Modulating effect of a selective endothelin A receptor antagonist on pulmonary endothelin system protein expression in experimental diaphragmatic hernia

Kavanagh, Mélanie; Seaborn, Tommy; Crochetière, Josiane; Fournier, Louis; Battistini, Bruno; Piedboeuf, Bruno; Major, Diane

doi:10.1016/j.jpedsurg.2005.05.058

Cited by 6 publications

(2 citation statements)

References 54 publications

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“…ET1 is elevated at admission in patients with CDH compared with healthy control subjects (31), and pulmonary expression of both endothelin A and B (ETA and ETB) receptors are increased in infants who died with PH at less than 3 days of age (32). Experimental models have yielded limited data, suggesting a possible developmental role of ET1 in CDH-associated lung hypoplasia (33) and abnormal ET1 signaling in fetal CDH (34)(35)(36). However, there are no longitudinal data in either humans or animal models to lend insight into the potential pathophysiological role of ET1 in vascular remodeling and growth in infants with CDH.…”

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confidence: 99%

Congenital Diaphragmatic Hernia

Keller

Tacy²,

Hendricks‐Muñoz³

et al. 2010

Am J Respir Crit Care Med

140

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Rationale: Endothelin-1 (ET1) is dysregulated in pulmonary hypertension (PH). It may be important in the pathobiology of congenital diaphragmatic hernia (CDH). Objectives: We hypothesized that ET1 levels in the first month would be higher in infants with CDH who subsequently expired or were discharged on oxygen (poor outcome). We further hypothesized that ET1 levels would be associated with concurrent severity of PH. Methods: We sampled plasma at 24 to 48 hours, and 1, 2, and 4 weeks of age in 40 prospectively enrolled newborns with CDH. We performed echocardiograms to estimate pulmonary artery pressure at less than 48 hours of age and weekly to 4 weeks. PH was classified in relationship to systemic blood pressure (SBP): less than 2/3 SBP, 2/3 SBP-systemic is related to pressure, or systemic-to-suprasystemic pressure. Measurements and Main Results: ET1 levels at 1 and 2 weeks were higher in infants with poor outcome compared with infants discharged on room air (median and interquartile range: 27.2 [22.6, 33.7] vs. 19.1 [16.1, 29.5] pg/ml, P 5 0. 03; and 24.9 [17.6, 39.5] vs. 17.4 [13.7, 21.8] pg/ml, P 5 0.01 at 1 and 2 weeks, respectively). Severity of PH was significantly associated with increasing ET1 levels at 2 weeks (16.1 [13.7, 21.8], 21.0 [17.4, 31.1], and 23.6 [21.9, 39.5] pg/ml for increasing PH class, P 5 0.03). Increasing severity of PH was also associated with poor outcome at that time (P 5 0.001). Conclusions: Infants with CDH and poor outcome have higher plasma ET1 levels and severity of PH than infants discharged on room air. Severity of PH is associated with ET1 levels.

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mentioning

confidence: 99%

Congenital Diaphragmatic Hernia

Keller

Tacy²,

Hendricks‐Muñoz³

et al. 2010

Am J Respir Crit Care Med

140

View full text Add to dashboard Cite

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“…In addition to its role in the regulation of vascular tone, ET-1 is a potent PASMC mitogen ( 22 ). There are many reports from both human and animal studies describing elevated serum ET-1 levels in infants with CDH with a direct correlation between serum levels and disease severity ( 24 , 25 , 32 ). ET-1 increases PASMC proliferation through direct mitogenic effects on PASMC ( 22 ) and increased ROS production ( 19 ).…”

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confidence: 99%

Altered pulmonary artery endothelial–smooth muscle cell interactions in experimental congenital diaphragmatic hernia

et al. 2015

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BackgroundPulmonary hypertension (PH) secondary to vascular remodeling contributes to poor outcomes in congenital diaphragmatic hernia (CDH), however mechanisms responsible are unknown. We hypothesized that pulmonary artery endothelial cell (PAEC) dysfunction contributes to smooth muscle cell (SMC) hyperplasia in experimental CDH.MethodsPAEC and SMC were isolated from fetal sheep with experimental CDH and controls. SMC growth was assessed alone and with SOD plus catalase and during co-culture with control or CDH PAEC with and without ET-1 siRNA transfection. ET-1 protein was measured in PAEC and PASMC lysates and supernatant. ROS production was measured in normal and CDH PAECs with and without ET-1 siRNA. PAEC growth and tube formation were measured with SOD plus catalase.ResultsCDH SMC growth was decreased and and increased with co-culture with CDH PAEC more than control PAEC. Treatment of CDH PAEC with SOD plus catalase or ET-1 siRNA prevented the increase in SMC growth seen with co-culture. ET-1 protein was increased in CDH PAEC and SMC. ROS production was increased in CDH PAEC and decreased with ET-1 SiRNA. SOD plus catalase restored CDH PAEC growth and tube formation.ConclusionsPAEC dysfunction in experimental CDH increases SMC proliferation via ET-1 induced ROS production by PAEC.

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Pathogenesis of congenital diaphragmatic hernia: Additional clues regarding the involvement of the endothelin system

Mesdag

Andrieux

Coulon

et al. 2013

American J of Med Genetics Pt A

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Congenital diaphragmatic hernia (CDH) has an incidence of around 1/3,000 births. The pathogenesis of this developmental anomaly remains largely unknown and the description of small chromosomal imbalances in cases of CDH is of major interest for the identification of candidate genes. We report on a tandem 4q31.23 triplication encompassing the EDNRA gene identified by array-CGH in a male presenting an isolated left postero-lateral CDH. This copy number variation was inherited from the asymptomatic father, carrier of a size-identical duplication. We demonstrate that EDNRA mRNA is over-expressed in the proband in blood tissue. Consistent with the expression of EDNRA in the developing diaphragm and the observation that the endothelin system is up-regulated in human and animal models of CDH, we conclude that the EDNRA triplication may be the cause of CDH in our patient.

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Modulating effect of a selective endothelin A receptor antagonist on pulmonary endothelin system protein expression in experimental diaphragmatic hernia

Cited by 6 publications

References 54 publications

Congenital Diaphragmatic Hernia

Congenital Diaphragmatic Hernia

Altered pulmonary artery endothelial–smooth muscle cell interactions in experimental congenital diaphragmatic hernia

Pathogenesis of congenital diaphragmatic hernia: Additional clues regarding the involvement of the endothelin system

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