Elevated immunoreactive endothelin-1 levels in newborn infants with persistent pulmonary hypertension

Rosenberg, Adam A.; Kennaugh, Jan M.; Koppenhafer, Stacia L.; Loomis, Mary; Chatfield, Barbara A.; Abman, S. H.

doi:10.1016/s0022-3476(05)81552-5

Cited by 205 publications

(100 citation statements)

References 31 publications

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“…We also found that ET1 levels were associated with the severity of PH, after adjusting for the timing of the sample. Prior studies using a similar ET1 assay have shown that newborns with PPHN have elevated ET1 levels compared with unaffected control subjects (31 6 4.7 vs. 15.1 6 4.1 pg/ml) (30). Findings in other patient populations may help explain the elevations in ET1 seen in our patients with poor outcome.…”

Section: Discussionsupporting

confidence: 53%

“…Prior studies demonstrate that elevated plasma ET1 levels correlate with severity of various diseases (24)(25)(26)(27) and decreased lung clearance (26,28,29) in PH from diverse etiologies. In newborns with PH (PPHN) plasma ET1 levels are highest in the most severely-affected infants requiring extracorporeal membrane oxygenation support and decrease with resolution of the illness (17,30). 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).…”

mentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 53%

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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“…13,14 Studies using various ET receptor antagonists have confirmed that ET1 is a critical factor in the pathogenesis of vascular remodeling in experimental models of chronic pulmonary hypertension and clinical observation of pulmonary hypertension. 15,16 In addition to the role of ET1 as a potent vasoconstrictor, it also acts directly to modulate the growth of human pulmonary vascular smooth muscle cells as an autocrine/paracrine mitogen. 17,18 Additional factors, such as serotonin, platelet-derived growth factor (PDGF) and angiotensins, have been postulated to contribute to pulmonary vasoconstriction, increased smooth muscle growth and increased matrix deposition.…”

Section: Introductionmentioning

confidence: 99%

Involvement of the bone morphogenetic protein system in endothelin- and aldosterone-induced cell proliferation of pulmonary arterial smooth muscle cells isolated from human patients with pulmonary arterial hypertension

et al. 2010

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Recent genetic studies have uncovered a link between familial and idiopathic pulmonary arterial hypertension (PAH) and germline mutations in the bone morphogenetic protein type-II receptor (BMPRII). The pathology of PAH is characterized by remodeling of the pulmonary arteries due to pulmonary artery smooth muscle cell (PASMC) hyperproliferation. Although increased endothelial injury and impaired suppression of PASMC proliferation are both critical for the cellular pathogenesis of PAH, a detailed molecular mechanism underlying PAH has yet to be elucidated. In the present study, we investigated the roles of the BMP system and other vasoactive factors associated with PAH (including endothelin (ET), angiotensin II (Ang II) and aldosterone) in the mitotic actions of PASMCs isolated from idiopathic and secondary PAH lungs. ET1 and aldosterone stimulated PASMC proliferation of idiopathic PAH more effectively than secondary PAH, whereas Ang II and ET3 failed to activate mitosis in either of the PASMC cell type. The effects of ET1 and aldosterone were blocked by bosentan, an ET type-A/B receptor (ETA/BR) antagonist, and eplerenone, a selective mineralocorticoid receptor (MR) blocker, respectively. Among the BMP ligands examined, BMP-2 and BMP-7, but not BMP-4 or BMP-6, significantly increased cell mitosis in both PASMC cell types. Notably, ET1-and aldosterone-induced mitosis and mitogen-activated protein kinase phosphorylation were significantly increased in the presence of BMP-2 and BMP-7 in PASMCs isolated from idiopathic PAH, although additive effects were not observed in PASMCs isolated from secondary PAH. Inhibition of extracellular signal-regulated kinase 1 (ERK1)/ERK2 signaling suppressed basal-, ET1-and aldosterone-induced PASMC mitosis more potently than that of stress-activated protein kinase/c-Jun NH2-terminal kinase inhibition. Given the fact that BMP-2 and BMP-7 upregulated ETA/BR and MR expression and that BMP-2 decreased 11bHSD2 (11b-hydroxysteroid dehydrogenase type 2) levels in PASMCs isolated from idiopathic PAH, BMPR-Smad signaling may have a key role in amplifying the ETA/BR and/or MR-ERK signaling in PASMCs of the PAH lung. Collectively, the functional link between BMP and ET and/or the MR system may be involved in the progress of PASMC mitosis, ultimately leading to the development of clinical PAH.

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“…ET-1 is present in high levels at birth, with a gradual fall during the early neonatal period in healthy individuals (6). Elevated ET-1 levels have been demonstrated in animal models of meconium aspiration (7), in neonates with PPHN (3,8,9), and in older children (10) and adults (11) with pulmonary hypertension. Furthermore, the plasma ET-1 level appears to positively correlate with disease severity (8,9,12).…”

mentioning

confidence: 99%

“…Elevated ET-1 levels have been demonstrated in animal models of meconium aspiration (7), in neonates with PPHN (3,8,9), and in older children (10) and adults (11) with pulmonary hypertension. Furthermore, the plasma ET-1 level appears to positively correlate with disease severity (8,9,12).Therapy for pulmonary hypertension in the neonate is currently targeted at preventing or reversing the sequelae of pulmonary endothelial dysfunction. iNO improves oxygenation and reduces the need for extracorporeal life support in some of the most severe cases (13).…”

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confidence: 99%

Endothelin-A Receptor Blockade and Inhaled Nitric Oxide in a Porcine Model of Meconium Aspiration Syndrome

et al. 2004

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Acute neonatal pulmonary hypertension is associated with increased activation of the endogenous endothelin pathway. We investigated the role of selective endothelin-A receptor blockade using i.v. BQ-123 in a piglet model of meconium aspiration syndrome. Meconium aspiration was induced in 18 anesthetized piglets. Six controls received no further intervention. Six piglets received 1 mg/kg BQ-123 at 120 min, with the addition of 20 ppm inhaled nitric oxide at 240 min. Six commenced nitric oxide therapy at 120 min, and were given i.v. BQ-123 at 240 min. The total study duration was 360 min. Meconium aspiration resulted in acute pulmonary hypertension and elevated endothelin-1 levels in all animals. There were no changes in pulmonary hemodynamics or endothelin-1 levels beyond 120 min in controls. In the group receiving BQ-123 first, this agent alone reduced the pulmonary artery pressure and pulmonary vascular resistance, and the subsequent addition of inhaled nitric oxide further reduced pulmonary artery pressure. In the group first receiving nitric oxide alone, this reduced the pulmonary artery pressure, and the addition of BQ-123 resulted in a fall in pulmonary vascular resistance. Endothelin-1 levels increased with both agents. BQ-123 was found to be a highly effective pulmonary vasodilator and augmented the effects of nitric oxide in this model of acute pulmonary hypertension. Abbreviations PPHN, persistent pulmonary hypertension of the newborn PVR, pulmonary vascular resistance ET, endothelin iNO, inhaled nitric oxide PPHN occurs when there is a failure of the normal rapid fall in PVR and increase in pulmonary blood flow with the onset of respiration at birth (1). Meconium aspiration syndrome is the single most common cause of PPHN, and can result in significant morbidity and mortality in term and near-term infants (2).The normal transition from the high-resistance fetal circulation to the low-resistance postnatal pulmonary circulation is associated with activation of the endogenous vasodilator nitric oxide-cyclic guanosine 5'-monophosphate pathway, and reduced release of the potent pulmonary vasoconstrictor, ET (3). The ET-1 isopeptide is a 21-amino acid polypeptide (4) that is produced within the pulmonary endothelium by the cleavage of its precursor, pro-ET (big ET), by ET converting enzyme. ET-1 is released by the vascular endothelium, and produces its effects through its interaction with at least two receptor subtypes-the A and B receptors, located on the vascular smooth muscle and endothelium. The pulmonary vasoconstrictor effects of ET-1 result mainly from activation of the G-proteincoupled smooth muscle A receptor, whereas stimulation of the endothelial ET-B receptor has been shown to result in vasodilatation (5). ET-1 is present in high levels at birth, with a gradual fall during the early neonatal period in healthy individuals (6). Elevated ET-1 levels have been demonstrated in animal models of meconium aspiration (7), in neonates with PPHN (3,8,9), and in older children (10) and adults (11) with pulmo...

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Elevated immunoreactive endothelin-1 levels in newborn infants with persistent pulmonary hypertension

Cited by 205 publications

References 31 publications

Congenital Diaphragmatic Hernia

Congenital Diaphragmatic Hernia

Involvement of the bone morphogenetic protein system in endothelin- and aldosterone-induced cell proliferation of pulmonary arterial smooth muscle cells isolated from human patients with pulmonary arterial hypertension

Endothelin-A Receptor Blockade and Inhaled Nitric Oxide in a Porcine Model of Meconium Aspiration Syndrome

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