n=8) and CDH (n=8). Reverse transcription polymerase chain reaction was performed to evaluate the relative amount of angiotensinogen (AGT), angiotensin II type 1 receptor with 1a and 1b subtypes (AT(1a)R and AT(1b)R), angiotensin II type 2 receptor (AT(2)R), angiotensin-converting enzyme (ACE) and renin expression in the kidney. AT(1a)R, AT(1b)R, AT(2)R, AGT and renin levels were significantly decreased in the kidney of CDH rats compared with controls. We did not find a significant difference in ACE between CDH animals and controls. Our data show that the downregulation of RAS may play an important role in the pathogenesis of renal hypoplasia in the nitrofen-induced CDH.

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Congenital diaphragmatic hernia: searching for answers

Cited by 65 publications

References 78 publications

Altered regulation of retinoic acid synthesis in nitrofen-induced hypoplastic lung

Altered regulation of retinoic acid synthesis in nitrofen-induced hypoplastic lung

Congenital diaphragmatic hernia in CHARGE syndrome

Altered renin–angiotensin system gene expression causes renal hypoplasia in the rats with nitrofen-induced diaphragmatic hernia

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