. COPD is one of the leading causes of disability worldwide and is the only major disease for which the prevalence and mortality rates continue to rise. One of the primary components of COPD is emphysema, an irreversible destruction of lung tissue, but the mechanisms underlying this alveolar destruction remain elusive and controversial. In the present work, we propose new hypotheses, based on novel experimental approaches in a mouse model, that could directly impact our understanding ofthe mechanisms underlying the chronic nature of this debilitating pathology. The experimental model involves an acute intratracheal elastase insult. Although this acute injury model may seem unrelated to the chronic disease progression seen in humans, the elastase itself does little acute parenchymal damage and is in fact itself degraded in about a day. Its effects, however, are long reaching, leading to an altered inflammatory milieu that develops into the chronic loss of alveolar surface area and lung elasticity that continues to worsen for as long as the animal lives. Our preliminary evidence suggests a novel mechanism that may play a key role in the progressive worsening of emphysema. Experiments are designed to test the hypothesis that acute focal lung damage initiates a CD8+ T cell to Tc17 response that subsequently activates chronic macrophage destruction of parenchymal tissue. The involvement of IL-17 in this process is novel, and there is little known about its potential role in this chronic disease. In addition, the temporal dynamics of how macrophages are involved, how they are recruited, how they are activated, and how they potentially mobilize other cells and cytokines remains poorly understood. Normally macrophages serve a protective role in lung defenses, but why a single acute elastase insult leads to an endless activity of these cells with concomitant lung damage is unknown. To address these questions, we have devised several novel experimental approaches that will focus on the interaction between the CD8+ T cells and the dynamics of macrophage activation. The information gleaned from our studies will impact on our understanding of this process and possibly lead to new potential therapies to break the cycle of progressive destruction in chronic emphysema. Programmatic interactions and synergy.
The aims i n Project 1 have considerable interaction with the other two projects in this PPG. Project 2 deals with mechanisms underlying how the lung responds to an acute bleomycin injury and emphasizes the interaction between T cells and macrophages, especially the effect of alternate activation. Dr. Horton carried out some ofthe basic preliminary work measuring IL-17 and is a coinvestigator on the project. Dr. Mitzner is also involved as a coinvestigator doing pulmonary function measurements in Dr. Horton's project. Project 3 investigates the effects of chronic ischemia. Using the mouse model of chronic ischemia in Project 1, Dr. Wagner helped generate preliminary work in Project 1 showing the absence of emphysema caused by elastase in lungs that lacked normal perfusion. In addition Dr. Mitzner helped with the model generation that forms the core of Dr. Wagner's current project. Dr. Wagner also plans to examine the effect of macrophage activation status in her model of chronic ischemia, but she suggests a proangiogenic role for the macrophages, whereas Projects 1 and 2 emphasize their destructive actions. Program discussions and interactions may help to determine why and when one function becomes dominant. Project 1 also will make heavy use of both the Flow Cytometry and Histology Cores.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Johns Hopkins University
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