Abstract The adult mammalian lung contains diverse populations of cells that coordinate self-renewal during homeostasis and repair. However, these processes are dysregulated during lung diseases like chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis, COVID-19, and more. The lungs are composed of the airways and alveolar space, two compartments with distinct functions. Each compartment contains a unique set of epithelial cells, such as basal, secretory, and ciliated cells in the airways. The alveolar space, where gas exchange occurs, is lined by alveolar type 2 cells (AT2s) and alveolar type 1 cells (AT1s). Additionally, emerging studies have examined the regulation of lung epithelium by other cell types like immune, endothelial, and mesenchymal cells. Among the mesenchymal cells that support lung epithelial stem cell niches are populations of smooth muscle cells and fibroblasts that facilitate airway regeneration. In the alveoli, distinct fibroblast populations have been identified that promote alveolar regeneration. Lung perturbations that affect specific compartments of the lung require the activation of local epithelial-mesenchymal interactions to restore homeostasis. However, the tissue-wide consequences of location-specific lung injuries is not well known. In my work, I propose to study the effects of airway injury on the alveolar compartment of the lung. I hypothesize that airway injury dysregulates homeostasis of the alveolar epithelium via alterations of the alveolar-associated lung mesenchyme. I will use a murine model of airway injury (naphthalene), which selectively ablates club cells of the airway epithelium, to determine if the alveolar epithelium or alveolar-supportive mesenchyme is dysregulated in a tissue-wide response. My preliminary work demonstrates an increase in proliferative AT2s during the regenerative phase of the airway injury response. Additionally, single cell RNA-sequencing of the lung mesenchyme from these injured mice demonstrated transcriptional changes in response to the airway injury. Through a combination of in vivo, in vitro, and computational approaches, I will 1) define the effect of airway injury on the alveolar epithelium and 2) determine if alveolar Pdgfrα-expressing fibroblasts, a mesenchymal population known to support alveolar regeneration, are altered in airway regeneration. Together, these studies will provide novel insights into alveolar compartment disruptions that accompany airway repair, advancing our understanding of how tissue-wide dysfunction occurs in complex lung diseases.