STRUCTURE AND FUNCTION OF SURFACTANT APOPROTEINS

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For optimal gas exchange the pulmonary alveolus must remain in an inflated state throughout the respiratory cycle. For this to occur the strong surface forces acting at the air-water interface in the alveolar lumen must be reduced by the presence of a functional surfactant. Because respiratory demands vary rapidly over a wide range with changing levels of activity and in disease states, the surfactant system must be capable of quickly responding to such changes with adjustments in rates of secretion and clearance at the alveolar level. This all implies the surfactant system must be under multiple levels of regulation and therefore contain molecules that both encode regulatory signals and respond to them (typically protein ligands and receptors) as well as molecules which primarily alter surface tension (typically amphipathic molecules such as phospholipids). Our broad objective is to contribute to a detailed understanding of the molecular controls of surfactant metabolism and how they may be altered in disease states. We will test the general hypothesis that specific surfactant apoproteins determine the structure of surfactant forms and are important in regulating the bi-directional flux of surfactant between alveolar lining cells and the alveolar lumen. Two novel observations made during the last grant period are important to the current proposal. First, our results suggested the fusogenic activity of SP-B may be relevant to lamellar body assembly. This idea is supported by findings in mice and accumulation of alveolar surfactant suggested an unsuspected role for SP-D in surfactant homeostasis. In this application we propose to study the molecular actions of surfactant protein-B that might be relevant to lamellar body assembly, and second, the role(s) of surfactant protein-D and cytokines in the regulation of alveolar type II cell proliferation and surfactant turnover.