Even though years of research have advanced our understanding of idiopathic pulmonary fibrosis (IPF), the expanded knowledge on risk factors and mechanisms has not yet resulted in effective treatments to control or cure this disease. In patients with IPF, an aberrant wound healing response results in an extracellular matrix (ECM) with altered biochemical and biophysical properties. As key regulators of the wound healing response, macrophages should be able to prevent or resolve fibrosis by regulating the production and degradation of ECM proteins. However, the impact of direct interactions between (fibrotic) matrix and macrophages on the macrophages’ ability to orchestrate the wound healing response is still unclear, and therefore the focus of this thesis. A collagen type I-based in vitro model was developed to study the response of alveolar-like macrophages to collagen layers with varying morphology and stiffness. Macrophages were found to change their shape, behavior, and marker expression depending on the morphology of the collagen they were cultured on. To connect the in vitro effect of different collagen morphologies with the in vivo situation, the amount of structurally disrupted collagen was visualized in lung tissue from patients with IPF and controls. Higher levels of structurally disrupted collagen were found in patients with IPF, indicating that extensive collagen remodeling is taking place. Furthermore, to improve our understanding of macrophage polarization, an optical tweezers-based system was used to study macrophage activation upon a single biochemical stimulus on a single-cell level with very high spatiotemporal resolution. In conclusion, it is without doubt that macrophages are able to sense changes in their microenvironment and subsequently change their phenotype. However, a better understanding of fibrosis-related ECM changes and functional macrophage polarization is required to clarify the exact role of macrophage-matrix interactions in orchestrating the fibrotic response.
|Qualification||Doctor of Philosophy|
|Place of Publication||[Groningen]|
|Publication status||Published - 2021|