HAEMOPHILUS ANTIGEN REGULATION OF INFLAMMATION IN COPD

描述（改编自申请人的摘要） 气道炎症在COPD发病机制中的作用， 得到越来越多的认可。 无法分型的流感嗜血杆菌（NTHI）是 COPD患者肺部最常见的细菌病原体， 存在于这种疾病的各个阶段。 NTHI及其组件具有许多 对呼吸组织的促炎作用。 然而，NTHI的作用 作为COPD炎症的独立刺激因素尚未进行研究。 肺泡巨噬细胞对宿主与NTHI的相互作用至关重要。 此外，肺泡巨噬细胞对炎症刺激的反应明显 与肺外组织的巨噬细胞不同。 然而， 巨噬细胞与NTHI的关系，以及对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见解的研究 NTHI介导COPD炎症的免疫机制。 对于所有研究，将招募三组受试者： 患有COPD的吸烟者; B）没有COPD的前吸烟者;和c）健康的非吸烟者。 在具体目标1中，NTHI“定殖”与 气道腔和组织中的炎性细胞和介质， 测定 炎症细胞因子和弹性蛋白酶将在 计数支气管肺泡灌洗液（BAL）和炎性细胞 在BAL和支气管粘膜下层。 BAL和支气管活检中的NTHI 将通过培养、PCR和免疫染色进行检测。 在具体目标2中， NTHI外膜抗原的生物学效应 将测定巨噬细胞功能。 诱导调节性细胞因子， 粘附分子和肺泡巨噬细胞的功能能力 将评价免疫活性NTHI抗原。 炎性和 将功能参数与相同宿主血液的反应进行比较， 衍生的单核吞噬细胞。 鉴定完整的细菌和 导致COPD中免疫介导炎症的宿主成分将 最终导致改变疾病进展的新治疗策略 改善COPD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.