? Asthma is an enormous medical and economic burden worldwide and affects over 14 million Americans. Despite treatment with inhaled corticosteroid therapy, many asthmatic patients exhibit persistent symptoms of asthma, as well as accelerated decline in lung function. While asthma has classically been described as a disease of the proximal airways, physiologic, histologic, and immunologic data indicate that the distal lung is significantly involved in asthma and may be a cause of uncontrolled disease. Understanding the role of the distal lung in asthma has been hampered by difficulties in studying and treating this area. Chlorofluorcarbon (CFC) inhaled corticosteroids (ICS), the mainstay of asthma treatment, cannot effectively reach the distal lung due to their relatively large particle size. The recent transition to non-CFC inhalers has created a new class of extra-fine ICS aerosols which, theoretically, have a sufficiently small particle size to reach this region. To date, the effect of extra-fine ICS on distal lung inflammation remains unknown. The proposed study will evaluate the change in distal lung inflammation in mild to moderate steroid naive asthmatics at baseline and after treatment with a conventional ICS which mainly targets the proximal lung versus an extra-fine ICS which targets both the proximal and distal lung. The study will be conducted using a double-blinded, randomized crossover trial design. Before and after treatment, distal lung inflammation will be evaluated using: 1) messenger ribonucleic acid (mRNA) measures of inducible nitric oxide synthase, eotaxin, rantes, and interleukin-4 (IL-4) receptor alpha in distal airways obtained via distal lung brushings; and 2) lipopolysaccharide (LPS)-stimulated production of tumor necrosis factor (TNF)-alpha and MIP-1 alpha by alveolar macrophage obtained from distal bronchoalveolar lavage (BAL) aliquots. Non-invasive measures of small airways disease will also be obtained before and after treatment and correlated with the molecular and cellular markers of distal lung inflammation in an attempt to identify a valid non-invasive marker of small airways inflammation. Non-invasive markers of distal disease include: 1) quantitative analysis of thoracic computed tomography at residual volume (RV) before and after methacholine challenge; 2) physiologic measures of small airways disease including RV, FRC, isovolume FEF 25-75, and closing volume; and 3) the alveolar portion of exhaled nitric oxide (NO). This study will determine the potential to modify distal airways inflammation which may ultimately improve asthma control. ? ?
