The overall goal is to investigate the regulation of lipid metabolism in the lung with major emphasis on the lung surfactant system. Sufficient information concerning the pathways of synthesis and nature of the surfactant lipids and apoproteins has been obtained to allow concentration on the regulation processes of individual steps as well as concerted regulation of the system as a whole. In order to be able to identify regulatory steps and perturb the system, lungs from diabetic rats and rats fasted for up to 96 hours will be used. Both of these states are known to cause alterations in the surfactant system. The models for study include the isolated perfused lung, type II epithelial cells in primary culture and importantly, subcellular fractions isolated from type II cells.
The specific aims of the project are: (1) To continue to perform studies to establish in alveolar type II cells the pathways, subcellular location(s) and rate limiting steps in the synthesis of individual lipids of pulmonary surfactant and the regulation of production of each. (2) To initiate studies on the concerted regulation of the synthesis and accumulation of phospholipid components which constitute pulmonary surfactant as it is stored in the lamellar bodies of the type II cell. (3) To investigate at the biochemical level the secretion-reutilization cycle of pulmonary surfactant phospholipids by the type II cells. Reutilization studies will include defining the mechanism of cellular uptake including the specificity of uptake, factors which affect uptake and the fate of the phospholipids which are internalized by the type II cell, including intracellular location of such events. Secretion studies will include the effect of secretory rate on the rate of reutilization of surfactant and the effect of decreased reutilization on the secretory rate. A link between the process of reutilization of surfactant and the """"""""basal"""""""" secretory rate will be explored. And (4) to determine if the identified apoproteins of pulmonary surfactant found on the alveolar surface have a function in the processing, storage, secretions and reutilization of pulmonary surfactant. It is anticipated that the knowledge obtained from these studies will contribute significantly to better clinical care and ultimately prevention of respiratory distress syndrome in the newborn. As well, the knowledge obtained of the individual components of the surfactant system should add to our understanding of the molecular mechanisms involved which may apply to similar processes in other cells.
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