Innate Immunity and exacerbations of COPD

慢性阻塞性肺病患者的急性发作频率差异很大。决定病情恶化频率的因素尚不清楚。人的肺有一个复杂的、多方面的先天防御系统，它代表了抵御环境因素的第一道防线，无论是传染性的还是其他的，这些因素都可能导致病情恶化。我们假设先天肺防御的破坏允许能够引起急性发作的环境因子在气管支气管树中建立自己并诱导急性发作。此外，先天肺防御的一种或多种组分的破坏水平决定了COPD恶化的频率。稳定期COPD患者（n=320）将入组，将评估先天性肺防御的各种成分，并将其与未来12个月内经历的恶化次数相关联。在Specific Aim 1中，将确定纤毛黏液清除障碍是否与急性发作频率相关。在Specific Aim 2中，将测定痰液和支气管肺泡灌洗液中气道抗菌多肽的浓度，特别是溶菌酶、乳铁蛋白、分泌性白细胞蛋白酶抑制剂（SLPI）和表面活性剂蛋白A （SP-A）和D (SP-D)，并测定它们对急性发作频率的影响。在Specific Aim 3中，将确定肺泡巨噬细胞调节的导致COPD加重频率的基本免疫机制。具体来说，呼吸道病原体肺泡巨噬细胞吞噬功能受损导致COPD加重的作用和机制将被确定。此外，肺泡巨噬细胞对COPD加重的先天免疫调节特性也将被确定。在Specific Aim 4中，将探讨气道上皮细胞与细菌病原体的相互作用与急性发作频率之间的关系。具体来说，细菌粘附和气道上皮细胞对细菌病原体的免疫反应将被检查。本研究的总体目标是确定肺部先天防御的特定方面，这些方面决定了COPD加重的频率，这将作为减少加重的潜在治疗靶点。

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.