Immunoprotective Effects of Surfactant Proteins in Asthma

表面活性蛋白在哮喘中的免疫保护作用

• 批准号: 7917407
• 负责人: JO RAE WRIGHT
• 金额: $ 44.84万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7917407
• 关键词: Acute Lung Injury; Affect; Air; Allergens; Allergic; Alveolar; Alveolar Macrophages; Antibodies; Antibody Formation; Antigen Presentation; Antigen-Presenting Cells; Antigens; Area; Asthma; B-Lymphocytes; Bacteria; Binding; Breathing; C-terminal; CD80 gene; Calcium; Calmette-Guerin Bacillus; Carbohydrates; Cell Death; Cell division; Cell physiology; Cell surface; Cells; Child; Chronic; Chronic lung disease; Collectins; Complement; Cross Presentation; Cytokine Receptors; Dendritic Cells; Disease; Effector Cell; Endocytosis; Enhancing Antibodies; Epithelium; Exhibits; Family; Gases; Germ Lines; Histamine Release; Host Defense; Host Defense Mechanism; Immune; Immune response; Immune system; Immunity; In Vitro; Inflammation; Inflammatory; Injury; Irrigation; Irritants; Knockout Mice; Lectin; Lipopolysaccharides; Liquid substance; Liver; Lung; Lung diseases; Lymphocyte; Lymphocyte Activation; Lymphocyte Function; MHC Class II Genes; Maintenance; Major Histocompatibility Complex; Mannose Binding Lectin; Mannose-Binding Lectins; Mediating; Mediator of activation protein; Microbe; Muramidase; Mus; N-terminal; Natural Killer Cells; Opsonin; Ovalbumin; Oxidants; Particulate; Pathogenesis; Patients; Peptides; Phagocytosis; Phenotype; Plasma Cells; Play; Predisposition; Principal Investigator; Process; Production; Proliferating; Protein Family; Proteins; Publishing; Pulmonary Surfactant-Associated Protein A; Pulmonary Surfactant-Associated Protein D; Pulmonary Surfactants; Rattus; Respiratory physiology; Role; Sampling; Serum; Sterility; Structure of lymph node of thorax; Surface; Surface Tension; System; T-Cell Proliferation; T-Lymphocyte; Testing; Tissues; Toll-like receptors; Viral; Virus; acquired immunity; airway epithelium; anergy; antigen challenge; antigen processing; cytokine; cytotoxic; design; granulocyte; immune clearance; improved; in vivo; killer T cell; lung injury; lymphocyte proliferation; macrophage; mast cell; member; monocyte; mouse model; neuronal cell body; neutrophil; particle; pathogen; programs; receptor; response; surfactant; uptake

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.

虽然传统上认为肺表面活性物质是一种表面张力降低物质，