Innate Immunity and exacerbations of COPD

COPD患者的急性加重频率差异很大。决定急性加重频率的因素知之甚少。人肺具有复杂的、多方面的、先天的防御系统，其代表了抵抗能够引起恶化的环境因子（传染性或其他）的第一道防线。我们假设先天性肺防御的破坏允许能够引起急性加重的环境因子在气管支气管树中建立自己并诱导急性加重。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。将入组稳定期COPD患者（n=320），评估先天性肺防御的各种组成部分，并将其与未来12个月内发生的急性加重次数相关联。在具体目标1中，将确定粘膜纤毛清除障碍是否与急性加重频率相关。在特定目标2中，将测定痰液和支气管肺泡灌洗液中气道抗菌多肽（特别是溶菌酶、乳铁蛋白、分泌性白细胞蛋白酶抑制剂（SLPI）和表面活性蛋白A（SP-A）和D（SP-D））的浓度，并测定其对急性加重频率的影响。在特定目标3中，将确定由肺泡巨噬细胞调节的导致COPD加重频率的基本免疫机制。具体而言，将确定肺泡巨噬细胞对导致COPD急性加重的呼吸道病原体的吞噬作用受损的作用和机制。此外，将确定促成COPD恶化的肺泡巨噬细胞的先天免疫调节特性。在具体目标4中，将探索气道上皮细胞与细菌病原体的相互作用与急性加重频率之间的关系。具体而言，将检查气道上皮细胞对细菌病原体的细菌粘附和免疫应答。本研究的总体目标是确定决定COPD急性加重频率的肺先天防御的特定方面，这些方面将作为减少急性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.