Cigarette smoke (CS) is the primary cause of chronic obstructive pulmonary disease (COPD), a devastating disease characterized by progressive lung function decline, afflicting 13% of the world’s population and causing 150,000 deaths annually in the United States. Given the growing burden, there is a pressing need to determine cellular mechanisms that govern COPD and develop therapies to target them. The lung epithelium is a barrier between the external environment and the rest of the body. It is regularly exposed to inhaled irritants, such as cigarette smoke (CS), that can result in tissue damage. There is a growing recognition that epithelial dysfunction is an early driver of tissue remodeling in COPD.

We have shown that COPD epithelial cells exhibit cellular plasticity due to increases in the polymerized actin, a phenotype recapitulated with repetitive CS injury. This cellular plasticity transforms the epithelium from stationary to mobile cells8. The motility is mediated by increased focal adhesions through which the epithelium interacts with the matrix to propel the cell forward. Our data shows that decreasing the fraction of polymerized actin inhibits epithelial movement. Focal adhesions are formed with actin stress fibers and linker proteins such as vinculin which provide the mechanical cues required for cellular movement. Focal adhesions are the main interaction between the extracellular matrix (ECM) and epithelium and are critical in mediating cellular repair. We propose to use 3D co-culture models and PCLS explants to study the mechanisms of mediating epithelial-ECM/fibroblast interaction, specifically in terms of the ECM protein HAPLN.