Failure of the pulmonary circulation to achieve or sustain the normal decrease in pulmonary vascular resistance (PVR) at birth contributes significantly to the pathophysiology of two major clinical problems of post-natal adaptation: hyaline membrane disease (HMD) and persistent clinical pulmonary hypertension of the newborn (PPHN). Although surfactant therapy is effective in many premature neonates with severe HMD, patients who fail to respond have several disease which is characterized by elevated PVR and high mortality. In PPHN, a clinical syndrome of mostly full-term neonates high PVR causes right-to-left extra-pulmonary shunt and several hypoxemia. Mechanisms underlying pulmonary vascular dysfunction in premature neonates with sever HMD are poorly understood, but reflect the effect of immaturity and the response to acute post-natal lung injury. In contrast, altered pulmonary vascular reactivity and structure in mature neonates with severe PPHN are often due to chronic intrauterine stress. In both diseases, the pulmonary circulation fails to adapt to post-natal life with adequate reduction in PVR, causing profound hypoxemia and poor outcome. Experimental studies suggest that the endogenous nitric oxide (NO)-cGMP cascade (which includes activities of at least 3 enzyme systems: NO synthase (NOS), soluble guanylate cyclase (sGC) AND cGMP-specific (Type V) phosphodiesterase; PDE 5) modulates pulmonary vascular tone and reactivity in utero and contributes to the normal fall in PVR at birth. Since maturational changes in the NO-cGMP cascade occur during fetal life, the effects of premature birth and lung injury on pulmonary vasoreactivity are closely linked with disruption of normal developmental changes in endothelial and smooth muscle function. Whether altered NO-cGMP activity, such as an imbalance between NO5 and PDE5 activities, contribute to high PVR and abnormal vascoreactivity in diseases associated with failure of the pulmonary transition is unknown. In addition, inhaled NO has successfully treated many neonates with several PPHN, prematures with severe HMD, little is known about its potential toxicity, non-vasodilator effects in the developing lung, mechanisms underlying poor responsiveness in some patients, or possible effects on the endogenous NO-cGMP cascade. To examine mechanisms contributing to abnormalities of the perinatal pulmonary circulation and to better understand inhaled NO therapy, they propose a series of parallel experiments which examines the biochemistry and pathophysiology of the NO-cGMP cascade in the normal developing lung circulation and established models of HMD and PPHN in fetal lambs. These studies will test the hypothesis that: 1) severe prematurity and vascular injury due to acute post-natal lung injury or chronic hypertension in utero alter the pulmonary vascular NO-cGMP cascade, causing abnormal vasoreactivity and sustained elevations of PVR after birth; and 2) strategies which increase lung NO activity, such as inhaled NO therapy, inhibition of PDE5, or both, will lower PVR and improve oxygenation without adverse effects in the developing lung.
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