Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality in the U.S. Efforts to improve the lives of COPD patients will depend on the development of novel therapies directed at specific mechanisms central to the pathogenesis of disease. Surfactant protein D (SP-D), an important innate immune molecule in the lung, plays a critical role in regulating inflammation in the lung. Our preliminary data demonstrate that SP-D is deficient in the lungs of subjects with COPD and that subjects using inhaled corticosteroids have higher levels of SP-D. The goals of this proposal are 1) to address an intense program of study for the candidate's career development as an independent clinical investigator, and 2) to elucidate the role of SP-D in promoting airway inflammation and COPD. The central hypothesis of our proposal states that smoking decreases SP-D expression and/or function in a manner that promotes airway inflammation and the pathogenesis of COPD. Further, we hypothesize that inhaled corticosteroids induce SP-D expression and that this mechanism contributes to their anti-inflammatory effects. To test these hypotheses, we propose a study with 3 specific aims.
Aim 1 will define the association between the quantity and/or quaternary structure of SP-D and COPD, controlling for smoking status.
In Aim 2, we will determine the relationship between the quantity and/or quaternary structure of SP-D and airway inflammation.
Aim 3 will determine whether levels of SP-D, its quaternary structure, and inflammatory cytokine expression in bronchoalveolar lavage are altered by initiation of inhaled corticosteroid (ICS) treatment. In order to address these specific aims, we have designed a cross-sectional study of COPD subjects, healthy smokers with normal lung function, and healthy non-smokers. All subjects will undergo bronchoscopy for collection of bronchoalveolar lavage specimens. Surfactant protein D and its constituent quaternary structures will be quantified in bronchoalveolar lavage by enzyme-linked immunosorbance assay and semi-quantitative, native gel, Western blotting. Parallel studies will examine the effect of SP-D on secretion of inflammatory cytokines in cultured macrophages. The completion of this project will advance our understanding of the regulation of lung inflammation in COPD and provide the candidate with vital knowledge and skills in the fields of COPD biology and molecular epidemiology, furthering his goal of becoming an independent clinical investigator.
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