Endothelin-1 in persistent pulmonary hypertension of the neonate

Abstract

To the Editor:Rosenberg et al. (J Pediatr 1993;123:109-14) reported that circulating immunoreactive endothelin-1 (irET-1) levels were elevated in a heterogeneous group of neonates with persistent pulmonary hypertension of the newborn (PPHN). Whereas irET-1 levels were found to correlate with disease severity, decline of irET-1 levels correlated with resolution of disease only in those neonates who did not require extracorporeal membrane oxygenation (ECMO) therapy. The irET-1 levels predicted which patient required ECMO therapy but did not correlate with resolution of disease or successful decannulation from ECMO. We have several comments and questions:1. Infants with PPHN who required ECMO support had higher irET-1 levels than those that did not require ECMO therapy. The former group had a higher mean pre-ECMO oxygenation index (OI) and alveolar-arterial difference in partial pressure of oxygen (Pa-a]o2). These results are consistent with data showing that hypoxia increases preproendothelin messenger RNA levels and protein product in cultured human umbilical vein endothelial cells from infants with PPHN.1Kourembanas S Marsden PA McQuillan LP et al.Hypoxia induces endothelin gene expression and secretion in cultured human endothelium.J Clin Invest. 1991; 88: 1054-1057Crossref PubMed Scopus (628) Google Scholar, 2Kourembanas S Hypoxic responses of the neonatal endothelium.Semin Perinatol. 1992; 16: 140-146PubMed Google Scholar Rosenberg et al. showed that, with time, irET-1 levels decrease significantly in infants treated without ECMO; the levels remain essentially unchanged in those with PPHN who are treated with ECMO. It would be interesting to attempt to correlate irET-1 levels during ECMO therapy with respective OI and/or P(a-a)o2 calculations, to determine whether the relatively constant levels of irET-1 levels in PPHN treated with ECMO resulted from a persistently elevated OI, P(a-a)o2, or both.2. The authors found no correlation between pre-ECMO irET-1 levels and the duration of ECMO support, or between the day 5 irET-1 level and the time to ECMO decannulation. In addition to vasoactive properties, endothelin-1 has mitogenic properties for subjacent smooth muscle cells (proliferation and migration) in the pulmonary vascular bed. Does responsiveness to inhaled nitric oxide correlate with irET-1 levels? The authors state that PPHN may be related to increased production of endothelin-1 or decreased production of endothelium-derived relaxing factor. Are they suggesting that there may be a feedback modulation of the two systems?3. Administration of heparin reduces irET-1 levels in cultured media of umbilical vein endothelial cells.3Rosenfeld L Arrigo LMG Dweck HS Heparin (HEP) reduces immunoreactive endothelin-1 (ET-1) levels in the media of cultured endothelial cells [Abstract].Pediatr Res. 1993; 33: 56ACrossref PubMed Scopus (108) Google Scholar, 4Imai T Hirata Y Emori T et al.Heparin has an inhibitory effect on endothelin-1 synthesis and release by endothelial cells.Hypertension. 1993; 21: 353-358Crossref PubMed Scopus (55) Google Scholar If both the OI and P(a-a)o2 values did not differ in infants with PPHN who received ECMO therapy and infants with PPHN who were treated conservatively, how can the authors reconcile the fact that the former group had elevated levels of irET-1 during systemic heparinization while receiving ECMO therapy?4. Several reports indicate that surfactant therapy may decrease morbidity in meconium aspiration syndrome, sepsis, and congenital diaphragmatic hernia, among others.5Jobe AH Pulmonary surfactant therapy.N Engl J MEd. 1993; 328: 861-868Crossref PubMed Scopus (558) Google Scholar, 6Glick PL Leach CL Besner GE et al.Pathophysiology of congenital diaphragmatic hernia. III. exogenous surfactant therapy for the high risk neonate with CDH.J Pediatr Surg. 1992; 27: 866-869Abstract Full Text PDF PubMed Scopus (128) Google Scholar, 7Wilcox DT Glick PL Karamanoukian H Rossman J Morin III, FC Holm BA Pathophysiology of congenital diaphragmatic hernia. V. Effect of exogenous surfactant therapy on gas exchange and lung mechanics in the lamb congenital diaphragmatic hernia model.J PEDIATR. 1994; 124: xx-xxxAbstract Full Text Full Text PDF Scopus (80) Google Scholar Can the authors explain why surfactant-treated infants with hyaline membrane disease had lower endothelin-1 levels than "normal" (untreated) infants? Perhaps exogenous surfactant, pulmonary compliance, or barotrauma may be modulators of endothelin-1 release.9/35/52854 To the Editor:Rosenberg et al. (J Pediatr 1993;123:109-14) reported that circulating immunoreactive endothelin-1 (irET-1) levels were elevated in a heterogeneous group of neonates with persistent pulmonary hypertension of the newborn (PPHN). Whereas irET-1 levels were found to correlate with disease severity, decline of irET-1 levels correlated with resolution of disease only in those neonates who did not require extracorporeal membrane oxygenation (ECMO) therapy. The irET-1 levels predicted which patient required ECMO therapy but did not correlate with resolution of disease or successful decannulation from ECMO. We have several comments and questions:1. Infants with PPHN who required ECMO support had higher irET-1 levels than those that did not require ECMO therapy. The former group had a higher mean pre-ECMO oxygenation index (OI) and alveolar-arterial difference in partial pressure of oxygen (Pa-a]o2). These results are consistent with data showing that hypoxia increases preproendothelin messenger RNA levels and protein product in cultured human umbilical vein endothelial cells from infants with PPHN.1Kourembanas S Marsden PA McQuillan LP et al.Hypoxia induces endothelin gene expression and secretion in cultured human endothelium.J Clin Invest. 1991; 88: 1054-1057Crossref PubMed Scopus (628) Google Scholar, 2Kourembanas S Hypoxic responses of the neonatal endothelium.Semin Perinatol. 1992; 16: 140-146PubMed Google Scholar Rosenberg et al. showed that, with time, irET-1 levels decrease significantly in infants treated without ECMO; the levels remain essentially unchanged in those with PPHN who are treated with ECMO. It would be interesting to attempt to correlate irET-1 levels during ECMO therapy with respective OI and/or P(a-a)o2 calculations, to determine whether the relatively constant levels of irET-1 levels in PPHN treated with ECMO resulted from a persistently elevated OI, P(a-a)o2, or both.2. The authors found no correlation between pre-ECMO irET-1 levels and the duration of ECMO support, or between the day 5 irET-1 level and the time to ECMO decannulation. In addition to vasoactive properties, endothelin-1 has mitogenic properties for subjacent smooth muscle cells (proliferation and migration) in the pulmonary vascular bed. Does responsiveness to inhaled nitric oxide correlate with irET-1 levels? The authors state that PPHN may be related to increased production of endothelin-1 or decreased production of endothelium-derived relaxing factor. Are they suggesting that there may be a feedback modulation of the two systems?3. Administration of heparin reduces irET-1 levels in cultured media of umbilical vein endothelial cells.3Rosenfeld L Arrigo LMG Dweck HS Heparin (HEP) reduces immunoreactive endothelin-1 (ET-1) levels in the media of cultured endothelial cells [Abstract].Pediatr Res. 1993; 33: 56ACrossref PubMed Scopus (108) Google Scholar, 4Imai T Hirata Y Emori T et al.Heparin has an inhibitory effect on endothelin-1 synthesis and release by endothelial cells.Hypertension. 1993; 21: 353-358Crossref PubMed Scopus (55) Google Scholar If both the OI and P(a-a)o2 values did not differ in infants with PPHN who received ECMO therapy and infants with PPHN who were treated conservatively, how can the authors reconcile the fact that the former group had elevated levels of irET-1 during systemic heparinization while receiving ECMO therapy?4. Several reports indicate that surfactant therapy may decrease morbidity in meconium aspiration syndrome, sepsis, and congenital diaphragmatic hernia, among others.5Jobe AH Pulmonary surfactant therapy.N Engl J MEd. 1993; 328: 861-868Crossref PubMed Scopus (558) Google Scholar, 6Glick PL Leach CL Besner GE et al.Pathophysiology of congenital diaphragmatic hernia. III. exogenous surfactant therapy for the high risk neonate with CDH.J Pediatr Surg. 1992; 27: 866-869Abstract Full Text PDF PubMed Scopus (128) Google Scholar, 7Wilcox DT Glick PL Karamanoukian H Rossman J Morin III, FC Holm BA Pathophysiology of congenital diaphragmatic hernia. V. Effect of exogenous surfactant therapy on gas exchange and lung mechanics in the lamb congenital diaphragmatic hernia model.J PEDIATR. 1994; 124: xx-xxxAbstract Full Text Full Text PDF Scopus (80) Google Scholar Can the authors explain why surfactant-treated infants with hyaline membrane disease had lower endothelin-1 levels than "normal" (untreated) infants? Perhaps exogenous surfactant, pulmonary compliance, or barotrauma may be modulators of endothelin-1 release. Rosenberg et al. (J Pediatr 1993;123:109-14) reported that circulating immunoreactive endothelin-1 (irET-1) levels were elevated in a heterogeneous group of neonates with persistent pulmonary hypertension of the newborn (PPHN). Whereas irET-1 levels were found to correlate with disease severity, decline of irET-1 levels correlated with resolution of disease only in those neonates who did not require extracorporeal membrane oxygenation (ECMO) therapy. The irET-1 levels predicted which patient required ECMO therapy but did not correlate with resolution of disease or successful decannulation from ECMO. We have several comments and questions: 1. Infants with PPHN who required ECMO support had higher irET-1 levels than those that did not require ECMO therapy. The former group had a higher mean pre-ECMO oxygenation index (OI) and alveolar-arterial difference in partial pressure of oxygen (Pa-a]o2). These results are consistent with data showing that hypoxia increases preproendothelin messenger RNA levels and protein product in cultured human umbilical vein endothelial cells from infants with PPHN.1Kourembanas S Marsden PA McQuillan LP et al.Hypoxia induces endothelin gene expression and secretion in cultured human endothelium.J Clin Invest. 1991; 88: 1054-1057Crossref PubMed Scopus (628) Google Scholar, 2Kourembanas S Hypoxic responses of the neonatal endothelium.Semin Perinatol. 1992; 16: 140-146PubMed Google Scholar Rosenberg et al. showed that, with time, irET-1 levels decrease significantly in infants treated without ECMO; the levels remain essentially unchanged in those with PPHN who are treated with ECMO. It would be interesting to attempt to correlate irET-1 levels during ECMO therapy with respective OI and/or P(a-a)o2 calculations, to determine whether the relatively constant levels of irET-1 levels in PPHN treated with ECMO resulted from a persistently elevated OI, P(a-a)o2, or both. 2. The authors found no correlation between pre-ECMO irET-1 levels and the duration of ECMO support, or between the day 5 irET-1 level and the time to ECMO decannulation. In addition to vasoactive properties, endothelin-1 has mitogenic properties for subjacent smooth muscle cells (proliferation and migration) in the pulmonary vascular bed. Does responsiveness to inhaled nitric oxide correlate with irET-1 levels? The authors state that PPHN may be related to increased production of endothelin-1 or decreased production of endothelium-derived relaxing factor. Are they suggesting that there may be a feedback modulation of the two systems? 3. Administration of heparin reduces irET-1 levels in cultured media of umbilical vein endothelial cells.3Rosenfeld L Arrigo LMG Dweck HS Heparin (HEP) reduces immunoreactive endothelin-1 (ET-1) levels in the media of cultured endothelial cells [Abstract].Pediatr Res. 1993; 33: 56ACrossref PubMed Scopus (108) Google Scholar, 4Imai T Hirata Y Emori T et al.Heparin has an inhibitory effect on endothelin-1 synthesis and release by endothelial cells.Hypertension. 1993; 21: 353-358Crossref PubMed Scopus (55) Google Scholar If both the OI and P(a-a)o2 values did not differ in infants with PPHN who received ECMO therapy and infants with PPHN who were treated conservatively, how can the authors reconcile the fact that the former group had elevated levels of irET-1 during systemic heparinization while receiving ECMO therapy? 4. Several reports indicate that surfactant therapy may decrease morbidity in meconium aspiration syndrome, sepsis, and congenital diaphragmatic hernia, among others.5Jobe AH Pulmonary surfactant therapy.N Engl J MEd. 1993; 328: 861-868Crossref PubMed Scopus (558) Google Scholar, 6Glick PL Leach CL Besner GE et al.Pathophysiology of congenital diaphragmatic hernia. III. exogenous surfactant therapy for the high risk neonate with CDH.J Pediatr Surg. 1992; 27: 866-869Abstract Full Text PDF PubMed Scopus (128) Google Scholar, 7Wilcox DT Glick PL Karamanoukian H Rossman J Morin III, FC Holm BA Pathophysiology of congenital diaphragmatic hernia. V. Effect of exogenous surfactant therapy on gas exchange and lung mechanics in the lamb congenital diaphragmatic hernia model.J PEDIATR. 1994; 124: xx-xxxAbstract Full Text Full Text PDF Scopus (80) Google Scholar Can the authors explain why surfactant-treated infants with hyaline membrane disease had lower endothelin-1 levels than "normal" (untreated) infants? Perhaps exogenous surfactant, pulmonary compliance, or barotrauma may be modulators of endothelin-1 release. 9/35/52854