n-(1-methyl-5-indolyl)-n--(3-methyl-5-isothiazolyl)urea and Scleroderma--Systemic

Release of 5-hydroxytryptamine (5-HT; serotonin) from activated platelets following microvascular injury leads to tissue fibrosis. 5-HT strongly induces extracellular matrix synthesis in dermal fibroblasts in a transforming growth factor beta 1 (TGF-β1)-dependent manner.. To evaluate anti-fibrotic properties of inhibitors of 5-HT. Stimulation of HADF cells with 5-HT/TGF-β1 led to the increased expression of pro-fibrotic genes which was significantly reduced by both terguride and SB204741. Expression of anti-fibrotic genes was not affected upon incubation with the inhibitors. In 5-HT-stimulated HADF, treatment with terguride and SB204741 decreased type I collagen and α-SMA. In 5-HT/TGF-β1 stimulated HADF, terguride and SB204741 treatment reduced ERK1/2 and STAT3 phosphorylation but did not influence Smad3 phosphorylation.. Terguride and SB204741 reduce pro-fibrotic potential of HADF cells and suppress TGF-β1-mediated non-canonical pathways, ERK1/2 and STAT3 which have been implicated in the regulation of pro-fibrotic genes and in the development of fibrosis. Taken together, our data suggest that 5-HT inhibitors might reduce fibrosis via suppression of TGF-beta1-mediated non-canonical signaling pathways. These observations have important therapeutic implications for fibrotic disorders like scleroderma.

Topics: Adult; Cells, Cultured; Extracellular Matrix Proteins; Extracellular Signal-Regulated MAP Kinases; Female; Fibroblasts; Fibrosis; Gene Expression Regulation; Humans; Indoles; Lisuride; Phenotype; Phosphorylation; Receptor, Serotonin, 5-HT2B; Scleroderma, Systemic; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Signal Transduction; Skin; STAT3 Transcription Factor; Transforming Growth Factor beta1; Urea