PhD defence E.M. van Dijk

WNT pathway activation in COPD: a two way street between signalling and pathology

Chronic Obstructive Pulmonary Disease (COPD) is a life-threatening disease characterized by inflammation, tissue destruction (emphysema), scar tissue formation (fibrosis), and increased oxidative stress in the lungs. These processes result in airflow limitation, impairing the lung function and quality of life of patients. COPD is the fourth leading cause of death worldwide. Available treatments only alleviate symptoms whereas the disease cannot be cured or halted. In order to develop disease-modifying therapeutics it is crucial to unravel the cellular mechanisms and signalling pathways underlying COPD. The WNT signalling pathway is a promising therapeutic target. WNT signalling is involved in lung development and repair, but is altered in COPD. The mechanisms underlying this alteration and their contribution to COPD pathology are not understood. Therefore, the objective of the thesis of Eline van Dijk is to establish the role of WNT signalling in COPD. We demonstrate that WNT pathway activation may contribute to pulmonary inflammatory processes, fibrotic responses and emphysema, and is involved in ageing of the lung. Specifically, we show that the growth factors WNT-5A and WNT-5B and their receptors FZD2 and FZD8 are involved in these processes. In addition, we demonstrate that oxidative stress alters the structure of WNT-5B, resulting in enhanced WNT-5B-mediated inflammatory responses. Inhibiting WNT signalling by interfering with the above-mentioned WNTs and FZDs may therefore have beneficial therapeutic effects in the treatment of COPD. The precision cut lung slice model we developed in this thesis could serve as a good tool to screen these novel drug targets on the above-mentioned pathophysiological processes.

Dissertation

Promotores: Prof.dr. R. Gosens en Prof.dr. H. Meus