The themes of this proposal are: 1) that alterations of growth of the pulmonary microcirculation contribute substantially to the genesis and maintenance of pulmonary vascular disease associated with many cardiorespiratory disorders of the newborn and 2) that quantitative assessment of metabolic functions of pulmonary endothelium will provide a sensitive biochemical probe of microcirculatory growth and integrity during pathologic as well as normal development. To test these hypotheses, we outline a comprehensive quantitative functional and structural assessment of the pulmonary microcirculation in lambs with aberrations of pulmonary vascular development. Two groups will be studied: a) chemically-induced lung injury via delivery of bleomycin with a s.c. osmotic pump during the first week of life; and b) surgically-induced lung changes in the left lung after right pulmonary artery ligation in one day old lambs. Conscious lambs will be studied for one week to six months. Indicator-dilution techniques will be used to quantify the apparent kinetics (maximal velocity: Vmax; concentrataion at Vmax/e2:Km) of Pulmonary angiotensin-converting enzyme (ACE) activity. Pulmonary amine uptake will also be measured in-line with a nuclear detection system and (125I)-meta-iodo-benzyl-guanidine (a photon-emitting synthetic substrate that mimics norepinephrine uptake in biological systems). These biochemical properties of the endothelium will be correlated with physiological assessment of gas exchange surface area (carbon monoxide diffusing capacity) as well as post-mortem morphometric assessment of the microcirculation (stereologic evaluation of the alveolar septum after glutaraldhyde fixation and election microscopy) and arterial circulation (barium sulfate fixation, radiography with light microscopy). We have already shown that Vmax of pulmonary ACE is directly proportional to perfused area during normal development. These new data during pathologic states will provide information regarding: 1) the degree to which alterations in the pulmonary microvascular structure and growth are reflected in lung metabolic function and gas exchange. 2) the diagnostic potential of in vivo metabolic measures to detect abnormalities in microvascular development for clinical as well as experimental use. 3) the role of the pulmonary microcirculation, independent of or in addition to the pulmonary arterial circulation, in the pathogenesis of pulmonary vascular disease.
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