Background Idiopathic pulmonary fibrosis (IPF) has a poor prognosis and limited responsiveness to available treatments. It is characterised by epithelial cell injury, fibroblast activation and proliferation and extracellular matrix deposition. Serotonin (5-hydroxytryptamine; 5-HT) induces fibroblast proliferation via the 5-HTR_2A and 5-HTR_2B receptors, but its pathophysiological role in IPF remains unclear. A study was undertaken to determine the expression of 5-HT receptors in IPF and experimental lung fibrosis and to investigate the effects of therapeutic inhibition of 5-HTR_2A/B signalling on lung fibrosis in vivo and in vitro.

Methods and results Quantitative RT-PCR showed that the expression of 5-HTR_1A/B and 5-HTR_2B was significantly increased in the lungs of patients with IPF (n=12) and in those with non-specific interstitial pneumonia (NSIP, n=6) compared with transplant donors (n=12). The expression of 5-HTR_2A was increased specifically in IPF lungs but not in NSIP lungs. While 5-HTR_2A protein largely localised to fibroblasts, 5-HTR_2B localised to the epithelium. To assess the effects of 5HTR_2A/B inhibition on fibrogenesis in vivo, mice were subjected to bleomycin-induced lung fibrosis and treated with the 5-HTR_2A/B antagonist terguride (or vehicle) in a therapeutic approach (days 14–28 after bleomycin). Terguride-treated mice had significantly improved lung function and histology and decreased collagen content compared with vehicle-treated mice. Functional in vitro studies showed that terguride is a potent inhibitor of transforming growth factor β₁- or WNT3a-induced collagen production.

Conclusion The studies revealed an increased expression of 5-HTR_2A specifically in IPF. Blockade of 5-HTR_2A/B signalling by terguride reversed lung fibrosis and is thus a promising therapeutic approach for IPF.