HAEMOPHILUS ANTIGEN REGULATION OF INFLAMMATION IN COPD

描述(改编自申请人的摘要) 呼吸道炎症在COPD发病机制中的作用 得到了越来越多的认可。非分型流感嗜血杆菌(NTHI) COPD患者肺部最常见的细菌病原体是 在这种疾病的所有阶段都存在。NTHI及其组件有许多 对呼吸道组织的促炎作用。尽管如此，NTHI的作用 作为COPD炎症的一种独立刺激因素还没有被探索。 肺泡巨噬细胞是宿主与NTHI相互作用的关键细胞。 此外，肺泡巨噬细胞对炎症刺激有明显的反应。 与肺外组织的巨噬细胞不同。然而，肺泡的相互作用 携带NTHI的巨噬细胞及其对COPD发病机制的影响 未知。研究人员建议进行旨在获得更广泛洞察力的研究 探讨NTHI介导COPD炎症的免疫学机制。 对于所有研究，将招募三组受试者：a)前者 患有慢性阻塞性肺病的吸烟者；b)没有慢性阻塞性肺病的既往吸烟者；以及c)健康的非吸烟者。 在具体目标1中，NTHI“殖民化”与 气道腔和组织中的炎性细胞和介质将 下定决心。炎性细胞因子和弹性蛋白酶将在 将对支气管肺泡灌洗液(BAL)液和炎症细胞进行计数 在BAL和支气管粘膜下层。支气管肺泡灌洗液和支气管活检组织中的NTHI 将通过培养、聚合酶链式反应和免疫染色进行检测。在具体目标2中， NTHI外膜抗原对肺泡的生物学作用 巨噬细胞功能将被测定。诱导调节性细胞因子， 肺泡巨噬细胞黏附分子和功能的研究 将评估具有免疫活性的NTHI抗原。炎症性和 功能参数将与同一宿主血液的反应进行比较- 衍生的单核巨噬细胞。整合型细菌和细菌的鉴定 促进COPD免疫介导性炎症的宿主成分将 最终导致改变疾病进展的新治疗策略 并改善慢性阻塞性肺疾病的预后。

DESCRIPTION (adapted from the applicants' abstract) The contribution of airway inflammation to the pathogenesis of COPD has received increasing recognition. Nontypeable Haemophilus influenzae (NTHI) is the most common bacterial pathogen in the lungs of patients with COPD, and is present in all stages of this disease. NTHI and its components have numerous proinflammatory effects on respiratory tissues. Nonetheless, the role of NTHI as an independent stimulus to inflammation in COPD has not been explored. Alveolar macrophages are critical to host interactions with NTHI. Furthermore, alveolar macrophages respond to inflammatory stimuli distinctly unlike macrophages of extra-pulmonary tissues. Yet interactions of alveolar macrophages with NTHI, and the impact on pathogenesis of COPD, remains unknown. The investigators propose studies designed to gain broader insight into the immunologic mechanisms by which NTHI mediates inflammation in COPD. For all studies, three groups of subjects will be recruited: a) former smokers with COPD; b) former smokers without COPD; and c) healthy non-smokers. In Specific Aim 1, the association between NTHI 'colonization' and levels of inflammatory cells and mediators, in the airway lumen and in tissues, will be determined. Inflammatory cytokines and elastase will be measured in bronchoalveolar lavage (BAL) fluid and inflammatory cells will be enumerated in BAL and in bronchial submucosa. NTHI in the BAL and bronchial biopsies will be detected by culture, PCR and by immunostaining. In Specific Aim 2, the biological effects of outer membrane antigens of NTHI on alveolar macrophage function will be determined. Induction of regulatory cytokines, adhesion molecules and functional capabilities of alveolar macrophages by immunologically active NTHI antigens will be evaluated. Inflammatory and functional parameters will be compared with responses of same-host blood- derived mononuclear phagocytes. Identification of the integral bacterial and host components that contribute to immune-mediated inflammation in COPD will ultimately lead to novel therapeutic strategies to alter disease progression and improve outcome in COPD.