Innate Immunity and exacerbations of COPD

在慢性阻塞性肺疾病患者中，病情恶化的频率差异很大。决定病情恶化频率的因素还知之甚少。人类的肺部有一个复杂的、多方面的、天生的防御系统，它代表着抵御环境因素的第一道防线，无论是传染性的还是非传染性的，这些环境因素都能够导致病情恶化。我们假设，先天肺防御系统的破坏使能够导致病情恶化的环境因素在气管、支气管树上确立自身并诱发病情恶化。此外，肺固有防御的一个或多个成分的破坏程度决定了COPD恶化的频率。将纳入320名稳定的COPD患者，将评估先天肺防御的各种成分，并将其与未来12个月经历的恶化次数相关联。在特定的目标1中，将确定粘液纤毛清除障碍是否与病情加重的频率有关。在特定的目标2，将测定痰和支气管肺泡灌洗液中呼吸道抗菌多肽的浓度，特别是溶菌酶、乳铁蛋白、分泌性白细胞蛋白酶抑制物(SLPI)和表面活性蛋白A(SP-A)和D(SP-D)，并确定它们对病情恶化频率的影响。在特定的目标中，将确定由肺泡巨噬细胞调节的导致COPD加重频率的三种基本免疫机制。具体地说，将确定导致COPD加重的呼吸道病原体的肺泡巨噬细胞吞噬功能受损的作用和机制。此外，还将确定导致COPD恶化的肺泡巨噬细胞的固有免疫调节特性。在具体目标4中，将探讨呼吸道上皮细胞与细菌病原体的相互作用与病情加重的频率之间的关系。具体地说，将检查细菌黏附和呼吸道上皮细胞对细菌病原体的免疫反应。这项研究的总体目标是确定肺固有防御的特定方面，这些方面决定了COPD恶化的频率，这些方面将作为潜在的治疗目标来减少恶化。

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.