The Cardiovascular Research Center at Massachusetts General Hospital


Jesse Roberts

Jesse Roberts

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Science - Molecular mechanisms of newborn and infant lung diseases
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.

Recently, we discovered that modulating transforming growth factor-beta (TGF-beta) activity can improve the development of the injured newborn lung and might provide an important new way to prevent or treat bronchopulmonary dysplasia in premature infants [8]. Bronchopulmonary dysplasia (BPD) is an important lung disease of premature newborns that afflicts nearly 10,000 - 20,000 infants per year in the United States. Although the precise causes of BPD are not fully understood, it appears to be associated with the inhibition of normal pulmonary development in the injured lung. In premature infants, BPD is associated with an increase need for oxygen therapy, long-term difficulties with breathing, and poor body growth and neurological development. Infants with BPD often require prolonged hospitalizations and medical therapies. BPD can also cause lung problems into adulthood. Along with asthma, BPD accounts for the highest expenditure of health care dollars for pediatric patients in the United States.

Studies suggest that abnormalities in cytokines and growth factors can contribute to the abnormal lung development observed in infants with BPD. For example, the levels of several of these mediators are changed in newborns and infants with lung injury that develop BPD. One of these mediators, TGF-beta, has been observed to be increased in premature infants that develop BPD. We were specifically interested in this mediator because studies by others showed that it regulates some cellular changes that might be required for lung development and that it has been observed to be a key player in other lung diseases such as Marfan's disease. Moreover, TGF-beta has been observed to interact with nitric oxide and cGMP signaling in cells normally observed in the lung. However, the direct role of TGF-beta in mediating newborn lung injury and affecting the lung development problems observed in BPD were unknown. In collaboration with scientists from the Genzyme Corporation, who have expertise in TGF-beta modulating molecules, and using a mouse model of BPD, we observed that TGF-beta is expressed in the periphery of the developing lung, where BPD occurs, and that TGF-beta activity is increased in lung injury. Importantly, we observed that treating the mice with an antibody not only decreased the abnormal TGF-beta activity in the injured developing lung, but it also improved lung development (see figure below). These very exciting data show that TGF-beta is an important player in the severe inhibition of pulmonary development that is observed in BPD, but they also point the way to using molecular inhibitors of TGF-beta to prevent or treat BPD.



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 directed at figuring out how modulating cytokines in the injured newborn lung might improve pulmonary development. We anticipate that these fundamental studies will lead to the discovery of important new ways to prevent and treat important lung diseases in newborns and infants.

In summary, our studies reveal that modulating the activity of key signaling molecules like nitric oxide and TGF-beta can importantly protect the injured developing lung and might have an important role in preventing important pulmonary diseases of newborns and infants.

Publications:
To find out more about Jesse Roberts' research, read the selected publications listed below.

References:

    1. 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.

    2. 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.

    3. Roberts, J.D., et al., Inhaled nitric oxide in persistent pulmonary hypertension of the
        newborn. Lancet, 1992. 340(8823): p. 818-9.

    4. 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.

    5. Roberts, J.D., Jr., et al., Inhaled nitric oxide in congenital heart disease. Circulation,
        1993. 87(2): p. 447-53.

    6. 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.

    7. 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.

    8. Nakanishi H, et al. TGF-beta neutralizing antibodies improve pulmonary alveologenesis
        and vasculogenesis in the injured newborn lung. Am J Physiol Lung Cell Mol Physiol,
        2007.

Additional information:

    1. 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.

    2. Roberts, J.D., Jr. and W.M. Zapol, Inhaled nitric oxide. Semin Perinatol, 2000. 24(1):
        p. 55-8.

For patients interested in seeing Dr. Roberts in his clinical practice, click here or call 617-726-9040.


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