PROJECT SUMMARY Emphysema is a common pathologic manifestation of Chronic Obstructive Pulmonary Disease (COPD), the fourth leading cause of death in the United States. The most important modifiable risk factor for emphysema is chronic exposure to cigarette smoke (CS). Yet, not all smokers develop emphysema and, therefore, cellular responses to CS are important mechanisms underlying disease progression. Our long-term goal is to define the cellular responses to CS and oxidative stress that protect the lung from emphysema. We have identified a cytoprotective role for the innate immune cytokine Macrophage Migration Inhibitory (MIF). MIF decreases oxidative stress and consequences of oxidative stress (e.g. cellular senescence and apoptosis) in lung endothelial cells, and mice with a genetic deletion of Mif are susceptible to emphysema. MIF is secreted in response to CS, but, paradoxically, MIF is decreased in patients with severe COPD. Targeting MIF, or its downstream pathways, may be therapeutic. However, MIF is a pleiotropic molecule with broad regulatory effects. To translate MIF biology into therapy, it will be essential to dissect out its cytoprotective pathways. Our goal for this proposal is to determine the mechanisms through which MIF antagonizes the development of emphysema. Our preliminary data suggests MIF mediates its protective effects through its receptor CD74. Our hypothesis is MIF protects against the development of emphysema by mitigating CS-mediated endothelial senescence in a CD74 dependent manner. In Aim 1, we will define the mechanism through which the MIF-CD74 interaction reduces endothelial senescence. In Aim 2, we will determine the role of endothelial CD74 in regulating susceptibility to emphysema. In Aim 3, we will determine the therapeutic potential of targeting MIF-CD74 interactions in emphysema. Completion of these aims will significantly advance our understanding of the pathogenesis of emphysema and may identify precision-based approaches based on MIF biology for treating patients with emphysema.