Although persistent pulmonary hypertension of the newborn (PPHN) is a significant clinical problem associated with marked morbidity and mortality, its pathogenesis and pathophysiology are poorly understood. Characterized by the failure to achieve or sustain pulmonary vasodilation at birth, or by the presence of an exaggerated response to hypoxia or other vasoconstrictor stimuli, PPHN is often associated with remodeling of the pulmonary vasculature in utero. Previous animal studies have suggested that chronic hypoxia or hypertension may cause structural alterations of the fetal pulmonary vascular bed. However, etiologic and pathophysiologic mechanisms contributing to altered vasoreactivity or structural abnormalities of the perinatal pulmonary circulation following exposure to chronic intrauterine hypoxia and hypertension are not known. In addition, although PPHN is often associated with acute asphyxia in the immediate postnatal period, the exact relationship between acute hypoxia and neonatal pulmonary hypertension is unclear. We hypothesize that chronic intrauterine stimuli, such as hypertension and hypoxia, can alter the fetal pulmonary circulation, leading to abnormal vascular reactivity and structural remodeling. Intrauterine injury to the pulmonary circulation may then lead to the inability to decrease pulmonary vascular resistance at birth, or to increased susceptibility to severe pulmonary vasoconstriction to acute asphyxia. Therefore, we propose to study the chronically-prepared fetal lamb in order to answer the following questions: 1. DO CHRONIC FETAL HYPERTENSION AND HYPOXIA CAUSE ABNORMAL VASCULAR REACTIVITY AND STRUCTURAL REMODELING OF THE FETAL AND TRANSITIONAL PULMONARY CIRCULATIONS? 2. CAN ACUTE ASPHYXIA OR PULMONARY HYPERTENSION CONTRIBUTE TO THE FAILURE OR POSTNATAL ADAPTATION OF THE PULMONARY CIRCULATION IN THE NORMAL FETUS, OR IN ANIMALS FOLLOWING CHRONIC HYPERTENSION OR HYPOXIA? 3. DO BIOACTIVE LIPIDS, SUCH AS ARACHIDONIC ACID METABOLITES OR PLATELET-ACTIVATING FACTOR, PLAY IMPORTANT ROLES IN THE PATHOGENESIS OR PATHOPHYSIOLOGY OF STRUCTURAL AND FUNCTIONAL CHANGES OF THE FETAL AND TRANSITIONAL PULMONARY CIRCULATIONS?
