Chronic Obstructive Pulmonary Disease (Chronic Bronchitis & Emphysema) is the 4th leading cause of mortality in the United States. it is the only major cause of mortality whose incidence is rising. COPD is disproportionately manifest in the geriatric population. Patients most often five for years with steadily progressive suffocation, punctuated by increasingly frequent exacerbations of respiratory insufficiency. Emphysema is histologically defined as the destruction of alveolar walls without significant fibrosis. Regeneration of alveoli in the emphysematous lung should improve pulmonary function and lessen the burden of this common disease. Marrow Stromal Cells (MSCs) are pluripotent cells that can be harvested from aduJt bone marrow and potentially be used in tissue repair. As emphysema primarily affects the aging population, we must first understand more about the effects of senescence on MSC recruitment to the injured lung before these cells can be used therapeutically. This proposal will test the hypothesis that MSCs from older adult rats exhibit reduced homing to the lung in the elastase model of emphysema. The 1st specific aim of the project will confirm the hypothesis that homing of senescence MSCs to the lung is compromised in the elastase-induced rat model of emphysema following intravenous administration. We will test this prediction by transplanting MSCs harvested from young adult and older adult male rats into female rats previously treated with intratracheal elastase and quantitating engraftment by chimerism of the X- & Y-chromosomes. Engraftment will be confirmed by fluorescent microscopy (of EGFP transduced MSCs) & immunohistochemistry. The 2nd specific aim of this proposal will investigate investigate age-dependent changes in MSC migration in vitro. The following predictions will be tested: 1) MSCs harvested from older adult rats will exhibit impaired migration toward a chemotactic stimulus. 2) The older adult rat MSCs will display relatively attenuated chemotaxis after exposure to an activating stimulus. These studies will expand our understanding of the biology of MSCs & their potential for lung repair in the geriatric population, hopefully leading to novel therapies for emphysema.
