An orally available, highly selective 5-hydroxytryptamine 2B (5-HT2B) receptor antagonist ameliorating pulmonary and dermal fibrosis

Wenglén, Christina; Arozenius, Helena; Pettersson, Lars; Ekström, Gunilla

doi:10.1183/13993003.congress-2019.pa2421

Cited by 1 publication

(2 citation statements)

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“…5-HT 2 receptor antagonists have been suggested to attenuate lung fibrosis by reducing TGF-β signaling measured, e.g., as reduced Smad2/3 phosphorylation. This was recently shown in a chronic graft-versus-host disease model where inhibition of the 5-HT 2B receptor using a highly selective antagonist resulted in reduced dermal fibrosis and lung fibrosis as well as a decreased Smad 2/3 phosphorylation, suggesting TGF-β involvement [ 50 ] ( Figure 1 ). The signaling pathways elicited by 5-HT 2 receptor activation is not yet elucidated in full context, but it has been speculated that 5-HT-induced profibrotic responses are partly mediated by a second messenger.…”

Section: Tgf-β—a Potential Second Messenger To 5-htmentioning

confidence: 60%

“…The 5-HT 2B receptor antagonism also hampered myofibroblast differentiation as seen with reduced pulmonary count of myofibroblasts in bleomycin-treated mice, a response that appeared to be generated by interfering with TGF-β1 [ 34 ]. Significant anti-fibrotic effects with, e.g., reduced ECM production have also been observed in in vivo disease models of SSc after therapeutic treatment with selective 5-HT 2B receptor antagonists [ 50 , 51 ]. These data imply a direct or indirect link between serotonergic signaling and TGF-β1 activity, where the mediators together drive important fibrotic remodeling processes.…”

Section: Tgf-β—a Potential Second Messenger To 5-htmentioning

confidence: 99%

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Pathological Insight into 5-HT2B Receptor Activation in Fibrosing Interstitial Lung Diseases

Löfdahl

Tornling

Wigén

et al. 2020

IJMS

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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-HT2B 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-HT2B 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-HT2B receptor as a potential disease target for PF-ILDs, which today have an urgent unmet need for therapeutic strategies.

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Section: Tgf-β—a Potential Second Messenger To 5-htmentioning

confidence: 60%