Smoking and airway innate host defense: in vivo studies

与不吸烟的人相比，健康的吸烟者(没有COPD)的呼吸道感染发生率更高， 吸烟也是慢性阻塞性肺疾病的主要危险因素。慢性阻塞性肺疾病的特点是慢性呼吸道阻塞， 减少粘液纤毛清除(MCC)、粘液高分泌和慢性呼吸道炎症。细菌 病毒感染是慢性阻塞性肺疾病急性加重的主要原因。。囊性纤维化(CF)， 呼吸道表面液体(ASL)脱水导致粘液纤毛清除(MCC)减少，定植 细菌和与MCC失效相关的疾病频繁恶化。CFTR诱发的异常 ASL溶质浓度和随后的ASL脱水是CF肺部疾病的中心原因。临床 COPD和囊性纤维化(CF)之间的相似之处表明，尽管发病机制不同，但 是它们在病理生理学上的关键相似之处。腺苷和嘌呤能对呼吸道水合的控制可能 在这两种疾病中都很重要，因为我们观察到(像慢性阻塞性肺病一样)COPD患者的ASL也降低了 相对于正常志愿者的脱水和腺苷水平。这个项目的首要假设是 吸烟容易由于ASL脱水而导致MCC降低，部分原因是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 通过比较这些呼吸道过程中的嘌呤和腺苷生物学变化来降低MCC 在正常志愿者和吸烟者之间。我们还假设吸烟会导致人口减少 巨噬细胞功能与呼吸道细菌定植。我们将在正常情况下比较我们的结果 志愿者和吸烟者来自类似研究的COPD(项目V)和CF(项目VI)患者，因为我们 怀疑吸烟引起的变化将模仿COPD的变化。我们还将检查MCC、水化和 正常志愿者和吸烟者吸入内毒素(一种细菌)后的呼吸道反应 烟草烟雾中发现的产品)和实验性病毒感染，以确定吸烟者的MCC是否较少 适应这些挑战。这些目标将为吸烟诱导的呼吸道提供新的体内数据。 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健康的重要性，并将阐明疾病机制和 适用于多种慢性阻塞性呼吸道疾病的治疗靶点。

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.