Chronic Obstructive Pulmonary Disease (COPD) is globally the third leading cause of death. COPD is characterized by a persistent and usually progressive airflow limitation, that is associated with an abnormal inflammatory response of the lungs to mainly cigarette smoke (CS), causing obstruction of the small airways and alveolar destruction (i.e., emphysema). Drugs that slow down the disease progression are still lacking, because of a poor understanding of the underlying mechanisms. In exciting preliminary studies, we have demonstrated for the first time that Toll-like receptor (TLR)7 is an important driver of human and experimental emphysema and COPD. We hypothesize that chronic CS exposure activates TLR7 directly and/or indirectly through single stranded RNA released from damaged airways and lung tissue. TLR7 activation induces oxidative stress, cell death and the release of cytokines/chemokines and proteases from TLR7-expressing cells (including bronchial epithelial cells, macrophages, dendritic cells, and mast cells), driving the pathogenesis of emphysema and COPD. In this project we will use a powerful combination of our experimental COPD models in vivo and primary human tissue and cells ex vivo to fully characterize the roles of TLR7 in the pathogenesis of emphysema and COPD and to elucidate the mechanisms of TLR7-driven pathogenesis. Finally, we will develop the most effective therapeutic anti-TLR7 treatment regime for emphysema and COPD.