ROLE OF SURFACTANT PROTEINS IN PULMONARY HOST DEFENSE

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Surfactant is a lipoprotein complex secreted by the alveolar epithelial type II cell into the liquid lining of the airspaces where it carries out two functions. First surfactant reduces surface tension at the air-liquid interface and second, surfactant participates in protecting the lung from pathogens. Work from the previous funding period as well as from other laboratories has provided evidence that the two hydrophilic surfactant proteins, SP-A and SP-D, opsonize and enhance the uptake of pathogens by alveolar macrophages. The levels of SP-A and SP-D are increased in a model of acute lung injury and can increase the migration of immune cells to sites of infection or inflammation. Our most recent data suggest that SP-A and SP- D also modulate immune cell responses that. if excessive could cause inflammation and damage the delicate pulmonary epithelium. It is well established that many immune cell responses are a double-edged sword: i.e. the responses that help fight invading pathogens can also harm the host tissue. We hypothesize that SP-A and SP-D exert selective effects on alveolar macrophages the primary immune cell in the non-inflamed lung and on neutrophils, the primary immune cell in the inflamed lung. The net result is that host tissue is effectively defended without induction of a damaging proinflammatory response. Four aims are proposed. Aim l is to determine if SP-A and SP-D selectively modulate production of cytokines by alveolar macrophages and neutrophils so that the host is defended but inflammation is minimized. Aim 2 is to define the mechanism by which SP-A down regulates macrophage production of TNF-alpha and to determine if SP-D has similar effects via similar mechanisms. Aim 3 is to investigate the functional significance of the interaction of SP-A and SP-D with neutrophils, and, in particular, to examine the role of SP-A and SP-D in facilitating the clearance of apoptotic neutrophils. Aim 4 is to investigate the role SP-A and SP-D receptors, including a membrane bound and soluble form of gp340, in regulating macrophage function. These studies will help define mechanisms of immune cell regulation and could have important implications for developing novel surfactant therapies for treatment of inflammatory and infectious lung diseases in adults and children.