• Microarray chips are scanned and analyzed using Affymatrix Microarray suite version 5 (MAS5). Using GeneSpring software the data is normalized and differential expression is determined using alveolar macrophages. [ Time Frame: Day 7 and Day 14 following initiation of therapy compared to baseline values obtained on screening ] [ Designated as safety issue: No ]
  

• St. George Respiratory questionnaire [ Time Frame: To be completed on Screening Day ] [ Designated as safety issue: No ]
  

The purpose of this study is to assess the effect of inhaled fluticasone (an inhaled corticosteroid) in combination with salmeterol (a long acting bronchodilator) on the pattern of the lung airway epithelium and alveolar macrophages gene expression of healthy smokers. We hypothesize that the administration of fluticasone in combination with salmeterol will result in reversibility of some of the airway epithelium and alveolar macrophage gene expression changes induced by cigarette smoking.

Background. Chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema, occurs in 15 to 20% of individuals who smoke, and is a leading cause of disease and mortality in the US (1, 2). Cigarette smoking is found to be the cause of approximately 90% of the cases of COPD in the US (1, 2). The human lung airway epithelium receives the initial brunt of cigarette smoking, and the airway epithelium and alveolar macrophages play a central role in the development of COPD (3-6). Asymptomatic healthy smokers have increased rate of cell proliferation in the airway epithelium consistent with the concept that the airway epithelium of smokers undergoes molecular changes that precede the development of COPD (7). Similarly, smoking increases the number and activates the alveolar macrophages present in the alveoli of human lung leading to the release of various mediators involved in the pathogenesis of COPD (4, 6, 8, 9).

Assessment of human lung airway epithelium and alveolar macrophages gene expression of healthy smokers compared to healthy non-smoking individuals demonstrate that the epithelium of the large and the small airways and the alveolar macrophages up- and down-regulate a variety of genes relevant to the pathogenesis of COPD (10-15). The differential gene expression in the epithelium of smokers compared to nonsmokers comprises genes in various functions, including genes involved in inflammation, cell repair, cell differentiation, cell death, detoxification, and cell signaling. While the airway epithelium is target for the stress of cigarette smoking, alveolar macrophages (the pulmonary representative of the bone marrow-derived mononuclear phagocyte system) are activated by smoking, and release a variety of mediators that can injure the fragile lung structure (4, 6, 16).

Thus, while the airway epithelium is injured by smoking, the alveolar macrophages contribute to the smoking-induced injury. Many studies in vitro and in vivo in animals and in humans demonstrate the role of the airway epithelium and alveolar macrophages in the development of COPD with the release of various pro-inflammatory mediators, and mediators involved in cell apoptosis, proteolysis, airway remodeling and obstruction contributing to the characteristic findings of inflammation and obstruction observed in the airways of individuals with COPD (3-9, 17, 18).

Administration of fluticasone (an inhaled corticosteroid) in combination with salmeterol (a long acting bronchodilator) to individuals with moderate to severe COPD results in reduction of hospitalization by approximately 30%, increased quality of life, and a decreased in the reduction of lung function (19, 20).

Similarly, following hospitalization with acute exacerbation of COPD, those individuals who receive inhaled steroids in combination with long acting bronchodilators have a lower re-hospitalization rate. The mechanisms by which inhaled steroids with long acting bronchodilators result in clinical improvement and increased quality of life in individuals with moderate to severe COPD and following acute exacerbations are poorly understood (19-24).