The respiratory distress syndrome (RDS) remains a major cause of morbidity and mortality for premature infants. While inadequate surfactant pools at birth precipitate the pathophysiology of RDS, very little is known about surfactant phospholipid metabolism during RDS and the effects of secondary pathophysiologic events on surfactant metabolism and function. Surfactant replacement therapy can effectively treat RDS as demonstrated in both animals and in early clinical trials; however, possible effects of that replacement therapy on endogenous surfactant metabolic pathways in the premature remain unexplored. This grant will combine biochemical and physiological studies of surfactant metabolism and function with measurements of pulmonary function such as the distribution of pulmonary blood flow, ventilation, and protein leak in the lungs of prematurely delivered and ventilated lambs with RDS. Surfactant metabolism (pool sizes, labeling kinetics, possible recycling), surfactant function (surface properties, aggregate sizes of surfactant within the airways, inhibitor), and the effect of treatment with natural sheep surfactant will be characterized. The permeability properties of the immature lung to preoteins and other large molecular weight molecules will be measured, and variables such as ventilation, surfactant treatment, and atelectasis that may affect the permeability will be studied. Other factors known to influence lung function in the premature such as birth asphyxia and the patent ductus arteriosus will be experimentally manipulated to better define the relationships between permeability changes and surfactant function. The experiments will provide quantitative measurements of multiple variables such that the relative importance of the different processes can be assessed. The overall goals are to establish an understanding of the relationships between surfactant function and metabolism and the pathophysiologic sequence of RDS, and to better characterize how exogenously administered surfactant affects the process.
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