dironyl and Fibrosis

Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by vasculopathy, inflammation and fibrosis. These three main disease-determining pathways are the target of the currently available treatments used to possibly modify the progression of disease-related manifestations, although this synergy has not been fully applied on SSc joint, skin or lung involvement yet. Areas covered: we describe the current status of SSc treatment/therapy performing a literature search in MEDLINE/Pubmed and Thomson Reuter's Web of Science for articles published until March 2016. Moreover, ongoing registered clinical trials (RCTs) on SSc were searched through clinicaltrials.gov website. Expert commentary: presently, promising drugs are under evaluation to target the different pathogenic pathways of systemic sclerosis: Tocilizumab and Abatacept for skin and lung fibrosis; Riociguat and Selexipag are approved for pulmonary arterial hypertension but promising anti-fibrotic effects are now being studied. Finally, several anti-fibrotic molecules are currently involved in RCTs, such as Nintedanib, IVA-337, Terguride.

Topics: Abatacept; Acetamides; Antibodies, Monoclonal, Humanized; Biological Products; Clinical Trials as Topic; Fibrinolytic Agents; Fibrosis; Humans; Hypertension, Pulmonary; Indoles; Inflammation; Joints; Lisuride; Lung; PubMed; Pyrazines; Pyrazoles; Pyrimidines; Scleroderma, Systemic; Skin

Cutaneous fibrosis seen in systemic sclerosis (SSc) is a generalized connective tissue disorder, characterized by a wide spectrum of microvascular and immunological abnormalities. Serotonin (5-hydroxytryptamine; 5-HT) is a neurotransmitter and immune modulator, is also an important mediator of bidirectional interactions between the vasoactive amines and the skin.5-HT, a commonly secreted amine, is a known inducer of fibrosis, although the mechanistic basis for it and growth factors regulating fibrosis and proliferation in the microenvironment are unclear. We review that as serotonin has powerful vasodilator, immunomodulator, and growth factor actions, this pathway could be involved in skin fibrotic. Since serotoninergic system play a role in skin fibrotic, and 5-HTs drugs, an usual treatment for this type of patients. These provides a future perspective for research and drug development.

Topics: Animals; Cell Growth Processes; Dopamine Agonists; Fibrosis; Humans; Lisuride; Precision Medicine; Receptor, Serotonin, 5-HT1A; Scleroderma, Systemic; Selective Serotonin Reuptake Inhibitors; Serotonin; Skin

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