Article Text

PDF
SAT0314 A novel highly selective 5-hydroxytryptamine 2B (5-HT2B) receptor antagonist ameliorating fibrosis in preclinical models of systemic sclerosis
  1. C Wenglén,
  2. L Pettersson,
  3. H Arozenius,
  4. G Ekström
  1. ANAMAR, Lund, Sweden

Abstract

Background Microvascular injury is one of the first pathological events in systemic sclerosis, and precedes the fibrosis. A consequence of vascular damage is the exposure of subendothelial connective tissue that causes activation of platelets and local serotonin (5-hydroxytryptamine, 5-HT) release. Binding of 5-HT to 5-HT2B receptors on e.g. fibroblasts results in increased myofibroblast differentiation and release of excessive amounts of matrix proteins subsequently leading to fibrosis. Thus, pharmacologic inhibition of 5-HT2B receptor signalling may represent a new treatment opportunity for systemic sclerosis.

Objectives The objective of the present study was to evaluate a novel highly selective 5-HT2B receptor antagonist for its ability to reduce the production of matrix proteins in human dermal fibroblasts and to ameliorate fibrosis in the tight-skin-1 model of systemic sclerosis.

Methods Dermal fibroblasts isolated from patients with systemic sclerosis were cultured with different concentrations of the 5-HT2B receptor antagonist AM1125 with or without 1 μM 5-HT. Anti-fibrotic effects were evaluated by measuring matrix production, myofibroblast differentiation and TGF-β production. The tight-skin-1 model was used to evaluate anti-fibrotic effects in vivo using a therapeutic treatment approach. AM1125 was administered at 10 and 50 mg/kg orally, b.i.d. from week 5 to week 10. Hypodermal thickening, myofibroblast counts and collagen production (hydroxyproline) were evaluated at the end of the treatment period.

Results In vitro the 5-HT2B receptor antagonist AM1125 dose-dependently reduced TGF-β, PAI, nuclear SMAD2/3 and collagens in human dermal fibroblasts. In addition, stress fiber formation and α-SMA mRNA were reduced indicating decreased myofibroblast differentiation. Therapeutic treatment with AM1125 at 50 mg/kg reduced hypodermal thickness (p<0.001), myofibroblast counts (p<0.05) and hydroxyproline content (p<0.01) in the tight-skin-1 model. In addition, the lower dose (10 mg/kg) reduced hypodermal thickness (p<0.001).

Conclusions The results demonstrate that the 5-HT2B receptor antagonist AM1125 prevents pro-fibrotic events in human dermal fibroblasts and attenuates dermal fibrosis using a therapeutic treatment approach in the tight-skin-1 model. Thus, 5-HT2B receptor antagonists, exemplified by the novel compound AM1125, could represent a new treatment opportunity for systemic sclerosis.

Disclosure of Interest C. Wenglén Employee of: AnaMar, L. Pettersson Employee of: AnaMar, H. Arozenius Employee of: AnaMar, G. Ekström Employee of: AnaMar

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.