Innate Immunity and exacerbations of COPD

先天免疫和慢性阻塞性肺病的恶化

• 批准号: 7008641
• 负责人: Sanjay Sethi
• 金额: $ 31.43万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7008641
• 关键词: alveolar macrophages; bacterial disease; bactericidal immunity; bronchial mucus; bronchoscopy; cell adhesion; chronic obstructive pulmonary disease; clinical research; diagnostic respiratory lavage; enzyme linked immunosorbent assay; gel mobility shift assay; host organism interaction; human morbidity; human subject; immune response; lactoferrin; lung lavage; lysozyme; medical complication; phagocytosis; polymerase chain reaction; protease inhibitor; pulmonary surfactants; respiratory airway clearance; respiratory infections

There is a wide variation in the frequency of exacerbations among patients with COPD. Factors that determine the frequency of exacerbations are poorly understood. The human lung has a complex, multifaceted, innate defense system that represents the first line of defense against environmental agents, infectious or otherwise, that are capable of causing exacerbations. We hypothesize that disruption of the innate lung defense allows environmental agents capable of causing exacerbations to establish themselves in the tracheobronchial tree and induce exacerbations. Furthermore, the level of disruption of one or more components of the innate lung defense determines the frequency of exacerbations in COPD. Patients (n=320) with stable COPD will be enrolled, various components of innate lung defense will be assessed and correlated with the number of exacerbations experienced over the next 12 months. In Specific Aim 1 whether impairment of mucociliary clearance is associated with frequency of exacerbations will be established. In Specific Aim 2 sputum and bronchoalveolar lavage concentrations of airway antimicrobial polypeptides, specifically lysozyme, lactoferrin, secretory leucocyte protease inhibitor (SLPI) and surfactant proteins A (SP-A) and D (SP-D) will be determined and their impact on frequency of exacerbations determined. In Specific Aim 3 fundamental immunologic mechanisms regulated by alveolar macrophages that contribute to frequency of exacerbations of COPD will be identified. Specifically, the role and mechanisms of impaired phagocytosis by alveolar macrophages of respiratory pathogens that contribute to COPD exacerbations will be determined. .In addition, innate immunoregulatory properties of alveolar macrophages that contribute to COPD exacerbations will be determined. In Specific Aim 4 the relationship between the interaction of airway epithelial cells with bacterial pathogens and frequency of exacerbations will be explored. Specifically, bacterial adherence and immunologic response of airway epithelial cells to bacterial pathogens will be examined. The overall goal of this research is to identify specific aspects of the innate defense of the lung that determine the frequency of exacerbations in COPD that will serve as potential therapeutic targets to reduce exacerbations.

COPD患者的加重频率存在很大差异。确定恶化频率的因素了解不足。人类的肺部具有复杂，多方面的先天防御系统，代表了针对环境因素（感染力或其他方式）的第一道防线，能够导致加重。我们假设对先天肺防御的破坏使能够导致恶化的环境药物在气管上树木中建立自己并引起加剧。此外，先天肺防御的一个或多个组成部分的破坏水平决定了COPD加重的频率。将招募患有稳定COPD的患者（n = 320），将评估与先天肺防御的各种组成部分，并与未来12个月内经历的恶化数量进行评估并相关。在特定的目标1中，是否会建立粘膜纤毛清除的损害是否与恶化的频率有关。在特定的目标中，气道抗菌多肽的痰液和支气管肺泡灌洗浓度，特别是溶菌酶，乳糖铁蛋白，分泌白细胞蛋白酶蛋白酶抑制剂（SLPI）和表面活性剂A（SP-A）和D（SP-A）和D（SP-D（SP-D）和D（SP-D（SP-D））将确定频率的频率。在特定的目标中，将确定受肺泡巨噬细胞调节的基本免疫机制，这些机制将被鉴定出导致COPD加剧频率的频率。具体而言，将确定呼吸道巨噬细胞受损的吞噬作用和机制，这些呼吸道病原体的肺泡巨噬细胞将确定有助于COPD加剧的病原体。此外，还将确定肺泡巨噬细胞的先天免疫调节特性，这些巨噬细胞有助于COPD加剧。在特定目标4中，将探索气道上皮细胞与细菌病原体的相互作用与恶化的频率之间的关系。具体而言，将检查气道上皮细胞对细菌病原体的细菌依从性和免疫反应。这项研究的总体目标是确定肺的先天防御的特定方面，这些方案决定了COPD中加重的频率，该频率将作为减少加重的潜在治疗靶标。