Tissue remodelling in pulmonary fibrosis linked to 5-HT2 receptor activation

After an injury, an immediate reparative response is triggered to replace the damaged tissue, however, in fibrosis, cells remain active despite wound resolution causing a steady build-up of fibrotic tissue. In pulmonary fibrosis,
there is a constant regeneration and remodelling of lung tissue where the thin architecture of alveoli become thickened, hampering efficient diffusion of oxygen, as seen in diseases like idiopathic pulmonary fibrosis (IPF). IPF
is a detrimental respiratory disease marked with enhanced extracellular matrix (ECM) deposition generating structural alterations in the lung. To provide new insight into the underlying pathological mechanisms of pulmonary
fibrosis, this thesis has examined how pro-fibrotic cellular responses may be driven by a specific receptor and how surrounding ECM may affect the disease progression of IPF. Serotonin (5-HT) and its 5-HT2B receptor have been
implicated in several fibrotic conditions, acting as important mediators during fibrosis. In our studies, examination of 5-HT2B receptor antagonists showed several anti-fibrotic effects, reducing both myofibroblast differentiation and
fibroblast proliferation as seen in human cell cultures, as well as attenuated production and deposition of ECM as observed in mouse models of pulmonary fibrosis. Beneficial add-on effects with the 5-HT2B receptor antagonists
on bronchodilation and immune modulation were shown ex vivo and in vivo, respectively. The continuous induction of fibroblast activity in IPF renders an altered ECM with a unique protein composition that influenced
cellular behaviour, as shown in this thesis. To elucidate the interplay between cells and ECM we have examined the fibroblast response to IPF-derived ECM, using decellularized lung scaffolds repopulated with healthy lung
fibroblasts. The IPF-ECM with enhanced tissue density and stiffness, programmed the fibroblasts to rebuild a IPF-like matrix, lacking normal production of basement membrane proteins as well as enhanced early induction of
disease associated proteins such as periostin and tenascin-C, and the proteoglycans decorin, versican and biglycan. Collectively these results show that several profibrotic responses can be attenuated by 5-HT2B receptor
antagonism, identifying the 5-HT2B receptor as a promising target for pulmonary fibrosis. Fibroblast activity is evidently influenced by surrounding ECM, triggering pathological remodelling of the lung resulting in cellular
activation. Taken together, the ECM niche plays an important role in the disease mechanisms leading to progression of IPF.