Immunoprotective Effects of Surfactant Proteins in Asthma

Duke University, Durham NC

Investigators

Linked publications & trials

Abstract

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