Induction of COPD Exacerbation by Haemophilus influenzae

流感嗜血杆菌诱导 COPD 恶化

• 批准号: 7471392
• 负责人: Dwight C Look
• 金额: $ 31.47万
• 依托单位: UNIVERSITY OF IOWA
• 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/7471392
• 关键词: Acute; Adherence; Bacteria; Bacterial Infections; Biological Assay; Biological Models; CCAAT-Enhancer-Binding Proteins; Cell Communication; Cell model; Cell surface; Chronic; Chronic Obstructive Airway Disease; Development; Dominant-Negative Mutation; Epithelial Cells; Gene Activation; Gene Expression; Goals; Haemophilus influenzae; Health Care Costs; Human; Immune response; Immunity; Infection; Inflammation; Inflammatory Response; Influenza; Integration Host Factors; Interleukin-8; Lead; Link; Lung diseases; Mediating; Morbidity - disease rate; Mus; NF-kappa B; Nontypable Haemophilus influenza; Numbers; Organism; Pathway interactions; Patients; Play; Quality of life; Regulation; Research Personnel; Role; Sampling; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Surface; System; Time; Tracheobronchial; Virulence Factors; Virulent; Work; airway epithelium; airway inflammation; base; defense response; human MAPK14 protein; mortality; novel; programs; respiratory; response

Acute exacerbations are an important contributor to the health care costs, quality of life, morbidity, and mortality of patients with chronic obstructive pulmonary disease (COPD). Airway bacterial infection may promote increased airway inflammation and lead to decreased airway function, and nontypable Haemophilus influenzae is the bacterial species most commonly isolated during COPD exacerbations. H. influenzae strains isolated from COPD patients during acute exacerbations induce more inflammation in a mouse airway infection, induce higher levels of interleukin-8 after interaction with human airway epithelial cells, and adhere more to epithelial cells compared to colonizing strains. Based on these observations, we hypothesize that specific H. influenzae surface molecules control airway epithelial cell interactions with bacteria that determine bacterial capacity to induce high levels of airway inflammation and COPD exacerbations. A better understanding of interactions between H. influenzae and epithelial cells that lead to airway inflammation may uncover strategies for selectively modifying damaging bacterial effects but not beneficial immunity in airway epithelium in patients with COPD. Accordingly, our specific aims are to: I. Compare the airway epithelial cell response to H. influenzae associated with COPD exacerbation versus colonization. We propose that H. influenzae associated with COPD exacerbations induce more inflammation compared to colonizing strains. To investigate this aim, we will take advantage of airway epithelial cell models (including primary cultures of human tracheobronchial epithelial cells) and their sensitivity to interaction with H. influenzae. Comparison of bacterial strains will be accomplished using assays of bacterial adherence and epithelial cell signal transduction pathways and gene expression. II. Determine epithelial cell mechanisms that detect and respond to H. influenzae associated with COPD exacerbations. We propose that specific molecules on the epithelial cell surface detect H. influenzae and activate specific signaling pathways leading to gene expression. To investigate this aim, we will take advantage of the same airway epithelial cell model systems for H. influenzae infection and epithelial cell responses. Critical molecules and pathways important in airway defense will be determined by detecting activation and using specific inhibitory strategies such as dominant-negative molecule expression. III. Identify bacterial factors that regulate the airway epithelial cell response to H. influenzae associated with COPD exacerbations. We propose that specific bacterial molecules interact with and/or are detected by epithelial cells, and that these molecules differ between strains of H. influenzae associated with exacerbation versus colonization. To investigate this aim, we will take advantage of multiple systems that differentiate the expression and function of specific bacterial virulence factors. Expression of important bacterial factors will be identified and linked to epithelial cell adherence and responses.

急性加重是慢性阻塞性肺部疾病（COPD）患者的医疗保健成本，生活质量，发病率和死亡率的重要因素。气道细菌感染可能会促进气道炎症增加并导致气道功能降低，而不可用的流感嗜血杆菌是在COPD加重过程中最常见的细菌物种。急性加重期间，从COPD患者中分离出的流感菌株会引起小鼠气道感染的更多炎症，与人类气道上皮细胞相互作用后，诱导了更高水平的白介素-8，与结肠菌株相比，更多地粘在上皮细胞上。基于这些观察结果，我们假设特定的流感表面分子控制气道上皮细胞与细菌的相互作用，这些细菌确定细菌能力诱导高水平的气道炎症和COPD加剧。更好地了解导致气道炎症的流感和上皮细胞之间的相互作用可能会发现COPD患者气道上皮的有选择性修饰细菌效应的策略，但无益。因此，我们的具体目的是：I。将气道上皮细胞的反应与与COPD加剧相关的COPD与定殖相关的流感。我们提出，与殖民菌株相比，与COPD加重相关的流感脑炎会引起更多的炎症。为了研究这一目标，我们将利用气道上皮细胞模型（包括人气管上皮细胞的主要培养物）及其对与流感嗜血杆菌相互作用的敏感性。细菌菌株的比较将使用细菌粘附和上皮细胞信号转导途径和基因表达的测定法完成。 ii。确定检测并响应与COPD加重相关的流感嗜血杆菌的上皮细胞机制。我们提出上皮细胞表面上的特定分子检测流感h。为了研究这一目标，我们将利用相同的气道上皮细胞模型系统用于流感惠氏菌感染和上皮细胞反应。在气道防御中重要的关键分子和途径将通过检测激活和使用特定抑制性策略（例如显性阴性分子表达）来确定。 iii。确定调节气道上皮细胞对与COPD恶化相关的流感的细菌因子。我们提出特定的细菌分子与上皮细胞相互作用和/或检测到，并且这些分子在与加重相对于定殖有关的流感流感菌株之间有所不同。为了研究这一目标，我们将利用多个系统来区分特定细菌毒力因子的表达和功能。重要的细菌因子的表达将被鉴定，并与上皮细胞的依从性和反应有关。