Although pulmonary surfactant has been traditionally viewed as a surface tension reducing substance, recent studies demonstrate that it also functions in host defense. Two surfactant proteins, SP-A and SP-D, arc members of a family of innate immune proteins known as collectins that bind pathogens and facilitate the clearance by immune cells. SF-A and SP-D also regulate a variety of immune cell functions. The hypothesis to be tested in this proposal is that SP-A and SP-D interact with cells of both the adapative and innate immune systems to coordinately maximize defense against inhaled particles and pathogens while minimizing potentially harmful inflammatory consequences. We propose that SF-A and SP-D enhance uptake and presentation of antigens by dendritic cells, as they passes through the airspace in response to an inflammatory challenge, and that SF-A and SP-D suppress lymphocyte activation while they are in the alveolar and airway compartments, thereby minimizing damage to the delicate pulmonary epithelium that could occur in the lymphocytes were constantly activated in the airspaces. These effects would maximize the ability of dendritic cells to present antigen once they migrate to the lymph nodes and encounter lymphocytes that are no longer suppressed by SP-A or SP-D. This model is consistent with previous observations that lung lymphocytes are hyporesponsive compared to circulating lymphocytes and with our preliminary data showing that SP-A an SP-D inhibit lymphocyte proliferation and enhance antigen presentation by dendritic cells. The hypothesis will be tested by investigating 4 specific aims.
Aim 1 is to determine if SP-A and SP-t enhance antigen uptake and presentation by dendritic cells.
Aim 2 is to determine if SP-A and SP-D affect production of regulatory molecules (cytokines, cell surface receptors, and co-stimulatory molecules) b) dendritic cells stimulated with either antigen or LPS.
Aim 3 is to investigate the mechanism by which SP-A and SP-D regulate lymphocyte activation.
Aim 4 is to define the role of SP-A and SP-D in the pathogenesis o inflammatory lung disease in vivo using SF-A and SP-D deficient mice. These studies will provide information about the role of SF-A and SP-D in regulating the functions of two important cells of the adaptive about immune system and contribute to our understanding of the role of SF-A and SP-D inflammatory lung diseases.
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