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 facilitatetheir clearance by immune cells. SP-A and SP-D also regulate a variety of immune cell functions. Theoverall hypothesis to be tested in this proposal is that SP-A and SP-D. which are synthesized and secretedby both alveolar and airway cells, interact with cells of both the adaptive and innate immune systems tocoordinatelv maximize defense against inhaled allergens and that cause and exacerbate asthma, whileminimizing an over exuberant immune response that could result in persistent inflammation, tissue damageand chronic lung disease. We propose to evaluate the roles of SP-A and SP-D in regulating functions oftwo immune cells that play a role in asthma pathogenesis: dendritic cells and T-lymphocytes. Preliminarystudies show that SP-D enhances antigen uptake and presentation by dendritic cells, that SP-A and SP-Dinhibit lymphocyte proliferation, modulate production of regulatory and inflammatory cvtokines by dendriticcells and that SP-A null mice have enhanced susceptibility to lung injury and allergic inflammation. Ourhypothesis is also supported by published studies showing that SP-A and SP-D inhibit allergen-inducedlymphocyte proliferation and histamine release by immune cells from asthmatic children and by studiesshowing 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 withmice.
Aim 2 will investigate the mechanism by which SP-A and SP-D regulate lymphocyte activation andwhether SP-A and SP-D directly or indirectly (via dendritic cells) affect T-cell proliferation and polarization toa TH1 or Tn2 phenotype.
Aim 3 is to investigate the role of SP-A and SP-D in the pathogenesis ofinflammatory lung disease using mouse models of asthma and chronic allergic inflammation in collectin nullmice.
Aim 4 is to compare characterize levels of SP-A and SP-D in lavage fluid from asthmatics andnormals. These studies will provide information about the role of SP-A and SP-D in regulating the functionsof two important cells of the adaptive immune system and contribute to our understanding of the role of SPAand SP-D inflammatory lung diseases. This project investigates the role of TLRs in chronic lung diseasein conjunction with Projects 2, 3 and 4. In addition, patient samples from Project 2 will be analyzed. Theproject will interact with all the Cores.
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