Mechanisms and consequences of disturbed crosstalk between cells and extracellular matrix in COPD

Chronic obstructive pulmonary disease (COPD) is characterized by alterations in extracellular matrix (ECM). Fibroblasts and airway smooth muscle cells (ASM) are responsible for ECM production in small airways. With the altered ECM environment the behavior of fibroblasts and ASM is changed, leading to an alteration in matrix production. We hypothesized that disturbed fibroblast/ASM - ECM cross-talk in COPD underlies ECM remodeling in small airways. We demonstrated that the mechanosensitive channel Piezo had higher expression in COPD IV ASM, together with downregulated functionality in COPD II. Altered response to stretching and decreased ECM gene expression upon Piezo activation supported a potential role for Piezo in regulating COPD tissue remodeling. Then we focused on the role of the lysyl oxidase family members (LOs) in COPD, covering changes in the gene and protein expression, as well as functional studies on airway contraction. These findings highlight the potential differential roles of LOs enzymes in COPD lung. We explored whether LOs-driven ECM modifications affected fibroblast behavior. Our investigations revealed that inhibition of LOs had no effect on healthy fibroblast–ECM cross-talk in vitro. Finally, we explored current three-dimensional (3D) ECM lung models and showed the transcriptional differences in the responses of healthy lung fibroblasts when cultured in a 3D versus 2D environment using a collagen hydrogel model. These results highlight the importance of 3D models of cell-ECM interactions as mimic for in vivo conditions. Overall, this thesis provides insights into the disrupted fibroblasts/ASM - ECM cross-talk in COPD, resulting in the remodeling of lung tissue.