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, 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. Disturbances in pulmonary cell death pathways (including apoptosis, necroptosis and ferroptosis), as well as impaired clearance of dead and dying cells (also called efferocytosis), contribute to the chronic inflammation and tissue destruction in patients with COPD. The first aim of this project is to characterize the pathogenic contribution of different modes of regulated cell death in experimental COPD and to therapeutically target these cell death modalities, using genetic and pharmacological inhibition of RIPK1 kinase activity – critical in the activation of several modes of regulated cell death – as well as the novel ferroptosis inhibitor UAMC-3203. The second aim is to elucidate the defects in the different phases of efferocytosis in both experimental and human COPD. Finally, boosting efferocytosis in stable and exacerbated experimental COPD, using the unique BELMO transgenic mice, will define its role in COPD pathogenesis, as well as its therapeutic potential.