Esomeprazole alleviates fibrosis in systemic sclerosis by modulating AhR/Smad2/3 signaling

Pharmacol Res. 2022 Feb:176:106057. doi: 10.1016/j.phrs.2022.106057. Epub 2022 Jan 5.

Abstract

Systemic sclerosis (SSc) is a connective tissue disease with the involvement of complex signaling pathways, such as TGF-β/Smad2/3. SSc can lead to severe multiple organ fibrosis, but no effective therapy is currently available because of its unclear pathogenesis. Exploring new treatments is the focus of recent research on SSc. Recent studies have implied a potential antifibrotic role of esomeprazole (ESO), but with currently unidentified mechanisms. Signaling of AhR, a ligand-dependent transcription factor, has been described as a key controller of fibrosis, tumorigenesis, and immune balance. Recently, it has been reported that ESO may be an exogenous agonist of AhR signaling, while no previous study has revealed the effects of ESO on SSc and its underlying mechanisms. In this study, we demonstrate that ESO suppresses the migration of SSc dermal fibroblasts, downregulates profibrotic markers, including COLIA1, α-SMA CTGF and MMP1, and limits collagen production potentially via the activation of AhR signaling. More importantly, ESO could block Smad2/3 phosphorylation concurrently with the reduction in collagen via AhR signaling. Moreover, our results from the bleomycin (BLM)-induced SSc model in skin and lung shows that ESO ameliorates fibrosis in vivo, which in keeping with our in vitro results. We conclude that ESO is a potential therapeutic drug for SSc fibrosis.

Keywords: Aryl hydrocarbon receptor; Esomeprazole; Fibrosis; Smad2/3; Systemic sclerosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / genetics
  • Animals
  • Bleomycin
  • Cells, Cultured
  • Collagen Type I, alpha 1 Chain / genetics
  • Connective Tissue Growth Factor / genetics
  • Cytokines / genetics
  • Esomeprazole / pharmacology
  • Esomeprazole / therapeutic use*
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibrosis
  • Humans
  • Lung / drug effects
  • Lung / metabolism
  • Lung / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Receptors, Aryl Hydrocarbon / genetics
  • Receptors, Aryl Hydrocarbon / metabolism
  • Scleroderma, Systemic / drug therapy*
  • Scleroderma, Systemic / genetics
  • Scleroderma, Systemic / metabolism
  • Scleroderma, Systemic / pathology
  • Signal Transduction / drug effects
  • Skin / drug effects
  • Skin / metabolism
  • Skin / pathology

Substances

  • Acta2 protein, mouse
  • Actins
  • CCN2 protein, mouse
  • Collagen Type I, alpha 1 Chain
  • Cytokines
  • Receptors, Aryl Hydrocarbon
  • Bleomycin
  • Connective Tissue Growth Factor
  • Esomeprazole