Chronic Obstructive Pulmonary Disease (COPD) remains a leading cause of death globally. Since the disease takes years and even decades to develop, limiting the development of disease-modifying therapy, there is a critical need for safer, more efficient disease models to translate to human systems. In vitro cell models of human airway epithelial cells on an air-liquid interface (ALI) are frequently used; however, ALI models lack the complex three-dimensional architecture and vast multicellular interactions between the resident cells found in the lungs. Alternatively, animal models of COPD can be informative but often require multiple animals and still require several months to demonstrate the pathologic changes of COPD. Living three-dimensional lung tissues, like Precision Cut Lung Slices (PCLS), have emerged as a promising tool for studying inflammatory diseases. PCLS allow for the investigation of disease in structurally relevant regions of the lungs, where all native cell types and extracellular changes are present. It also allows us to reduce the number of animals used for an experiment and decrease the amount of experiment-induced stress that animals can experience in traditional smoking chamber models. Using PCLS from mice and human lungs, we have developed a cigarette smoke exposure model to study some of the pathobiology and physiology of emphysema, such as alveolar destruction, cell death, metabolic activity, and mitochondria dysfunction. Here we also present a model for studying some adaptive immune response changes by re-introducing alveolar macrophages into the tissues and exposing them to cigarette smoke to explore their interactions with resident cells and extracellular matrix components.