title: Glycyrrhizin Ameliorates Fibrosis, Vasculopathy, and Inflammation in Animal Models of Systemic Sclerosis.
abstract: Systemic sclerosis (SSc) is a multisystem inflammatory and vascular disease resulting in extensive tissue fibrosis. Glycyrrhizin, clinically used for chronic hepatic diseases and itching dermatitis, modulates the pathological processes of inflammation, vasculopathy, and fibrosis in human diseases and their animal models. Therefore, we investigated a potential impact of glycyrrhizin on the key pathological manifestations of SSc, including inflammation, vasculopathy, and tissue fibrosis, with bleomycin-treated mice mimicking the fibrotic and inflammatory components of SSc and endothelial cell-specific Fli1-knockout mice recapitulating SSc vasculopathy. Glycyrrhizin significantly ameliorated dermal fibrosis in bleomycin-treated mice, which was partly attributable to blockade of transforming growth factor-β signaling in dermal fibroblasts through the down-regulation of thrombospondin 1, a latent transforming growth factor-β receptor, and transcription factors Smad3 and Ets1. Furthermore, bleomycin-dependent induction of T helper type 2-skewed immune polarization, M2 macrophage infiltration, and endothelial-to-mesenchymal transition were greatly suppressed in mice administered glycyrrhizin. Glycyrrhizin also improved vascular permeability of endothelial cell-specific Fli1-knockout mice by increasing the expression of molecules regulating vascular integrity. These results indicate that glycyrrhizin ameliorates bleomycin-induced dermal fibrosis through the inhibition of fibroblast activation, T helper type 2-skewed immune polarization, M2 macrophage infiltration, and endothelial-to-mesenchymal transition and improves endothelial Fli1 deficiency-dependent vascular disintegrity, implying its potential as a disease-modifying drug for SSc.
authors: Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors: Takashi
authors: T
authors: Yamashita
authors: Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan. Electronic address: yasano-tky@umin.ac.jp.
authors: Yoshihide
authors: Y
authors: Asano
authors: Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors: Takashi
authors: T
authors: Taniguchi
authors: Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors: Kouki
authors: K
authors: Nakamura
authors: Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors: Ryosuke
authors: R
authors: Saigusa
authors: Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors: Shunsuke
authors: S
authors: Miura
authors: Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors: Tetsuo
authors: T
authors: Toyama
authors: Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors: Takehiro
authors: T
authors: Takahashi
authors: Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors: Yohei
authors: Y
authors: Ichimura
authors: Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors: Ayumi
authors: A
authors: Yoshizaki
authors: Arthritis Center, Boston University School of Medicine, Boston, Massachusetts, USA.
authors: Maria
authors: M
authors: Trojanowska
authors: Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors: Shinichi
authors: S
authors: Sato
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000627:therapeutic use; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis; D019695:Glycyrrhizic Acid / Q000627:therapeutic use*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D012595:Scleroderma, Systemic / Q000188:drug therapy*; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018418:Th2 Cells / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014652:Vascular Diseases / Q000188:drug therapy*
chemical_list: D016212:Transforming Growth Factor beta; D001761:Bleomycin; D019695:Glycyrrhizic Acid