Sufactant Protein-A and Lung Defense

表面活性剂蛋白 A 和肺防御

• 批准号: 7172291
• 负责人: Thomas R Korfhagen
• 金额: $ 33.09万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7172291
• 关键词: A Mouse; Alveolar Macrophages; Anti-Inflammatory Agents; Anti-inflammatory; Bacterial Pneumonia; Binding; Biological Assay; Bioterrorism; Breathing; CD14 Antigen; CD14 gene; Cell Wall; Cell surface; Cells; Clinical; Co-Immunoprecipitations; Complex; Country; Cystic Fibrosis; Cytokine Activation; Data; Due Process; Epithelial Cells; Extracellular Domain; Funding; Genetic; Goals; Gram-Negative Bacteria; Immune system; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Knowledge; Ligand Binding; Lipids; Lipopolysaccharides; Lung; Lung diseases; Mediating; Microbe; Modeling; Morbidity - disease rate; Mus; Mutate; NF-kappa B; Numbers; Patients; Pattern; Plasmids; Pneumonia; Process; Production; Proteins; Pulmonary Surfactant-Associated Protein A; RNA; Regulation; Research Personnel; Role; Signal Transduction; Stress; Structure; TLR4 gene; Testing; Time; Toll-like receptors; Transfection; Transgenic Mice; Type II Epithelial Receptor Cell; Wild Type Mouse; base; cytokine; design; in vivo; microbial; mortality; mouse model; mutant; neutrophil; novel; novel strategies; pathogen; programs; receptor; surfactant; toll-like receptor 4

DESCRIPTION (provided by applicant): Pulmonary inflammatory processes due to bacterial pneumonia impose a considerable clinical burden of morbidity and mortality in the US and other countries. A number of microbes considered as potential bioterrorist threats cause severe pulmonary inflammation. During the previous funding period, studies using transgenic mice, demonstrated that surfactant protein-A (SP-A) reduces inflammation caused by microbes and microbial products. Studies from patients with pneumonia or cystic fibrosis (CF) demonstrated reduced concentrations of SP-A suggesting that SP-A modulates the extent of microbial induced pulmonary inflammation. The goal of the present application is to determine mechanisms whereby SP-A regulates pulmonary inflammatory responses. Recent studies have demonstrated important roles for toll-like receptors (TLR) in inducing inflammatory responses. TLR4 is a major receptor for LPS and gram-negative bacteria. LPS binds to CD14 and LPS/CD14 interacts with MD-2/TLR4 forming a cell surface tripartite receptor complex that transduces intracellular signals leading to activation of cytokines and other inflammatory modulators. SP-A does not bind smooth forms of LPS but SP-A blocks smooth LPS induced cytokine production in vivo and in vitro. The lack of binding to smooth LPS suggests that SP-A cannot simply be sequestering LPS from interactions with the TLR complex. TLR4, CD14, and MD-2 RNA are present in alveolar macrophages and mouse lung epithelial cells supporting the central hypothesis that SP-A alters inflammatory responses in the lung by reducing smooth LPS signaling through TLR-4 components. This hypothesis will be tested using smooth LPS mediated induction of NF-kappaB in cell transfections or LPS and gram-negative infection in mouse models to complete the following aims: (1) The SP-A structures and LPS receptor components that functionally interact to cause SP-A inhibition of LPS mediated signaling will be identified in vitro; (2) Mechanisms by which SP-A inhibits LPS mediated signaling will be determined by testing if SP-A alters interactions between TLR4 components necessary for LPS signaling in vitro; and (3) Structural domains of SP-A required for SP-A inhibition of LPS or gram-negative bacterial mediated signaling in vivo will be identified. The present application seeks to identify novel mechanisms of SP-A regulation of pulmonary inflammatory responses with the goal of identifying novel approaches to reducing pulmonary inflammation.

描述（由申请人提供）：由于细菌性肺炎引起的肺部炎症过程在美国和其他国家施加了相当大的发病和死亡率临床负担。 许多被认为是潜在生物恐怖威胁的微生物会引起严重的肺部炎症。 在上一个资金期间，使用转基因小鼠的研究表明，表面活性剂蛋白A（SP-A）减少了由微生物和微生物产物引起的炎症。 肺炎或囊性纤维化患者（CF）的研究表明，SP-A浓度降低，表明SP-A调节微生物诱导的肺部炎症程度。 本应用的目的是确定SP-A调节肺部炎症反应的机制。 最近的研究表明，Toll样受体（TLR）在诱导炎症反应中的重要作用。 TLR4是LP和革兰氏阴性细菌的主要受体。 LPS与CD14和LPS/CD14的结合与形成细胞表面三方受体复合物复合物的MD-2/TLR4相互作用，该复合物会传递细胞内信号，从而导致细胞因子和其他炎症调节剂的激活。 SP-A不结合LP的平滑形式，而SP-A阻断了光滑的LPS在体内和体外诱导的细胞因子产生。 缺乏与光滑LP的结合表明，SP-A不能简单地从与TLR复合物的相互作用中隔离LP。 TLR4，CD14和MD-2 RNA存在于肺泡巨噬细胞和小鼠肺上皮细胞中，这些细胞支持中心假设，即SP-A通过通过TLR-4成分减少平滑LPS信号传导来改变肺中炎症反应。 在小鼠模型中，将使用平滑的LPS介导的NF-kappab诱导NF-kappab诱导NF-kappab的诱导来测试该假设，以完成以下目的：（1）SP-A结构和LPS受体成分，这些结构和LPS受体成分在功能上与LPS介导的SP-A抑制LPS介导的信号传导的功能相互作用将在体外鉴定； （2）SP-A抑制LPS介导的信号传导的机制将通过测试SP-A在体外所需的TLR4组件之间的相互作用来确定； （3）将鉴定体内SP-A抑制LPS或革兰氏阴性细菌介导的信号传导所需的SP-A结构结构域。 本应用旨在鉴定SP-A调节肺部炎症反应的新机制，目的是确定减少肺部炎症的新方法。