Commonly diagnosed among male US Veterans of advancing age and with prior history of cigarette smoking, emphysema is a chronic lung disease in which loss of the alveolar-capillary gas exchange units ultimately leads to end-stage respiratory insufficiency. Thus, understanding the mechanisms underlying lung function impairment in emphysema and developing strategies to mitigate its development remains at the forefront of research into US Veteran’s health. Emphysema is associated with alveolar septal thinning, loss of extracellular matrix (ECM), especially elastin and collagen, and alveolar simplification due to loss of alveolar epithelial cells, endothelial cells and fibroblasts. While considerable attention has been focused on understanding how cigarette smoke (CS) exposure adversely impacts alveolar epithelial cells and endothelial cells, little is known about its effect on alveolar septal fibroblasts, which provide essential trophic and structural support to the alveolar epithelium. Using 2 validated mouse models of emphysema, we have observed that PDGFRα+ alveolar fibroblasts are eliminated from alveolar walls and septa prior to the pathologic development of airspace enlargement, raising the question of whether this event may play a causal and previously unexplored role in emphysema. Therefore, the goal of this VA Merit Award application is to test the hypothesis that emphysema is initiated by programmed cell death and loss of alveolar fibroblasts, which in turn leads to loss of trophic support to the alveolar epithelium. Through the use of genetic cell ablation and gain- and loss-of-function approaches in mice, we propose testing this hypothesis with three Specific Aims. Aim 1 will test the hypothesis that alveolar wall and septal fibroblast programmed cell death precedes the development of emphysema and leads to disrupted crosstalk with, and support to, alveolar epithelial cells. This hypothesis will be tested by investigating which alveolar fibroblast subsets are lost during emphysema development, when they are lost, the type of programmed cell death that occurs, and how their loss functionally affects alveolar epithelial cells. Aim 2 will test the hypothesis that loss of alveolar fibroblasts is sufficient to initiate the development of emphysema. This hypothesis will be tested using a conditional fibroblast ablation strategy followed by assessment of the rate of alveolar epithelial cell loss and emphysema development. The role of loss of specific alveolar fibroblast subsets in emphysema development will subsequently be determined by conditionally ablating defined lung fibroblast subsets. Lastly, Aim 3 will test the hypothesis that preventing alveolar fibroblast programmed cell death will maintain alveolar structural support and prevent emphysema development. This hypothesis will be tested in two phases. First, we will investigate the mechanisms of programmed cell death, with a focus on apoptosis and necroptosis. Second, based on this informa...