1. Introduction

The term interstitial lung disease (ILD) encompasses a large heterogeneous group of diffuse parenchymal lung disorders, of which primarily idiopathic pulmonary fibrosis (IPF), idiopathic nonspecific interstitial pneumonia, ILD associated with autoimmune diseases, hypersensitivity pneumonitis and sarcoidosis may present a progressive fibrosing (PF) phenotype [1]. Despite known or unknown causes and radiological patterns, the PF-ILDs have similarities regarding disease mechanisms with self-sustaining fibrosis [2], suggesting common pathogenetic pathways. In this review, we will address the potential role of serotonin (5-HT) and the 5-HT_2B receptor in three PF-ILDs: IPF, ILD associated with systemic sclerosis (SSc-ILD) and ILD associated with rheumatoid arthritis (RA-ILD).

2. The Serotonergic Pathways in Tissue Repair and Fibrosis

Serotonin (5-hydroxytryptamine, 5-HT) is a multifunctional signaling molecule, mainly recognized for its role in the central nervous system (CNS), where it regulates several behavioral processes. Even now, over 70 years after its discovery, the functional role of 5-HT is still not fully clarified, with emerging studies showing new biological influences and disease associations. A mechanistic link between fibrosis and 5-HT was first reported in the 1960s for a condition called carcinoid syndrome which is caused by neuroendocrine carcinoid tumors that secrete vast quantities of 5-HT [30]. The syndrome was characterized by tissue fibrosis, particularly affecting cardiac valves but also impacting on other organs including lung and skin. More recently, agonistic activity on the 5-HT_2B receptor has been implicated in causing fibrosis, which led to the recall of fenfluramine used in the treatment of obesity, as well as pergolide, a drug used to treat Parkinson’s disease [31,32].
The 5-HT_2B receptor agonistic activity of these drugs has been suggested to lead to myofibroblast activation in a transforming growth factor (TGF)-β1 dependent manner, resulting in fibrosis [33,34]. Besides the 5-HT_2B receptor, the receptor subtypes 5-HT_2A and 5-HT_2C
have also been suggested to be involved in fibrosis. 5-HT has been described to play a role in alveolar macrophage function through 5-HT_2C receptors and thereby affect fibrosis development [35], while the 5-HT_2A receptor has been shown to induce a TGF-β dependent
fibrotic response in vivo [36]. Among the other classes of receptors, 5-HT₇ was in a recent paper by Tawfik et al. suggested to mediate anti-inflammatory and anti-fibrotic effects in the bleomycin-induced lung fibrosis model in rats [37]. However, the cellular mechanisms
underlying PF-ILDs are still under investigation where the activation of specific 5-HT receptors remains an overlooked target in pulmonary fibrotic disorders. To understand the pathophysiological impact of 5-HT and the different 5-HT receptors, it is important to take into account the cellular context and the diversity in expression profile of the 5-HT receptors in different conditions. It is clear that activation of the 5-HT_2B receptor critically affects several profibrotic responses, whereby modulating its activity has been shown to attenuate fibrosis [34,38–40].

This entry is adapted from the peer-reviewed paper 10.3390/ijms22010225