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,? are members of a family of innate immune proteins known as collectins that bind pathogens and facilitate? their clearance by immune cells. SP-A and SP-D also regulate a variety of immune cell functions. The? overall hypothesis to be tested in this proposal is that SP-A and SP-D. which are synthesized and secreted? by both alveolar and airway cells, interact with cells of both the adaptive and innate immune systems to? coordinatelv maximize defense against inhaled allergens and that cause and exacerbate asthma, while? minimizing an over exuberant immune response that could result in persistent inflammation, tissue damage? and chronic lung disease. We propose to evaluate the roles of SP-A and SP-D in regulating functions of? two immune cells that play a role in asthma pathogenesis: dendritic cells and T-lymphocytes. Preliminary? studies show that SP-D enhances antigen uptake and presentation by dendritic cells, that SP-A and SP-D? inhibit lymphocyte proliferation, modulate production of regulatory and inflammatory cvtokines by dendritic? cells and that SP-A null mice have enhanced susceptibility to lung injury and allergic inflammation. Our? hypothesis is also supported by published studies showing that SP-A and SP-D inhibit allergen-induced? lymphocyte proliferation and histamine release by immune cells from asthmatic children and by studies? showing that SP-D null mice are more susceptible to allergic inflammation.
Four aims are proposed.
Aim 1 ? will determine the mechanisms by which SP-A and SP-D and their receptors, including toll like receptors? (TLRs), regulate dendritic cell function. Studies will be conducted in vitro with isolated cells and in vivo with? mice.
Aim 2 will investigate the mechanism by which SP-A and SP-D regulate lymphocyte activation and? whether SP-A and SP-D directly or indirectly (via dendritic cells) affect T-cell proliferation and polarization to? a TH1 or Tn2 phenotype.
Aim 3 is to investigate the role of SP-A and SP-D in the pathogenesis of? inflammatory lung disease using mouse models of asthma and chronic allergic inflammation in collectin null? mice.
Aim 4 is to compare characterize levels of SP-A and SP-D in lavage fluid from asthmatics and? normals. These studies will provide information about the role of SP-A and SP-D in regulating the functions? of two important cells of the adaptive immune system and contribute to our understanding of the role of SPA? and SP-D inflammatory lung diseases. This project investigates the role of TLRs in chronic lung disease? in conjunction with Projects 2, 3 and 4. In addition, patient samples from Project 2 will be analyzed. The? project will interact with all the Cores.
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