Mechanism of pathogenic macrophage activation in emphysema Summary Chronic obstructive pulmonary disease (COPD) is the 3rd leading cause of death in the U.S. and its prevalence is increasing globally. Emphysema, a key component of COPD most commonly associated with cigarette smoking, is defined by an irreversible loss of lung surface area and decrements in gas exchange that arise from progressive alveolar wall destruction. While elements that contribute to the initiation and pathogenesis of emphysema have been identified, including recurrent inflammation, oxidative stress, excess protease activity, cell death and genetics, we still lack clear mechanisms that would provide novel targets to slow or stop disease progression during or after smoking cessation. In this proposal, we have identified a novel role for pathologic macrophages in causing the progressive damage in emphysema. Strong preliminary data shows that IL-33 remains elevated in the lung after acute lung damage and is associated with an increase in Pathogenic Lung Macrophages (PLM) that have an altered M2 phenotype. Furthermore, our data also suggest that IL-17A is critical for this transition into PLM that work against the normal healing function of M2 macrophages. Although both IL-17A and IL-33 have been found in patients with COPD, little is known about how they impact the mechanism of progressive tissue destruction. Experiments will test a novel 2-step mechanism for lung macrophage activation in which IL-33 and IL-13, generated as a consequence of epithelial cell damage, initially result in conventional M2 activation, followed by second signal from IL-17A that modifies the macrophages to the PLM that mediate alveolar destruction. Our proposal is designed to test the central hypothesis that IL-33, IL-13 and IL-17A work together to promote the generation of pathogenic lung macrophages that play a principal role in progressive emphysema. Once the basic mechanisms are better understood in our first two aims, the third aim will test the hypothesis that the known plasticity of macrophages can be exploited to devise a therapeutic strategy to blunt or stop the progression of emphysema. The insights obtained from these studies should provide novel mechanistic insights and new potential therapeutic targets to limit the accelerated loss of lung function in humans with COPD.
Chronic obstructive pulmonary disease (COPD) is the 3rd leading cause of death in the U.S. Emphysema, a key component of COPD for which smoking is the chief risk factor, is characterized by irreversible airspace enlargement and airflow limitation that derives from progressive lung tissue destruction. In this project, we examine novel roles for pathogenic lung macrophages in sustaining the nonresolving inflammation and accelerated tissue destruction that often continue long after smoking cessation. Successful completion of this project will not only contribute significantly to the identification of mechanisms that drive emphysema, but also possibly lead to novel therapeutic targets to limit the decline of lung function in humans with COPD.