) 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.
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