This porposal outlines a comprehensive quantitative functional and structural assessment of the pulmonary microcirculation of developing mammals. Using a non-linear model of lung metabolism, information obtained from outflow curves of indicator dilution techniques will provide estimates of apparent kinetics (Vmax; Km) of pulmonary angiotensin-converting enzyme (ACE) activity and 5-hydroxytryptamine (5-HT) removal processes. These biochemical functional properties of the endothelium will be measured in conscious growing lambs (1 day to 2 months of age) and correlated with other physiological measures of the pulmonary circulation (i.e. pressure, flow, carbon monoxide diffusing capacity) as well as postmortem morphometric assessment of the microcirculation (stereological evaluation of the alveolar septum after gluteraldehyde fixation and electron microscopy) and arterial circulation (barium sulfate fixation, radiography with light microscopic morphometry). These associations of function and structure will be evaluated in normal lambs and guinea pigs, and in lambs developing with hyperperfusion and pulmonary hypertension (secondary to unilateral lung ligation or glass bead microembolism at 1 day of age) and guinea pigs whose microcirculation was obstructed with 500 u beads or more diffusely with 50 u beads. These data will describe the normal development of the pulmonary microcirculation as well as pathologic changes in the microciuculation which may occur during hyperperfusion, disrupted perfusion of hypertension - conditions underlying several forms of congenital heart and respiratory disease in the developing child. A potentially sensitive quantitative measure of endothelial cell function (i.e. lung metabolism) will be tested and its significance correlated with structural changes in the remodeling, growing pulmonary vasculature of developing mammals. This information may suggest a novel diagnostic approach to evaluate pulmonaryu microcirculatory function in the child with congenital heart disease - conditions frequently associated with disruption of the pulmonary vasculature. Furthermore, although there is considerable information about the arterial changes present with these pathologic states, little is known of the early changes in the capillary bed - clearly an important site because of its role in gas exchange as well as its contributions to vascular resistance.
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