Departments of Pediatrics and Anesthesia and Critical Care, Divisions of Newborn Medicine and Pediatric Anesthesia, and The Cardiovascular Research Center (CVRC)
Summary of Research
Lung injury in children often causes abnormal pulmonary arterial vasoreactivity and muscularization. Through processes that are incompletely understood, many children with lung injury develop progressive and irreversible pulmonary hypertension, intra- and extra-pulmonary shunting of deoxygenated blood, and severe hypoxemia. The long-term goals of my laboratory are to explore the fundamental mechanisms of lung injury and to develop novel therapies for pulmonary vascular disease.
We discovered that inhaled nitric oxide (NO) gas modulates pulmonary vasoconstriction associated with pulmonary vascular disease in the newborn. In the lung, NO is produced by endothelial cells diffuses into subjacent smooth muscle cells (SMC), where it increases cGMP levels and causes vasorelaxation. Because endogenous NO-cGMP signaling is decreased in patients with pulmonary vascular disease, we tested whether or not exogenous NO decreases pulmonary hypertension. In newborn lambs with pulmonary hypertension, we observed that low levels of inhaled NO rapidly cause pulmonary vasodilatation [1]. Furthermore, the dilator effect of inhaled NO was limited to the lungs since it did not cause systemic vasodilatation. After evaluating the dose-response to inhaled NO in the laboratory and developing a safe NO delivery system, we performed the first clinical trials of inhaled NO in pediatric patients with pulmonary hypertension [2]. Low levels of inhaled NO were observed to safely decrease hypoxemia and pulmonary hypertension in critically ill newborns with pulmonary vascular disease and intrapulmonary shunt [3]. Subsequently, my laboratory lead a prospective, randomized, placebo controlled, multicenter study that demonstrated that inhaled NO treatment decreases hypoxemia and the requirement for extracorporeal membrane oxygenation (ECMO) in newborns with pulmonary hypertension [4]. These studies stimulated investigations of inhaled NO in the pediatric lung through out the world and were pivotal in the acceptance of inhaled NO by the Federal Drug Administration of the United States as a therapy for pulmonary hypertension and hypoxemia in newborns. We also were the first to perform studies examining whether or not inhaled NO ameliorates pulmonary hypertension in patients with structural heart lesions. In the cardiac catheterization laboratory, we demonstrated that inhaled NO safely and selectively decreases pulmonary vasoconstriction in infants and children with congenital heart disease and pulmonary hypertension [5]. These later observations were the basis for several clinical trials that were performed demonstrating that inhaled NO prevents malignant pulmonary hypertension in many pediatric patients following cardiac surgery.
Our investigations also revealed that inhaled NO prevents abnormal pulmonary vascular remodeling in the injured lung. Previous studies indicate that NO signaling regulates cell proliferation. Our previous studies indicated inhalation NO is selectively delivered to the lung and has minimal systemic effects. Therefore, we tested whether or not inhaled NO decreases pulmonary artery cell proliferation in newborn animals with lung injury. We observed that inhaled NO attenuates abnormal pulmonary artery remodeling in newborn animals [6, 7]. Furthermore, we determined that inhaled NO protects the lung against abnormal remodeling by directly inhibiting the proliferation of pulmonary artery smooth muscle cell precursors. These fundamental discoveries have recently stimulated the formation of several clinical investigations that are testing whether or not inhaled NO prevents pulmonary vascular disease in newborns with lung injury.
My current laboratory investigations are directed at examining the fundamental mechanisms of PKG-mediated anti-proliferation. We are using molecular and biochemical techniques to identify specific PKG phosphorylation targets that account for its role in modulating vascular smooth muscle cell proliferation. These studies will provide important clues about potential therapeutic approaches that could prevent abnormal cell proliferation. We are also performing some exciting studies that are investigating whether modulation of cytokines in the injured newborn lung modulates pulmonary disease. We anticipate that these fundamental studies will lead to the discovery of new ways to prevent and treat important lung diseases in newborns and infants.
In summary, our studies reveal that inhaled NO is an important therapy for pulmonary vascular disease in newborns and children. Additionally, NO-PKG signaling is an important antiproliferative mechanism in vascular smooth muscle cells.
References
- Roberts, J.D., Jr., et al., Inhaled nitric oxide reverses pulmonary vasoconstriction in the hypoxic and acidotic newborn lamb. Circ Res, 1993. 72(2): p. 246-54.
- Roberts, J.D., Jr., et al., Inhaled Nitric Oxide (NO): A Selective Pulmonary Vasodilator for the Treatment of Persistent Pulmonary Hypertension of the Newborn (PPHN). Circulation, 1991. 84: p. A1279.
- Roberts, J.D., et al., Inhaled nitric oxide in persistent pulmonary hypertension of the newborn. Lancet, 1992. 340(8823): p. 818-9.
- Roberts, J.D., Jr., et al., Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. The Inhaled Nitric Oxide Study Group. N Engl J Med, 1997. 336(9): p. 605-10.
- Roberts, J.D., Jr., et al., Inhaled nitric oxide in congenital heart disease. Circulation, 1993. 87(2): p. 447-53.
- Roberts, J.D., Jr., et al., Continuous nitric oxide inhalation reduces pulmonary arterial structural changes, right ventricular hypertrophy, and growth retardation in the hypoxic newborn rat. Circ Res, 1995. 76(2): p. 215-22.
- Roberts, J.D., Jr., et al., Nitric oxide inhalation decreases pulmonary artery remodeling in the injured lungs of rat pups. Circ Res, 2000. 87(2): p. 140-5.
Additional Information
- Roberts, J.D., Jr. and P.W. Shaul, Advances in the treatment of persistent pulmonary hypertension of the newborn. Pediatr Clin North Am, 1993. 40(5): p. 983-1004.
- Roberts, J.D., Jr. and W.M. Zapol, Inhaled nitric oxide. Semin Perinatol, 2000. 24(1): p. 55-8.
Contact Information
Phone: 617-724-3104
Fax: 617-726-5806
