COPD is currently the fourth leading cause of death. It is a complex condition characterized by progressive airflow limitation resulting from emphysema and airway disease. Cigarette smoking is the major cause, but 20% of cases develop in non-smokers and smokers have varying degrees of susceptibility. Emphysema, which is characterized by lung tissue destruction, is thought to result from injury caused by smoke. Tissue destruction, however, represents an imbalance between tissue injury and the capacity of tissues to repair. Recent evidence suggests that early life events can contribute to COPD risk. Among these, exposure to cigarette smoke has been demonstrated to be a risk factor, and evidence supports the concept that maternal environmental smoke exposure is sufficient. The current proposal will test the hypothesis that fetal exposure as a result of maternal environmental smoke exposure leads to a defect in the maintenance of stem/precursor cells in the lung. As a result, the lung is unable to maintain repair functions with age and, as such, is predisposed to develop senile emphysema. This increased susceptibility to develop emphysema is exacerbated by exposure to smoke-induced injury in adulthood. This hypothesis will be tested by exposing pregnant mice to levels of smoke consistent with environmental exposures. Pups will then be monitored for lung cell repair functions and susceptibility to develop emphysema as they age. The role of stem cells will be evaluated by quantifying progenitor stem/cell functions in the exposed animals using in vivo and in vitro methods. Bone marrow (stem cell) transplants will be used to confirm the role of stem cells and to attempt to restore lung function. This will establish fetal environmental smoke exposure as a cause of adult COPD and provide a novel basis for therapy. ? ?
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