The WNT receptor Frizzled-8 in pulmonary remodelling and inflammation

Lung diseases as chronic obstructive pulmonary disease (COPD), asthma and pulmonary fibrosis are characterised by similar aberrant inflammatory and repair processes, leading to tissue remodelling. Recent studies have indicated an important role for WNT signalling in the development of these lung diseases. We previously found the expression of the WNT receptor Frizzled-8 (FZD8) to be increased in human lung fibroblasts of COPD patients. The objective of this thesis is to establish the functional role of the FZD8 receptor and its cognate WNT ligands in lung diseases, with focus on its role in COPD. We show that FZD8 regulates in part TGF-β-induced pro-fibrotic signalling and that WNT-5B, but not WNT-5A, functions as a ligand for FZD8 in fibroblast activation. Next, we found that the proteoglycan decorin functionally antagonizes WNT-5B-induced effects on fibroblast activation. Besides their structural role, fibroblasts can play an inflammatory role and we show that hereby fibroblasts have an upregulatory effect on in mucus secretion by airway epithelial cells via FZD8. In addition, FZD8 is genetically associated with chronic mucus hypersecretion as a clinical outcome of chronic bronchitis. Finally, we observed that acute cigarette smoke-induced neutrophilic inflammation is regulated by FZD8, while FZD8 is not involved in allergen-induced inflammation and remodelling in mouse models. Together, our findings indicate that FZD8 is a possible drug target for chronic bronchitis and lung fibrosis