10th Nils W. Svenningsen Memorial Lecture

Recent Advances in the Pathogenesis and Treatment of Persistent Pulmonary Hypertension of the Newborn
Steven H. Abman

Department of Pediatrics, University of Colorado School of Medicine and The Children's Hospital, Denver, Colo., USA

Address of Corresponding Author

Neonatology 2007;91:283-290 (DOI: 10.1159/000101343)

  Key Words

• Persistent pulmonary hypertension of the newborn
• Nitric oxide
• Cyclic GMP
• Pulmonary hypertension
• Rho-kinase
• Fasudil
• Superoxide dismutase
• Sildenafil
• BAY 41-2272
• Lung development
• Endothelin-1
• Vascular endothelial growth factor

  Abstract

Persistent pulmonary hypertension of the newborn (PPHN) is a clinical syndrome characterized by failure of the lung circulation to achieve or sustain the normal drop in pulmonary vascular resistance (PVR) at birth. Past laboratory studies identified the important role of nitric oxide (NO)-cGMP signaling in the regulation of the perinatal lung circulation, leading to the development and application of inhaled NO therapy for PPHN. Although inhaled NO therapy has improved the clinical course and outcomes of many infants, pulmonary hypertension can be refractory to inhaled NO, suggesting the need for additional approaches to severe PPHN. To develop novel therapeutic strategies for PPHN, ongoing studies continue to explore basic mechanisms underlying the pathobiology of PPHN in experimental models, including strategies to enhance NO-cGMP signaling. Recent studies have demonstrated that impaired vascular endothelial growth factor (VEGF) signaling may contribute to the pathogenesis of PPHN. Lung VEGF expression is markedly decreased in an experimental model of PPHN in sheep; inhibition of VEGF mimics the structural and functional abnormalities of PPHN, and VEGF treatment improves pulmonary hypertension through upregulation of NO production. Other studies have shown that enhanced NO-cGMP activity through the use of cGMP-specific phosphodiesterase inhibitors (sildenafil), soluble guanylate cyclase activators (BAY 41-2272), superoxide scavengers (superoxide dismutase), and rho-kinase inhibitors (fasudil) can lead to potent and sustained pulmonary vasodilation in experimental PPHN. Overall, these laboratory studies suggest novel pharmacologic strategies for the treatment of refractory PPHN.

Copyright © 2007 S. Karger AG, Basel

  Author Contacts

Steven H. Abman, MD
The Children's Hospital, B-395
1056 E. Nineteenth Avenue
Denver, CO 80218-1088 (USA)
Tel. +1 303 837 2522, Fax +1 303 837 2924, E-Mail steven.abman@uchsc.edu

  Article Information

Published online: June 7, 2007
Number of Print Pages : 8
Number of Figures : 2, Number of Tables : 1, Number of References : 76