Interstitial lung disease (ILD) encompasses a heterogeneous group of more than 200 conditions, of which primarily idiopathic pulmonary fibrosis (IPF), idiopathic nonspecific interstitial pneumonia, hypersensitivity pneumonitis, ILD associated with autoimmune diseases and sarcoidosis may present a progressive fibrosing (PF) phenotype. Despite different aetiology and histopathological patterns, the PF-ILDs have similarities regarding disease mechanisms with self-sustaining fibrosis, which suggests that the diseases may share common pathogenetic pathways. Previous studies show an enhanced activation of serotonergic signaling in pulmonary fibrosis, and the serotonin (5-HT)₂ receptors have been implicated to have important roles in observed profibrotic actions. Our research findings in support by others, demonstrate antifibrotic effects with 5-HT_2B receptor antagonists, alleviating several key events common for the fibrotic diseases such as myofibroblast differentiation and connective tissue deposition. In this review, we will address the potential role of 5-HT and in particular the 5-HT_2B receptors in three PF-ILDs: ILD associated with systemic sclerosis (SSc-ILD), ILD associated with rheumatoid arthritis (RA-ILD) and IPF. Highlighting the converging pathways in these diseases discloses the 5-HT_2B receptor as a potential disease target for PF-ILDs, which today have an urgent unmet need for therapeutic strategies.

Background: 5-hydroxytryptamine (5-HT) is well known as a stimulator of tissue fibrosis and a significant role of peripheral 5-HT_2B receptors in human fibrosis has been suggested. The pro-fibrotic effects of the 5-HT_2B receptor are believed to be mediated through activation of the TGF-β/Smad signaling pathway. Aims: To investigate effects of a selective 5-HT_2B receptor antagonist on fibrosis development and the TGF-β/Smad signaling pathway. Methods: The murine sclerodermatous chronic graft versus host disease (scGvHD) model was used to evaluate anti-fibrotic effects of the 5-HT_2B receptor antagonist, AM1476. Oral, twice daily treatment with AM1476 was applied day 21 to 49. Pulmonary fibrosis was evaluated using hydroxyproline content, Sirius Red staining and Ashcroft score. Dermal thickness, myofibroblast counts and collagen production were used to evaluate dermal fibrosis. The number of phosphorylated Smad3 (pSmad3) positive cells was used to evaluate inhibition of TGF-β signaling. Plasma was collected for exposure analysis. Results: AM1476, significantly reduced all measured pulmonary and dermal readouts in the scGvHD model using a therapeutic treatment approach. Plasma exposure supported target engagement. The number of pSmad3 positive cells was significantly reduced in treated animals. Conclusion: Inhibition of 5-HT_2B receptor activity resulted in anti-fibrotic effects in pulmonary and dermal fibrotic tissues. Reduction of pSmad3, reflecting TGF-β-inhibition, was observed. The highly selective 5-HT_2B receptor antagonist AM1476, represents a promising drug candidate for treatment of fibrotic conditions and is currently in development for Systemic Sclerosis.