Smoking and airway innate host defense: in vivo studies

吸烟和气道先天宿主防御：体内研究

• 批准号: 7231810
• 负责人: David B. Peden
• 金额: $ 45.34万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7231810
• 关键词: chronic obstructive pulmonary disease; clinical research; gel; human subject; immune response; infection; inflammation; lung; mucus; opportunistic infections; respiratory airway clearance; respiratory infections; smoking

Healthy smokers (without COPD) have increased occurrence of airway infections compared to non-smokers, and smoking is also the major risk factor for COPD. COPD is characterized by chronic airway obstruction, decreased mucociliary clearance (MCC), mucus hypersecretion, and chronic airway inflammation. Bacterial and viral infections are the leading causes of acute exacerbations of COPD. . In Cystic Fibrosis (CF), dehydration of the airway surface liquid (ASL) leads to decreased mucociliary clearance (MCC), colonization by bacteria and frequent exacerbations of disease related to MCC failure. The CFTR-induced anomalies in ASL solute concentration and subsequent ASL dehydration are a central cause of CF lung disease. Clinical similarities between COPD and Cystic Fibrosis (CF) suggest that despite differences in pathogenesis, there are key similarities in their pathophysiology. Adenosine and purinergic control of airway hydration are likely important in both diseases, as we have observed that (like CF) COPD patients also have decreased ASL dehydration and adenosine levels relative to normal volunteers. The overarching hypothesis of this project is that smoking predisposes to decreased MCC due to ASL dehydration, partly due to decreased ASL adenosine and diminished innate host defense. In Project IV, we will test the hypothesis that smokers have decreased MCC with alterations in purine and adenosine biology by comparing these airway processes between normal volunteers and smokers. We also hypothesize that smoking will cause decreased macrophage function and bacterial colonization of the airway. We will compare our results in normal volunteers and smokers to those from similarly studied COPD (Project V) and CF (Project VI) patients, as we suspect that smoking-induced changes will mimic those in COPD. We will also examine MCC, hydration and airway responses in normal volunteers and smokers after challenge with inhaled endotoxin (a bacterial product found in tobacco smoke) and experimental viral infection to determine if MCC in smokers is less adaptive to these challenges. These aims will provide novel in vivo data on smoking-induced airway pathophysiology in humans. The medical significance of these studies is that they will firmly establish the importance of mucus clearance to maintain respiratory health and will elucidate disease mechanisms and therapeutic targets applicable for many chronic obstructive airway diseases.

健康吸烟者（无COPD）与非吸烟者相比，气道感染的发生率增加， 吸烟也是COPD的主要危险因素。COPD的特征在于慢性气道阻塞， 降低的粘液纤毛清除率（MCC）、粘液分泌过多和慢性气道炎症。细菌 病毒感染是COPD急性加重的主要原因。.在囊性纤维化（CF）中， 气道表面液体（ASL）的脱水导致粘膜纤毛清除率（MCC）降低， 与MCC失败相关的疾病的频繁恶化。CFTR引起的异常， ASL溶质浓度和随后的ASL脱水是CF肺病的主要原因。临床 COPD和囊性纤维化（CF）之间的相似性表明，尽管发病机制不同， 在病理生理学上有着关键的相似之处腺苷和嘌呤能控制气道水化可能是 在这两种疾病中都很重要，因为我们观察到（像CF一样）COPD患者也有ASL降低， 脱水和腺苷水平相对于正常志愿者。这个项目的首要假设是 吸烟易导致由于ASL脱水而导致的MCC减少，部分原因是由于ASL减少 腺苷和减弱的先天宿主防御。在项目IV中，我们将测试吸烟者有 通过比较这些气道过程，减少MCC与嘌呤和腺苷生物学的改变 正常志愿者和吸烟者之间的差异。我们还假设吸烟会导致 巨噬细胞功能和气道细菌定植。我们将比较我们的结果在正常 志愿者和吸烟者与类似研究的COPD（项目V）和CF（项目VI）患者相比， 怀疑吸烟引起的变化将模仿COPD中的变化。我们还将检查MCC，水合作用和 正常志愿者和吸烟者吸入内毒素（一种细菌）后的气道反应 烟草烟雾中发现的产品）和实验性病毒感染以确定吸烟者中的MCC是否较少 适应这些挑战。这些目标将提供新的吸烟诱导气道的体内数据 人类的病理生理学这些研究的医学意义在于，它们将坚定地确立 粘液清除对维持呼吸系统健康的重要性，并将阐明疾病机制， 适用于许多慢性阻塞性气道疾病的治疗靶点。