CD14 AND LPS-INDUCED INFLAMMATION IN CHRONIC BRONCHITIS

描述（改编自申请人的摘要） 慢性支气管炎和COPD的特征是慢性嗜酸性粒细胞增多， 炎症，并与气道脓毒症和革兰氏阴性 细菌 吸烟是导致这些疾病的主要危险因素， 但只有20%的吸烟者会患上慢性阻塞性肺病。 革兰氏阴性菌的内毒素（ET） 阴性细菌可能在这种炎症中起重要作用。气道 ET可能直接来自感染气道的革兰氏阴性菌， 烟草烟雾是另一个丰富的ET来源。 研究人员建议， 对ET的反应性也是发展的重要风险因素， 吸烟者的COPD 一种机制，人们可能会更敏感的ET 是通过增强CD 14的产生，CD 14是ET的主要受体。 CD 14存在 以细胞结合形式和可溶形式存在于血清和气道中 分泌物。 急性过敏性哮喘患者气道可溶性CD 14表达增强 炎症 此外，C/T多态性已在- CD 14启动子基因（CD 14基因）的159位。 那些纯合子 已显示T等位基因的患者血清中可溶性CD 14增加， 与具有CT或CC基因型的那些相比，血液单核细胞上的CD 14表达。 研究人员提供的初步数据表明， 激发前痰液sCD 14和肺泡巨噬细胞CD 14表达 脂多糖（LPS，ET的一种形式）与中性粒细胞流入相关 在吸入LPS激发后的痰中。 另外，在鼻气道中， 过敏原增强粒细胞对LPS的反应， 局部sCD 14水平。 研究人员建议检查CD 14在决定 吸烟者对气道内毒素的反应性和COPD的风险 一是 研究者将确定巨噬细胞上的sCD 14和CD 14水平是否 增加了志愿者与实验诱导和自然发生 支气管炎和是否有增加的中性粒细胞对LPS的反应。 二是 研究人员确定气道CD 14是否与PMN对LPS的反应相关， 普通志愿者 第三，研究人员将确定气道CD 14是否 水平和LPS反应在健康志愿者与TT基因型为 CD 14基因型较CC、CT基因型高。 最后，研究人员将对COPD患者和健康人进行基因分型。 吸烟者，以确定T等位基因是否是COPD发展的危险因素 在那些吸烟的人身上。

DESCRIPTION (adapted from the applicants' abstract) Chronic bronchitis and COPD are characterized by chronic neutrophilic inflammation and is associated with both airway sepsis with gram-negative bacteria. Smoking is a major risk factor for development of these diseases, but only about 20 percent of smokers develop COPD. Endotoxin (ET) from gram- negative bacteria likely plays a significant role in this inflammation. Airway ET may come directly from gram-negative bacteria infecting the airway or from tobacco smoke as this is another rich source of ET. The investigators propose that responsiveness to ET also an important risk factor for development of COPD in smokers. One mechanism by which persons may be more sensitive to ET is by enhanced production of CD14, the primary receptor for ET. CD14 exists in both a cell bound form and as a soluble from in serum and airway secretions. Soluble CD14 in the airway is enhanced by acute allergic inflammation. Additionally, a C/T polymorphism has been identified at the - 159 position of the CD14 promoter gene (CD14 gene). Those persons homozygous for the T allele have been shown to have increased soluble CD14 in serum and CD14 expression on blood monocytes compared to those with CT or CC genotype. The investigators present preliminary data that demonstrates that levels of sCD14 in sputum and CD14 expression on alveolar macrophages prior to challenge with lipopolysacharride (LPS, a form of ET) correlates with neutrophil influx in sputum following inhaled LPS challenge. Also, in the nasal airway, allergen enhances granulocyte response to LPS in a fashion which correlates with local sCD14 levels. The investigators propose to examine the role that CD14 has in determining responsiveness to airway LPS and risk for COPD in smokers. First, the investigators will determine if the level of sCD14 and CD14 on macrophages is increased in volunteers with experimentally-induced and naturally occurring bronchitis and if they have increased neutrophil response to LPS. Second, the investigators determine if airway CD14 correlates with PMN response to LPS in normal volunteers. Third, the investigators will determine if airway CD14 levels and LPS response in healthy volunteers with the TT genotype for the CD14 gene is enhanced relative to that in those with the CC and CT genotype. Finally, the investigators will genotype cohorts of COPD patients and healthy smokers to determine if the T allele is a risk factor in development of COPD in those who smoke.