PhD defence C. (Chiara) Ciminieri

Targeting the COPD lung microenvironment for lung repair: mechanisms and novel therapeutic opportunities

Overall, the thesis of Chiara Ciminieri discovered several altered mechanisms in lung repair and validated them as new potential therapeutic options for COPD treatment.

Ciminieri: 'Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease of the lung and the third leading cause of death worldwide. The treatments currently available can ease some of the symptoms, but cannot prevent or revert disease progression. The aim of this thesis was to investigate the molecular mechanisms underlying failed tissue repair in order to identify new therapeutic targets to repair the injured lung tissue. We analyzed the effect of air pollution, specifically diesel particles, on the growth of “mini lungs” (organoids), and found that they were halting their growth by causing oxidative stress and reducing WNT/β-catenin signaling, an important molecular mechanism involved in organoids development. When we counteracted the diesel damage using anti-oxidants and activating WNT/β-catenin signaling, we were able to restore organoids growth.One of the alterations in WNT/β-catenin signaling in COPD is reduced expression of a receptor, FZD4. We found that blocking this receptor completely impairs lung organoids growth, pointing to an important role for this receptor in lung cell function, and an opportunity for new therapeutic options.The thesis also describes the effect of inflammation on the cells involved in lung repair, and found that targeting specific inflammatory mediators (IL-1β, CXCR1/2, LTβR signaling) can restore lung repair; we also show the different contribution of acute versus chronic inflammation on tissue repair and suggest a more targeted and timed approach to inflammation in COPD treatment.Overall, this thesis discovered several altered mechanisms in lung repair and validated them as new potential therapeutic options for COPD treatment.'

Promotors: Prof.dr. R. Gosens and Prof.dr. M. Köningshoff