TY - JOUR T1 - The role of 5-HT2 receptors in the early development of lung fibrosis JF - European Respiratory Journal JO - Eur Respir J VL - 44 IS - Suppl 58 SP - 1419 AU - Anna Löfdahl AU - Martina C. Holst AU - Lena Thiman AU - Christina Wenglén AU - Kristina Rydell-Törmänen AU - Anna-Karin Larsson Callerfelt AU - Gunilla Ekström AU - Gunilla Westergren-Thorsson Y1 - 2014/09/01 UR - http://erj.ersjournals.com/content/44/Suppl_58/1419.abstract N2 - In the fibrotic lung, myofibroblasts contribute to a remodeled ECM through deposition of matrix proteins. Serotonin (5-hydroxytryptamine, 5-HT) has been suggested to be associated with the development of fibrosis through e.g. differentiation and activation of myofibroblasts. The pro-fibrotic action is thought to be mediated by 5-HT class 2 (5-HT2) receptors.The aims of the study were to investigate the role of 5-HT and potential therapeutic effects of selective 5-HT2 receptor antagonists in the development of lung fibrosis.In human lung fibroblasts, cultured with or without TGF-β1, the effects of 5-HT and small molecule 5-HT2 receptor antagonists (EXT5/EXT9; new compounds in development) were studied. Expression of alpha-smooth muscle actin (α-SMA), evaluated with Western blot and qrt-PCR analysis, was used as readout for myofibroblast differentiation. The total amount of proteoglycans, representing ECM production, was measured by [35S] sulfate labeling in culture medium.TGF-β1 increased α-SMA production by 69% (±11) and the combination of TGF-β1 + 5-HT increased the α-SMA production by 107% (±18) after 24h. 5-HT2 receptors antagonists reduced the α-SMA production to levels seen without fibrotic stimuli. After treatment with EXT5 or EXT9, the total production of proteoglycans was reduced by 51% (±0.6) and 64% (±18), respectively. Preliminary in vivo data supports a reduced matrix production after treatment with 5-HT2 antagonists.Our findings have given important insight into the pro-fibrotic role of 5-HT and 5-HT2 receptors, influencing myofibroblasts differentiation and proteoglycan production in vitro; suggesting 5-HT2 receptors as potential therapeutic targets in early lung fibrosis. ER -