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 downregulation 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.

A pilot study of oral tranexamic acid and Glycyrrhizin compound in the treatment of recalcitrant Riehl’s melanosis

“…Its expression was significantly increased in a variety of skin diseases, such as psoriasis, alopecia areata, vitiligo, atopic dermatitis, Henoch‐Schönlein purpura (HSP), pemphigus, and drug‐induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DRESS) . Due to the similar pharmacological efficacy to corticosteroids but with milder side effects, Glycyrrhizin has been widely utilized in several dermatologic disorders for many years, such as active‐stage generalized vitiligo, psoriasis, alopecia areata, and is also reported to be effective in alleviating the symptoms of atopic dermatitis and systemic sclerosis in animal model . Based on the clinical observation that patients with recalcitrant Riehl’s melanosis may present with facial erythema and itching, which are signs of local inflammation, we applied Glycyrrhizin compound 75 mg orally three times a day for all enrolled patients, aiming to alleviate the inflammatory reaction.…”

“…[21][22][23][24][25] Due to the similar pharmacological efficacy to corticosteroids but with milder side effects, Glycyrrhizin has been widely utilized in several dermatologic disorders for many years, such as active-stage generalized vitiligo, 26 psoriasis, 27 alopecia areata, 28 and is also reported to be effective in alleviating the symptoms of atopic dermatitis and systemic sclerosis in animal model. 29…”

Markers and Biomarkers of Endothelium: When Something Is Rotten in the State

“…Glycyrrhizin significantly ameliorated dermal fibrosis in bleomycin-treated mice, which was partly attributable to blockade of TGF-β signaling in dermal fibroblasts through the downregulation of thrombospondin 1, a latent TGF-β receptor, and transcription factors Smad3 and Ets1. Furthermore, bleomycin-dependent induction of T helper type 2-skewed immune polarization, M2 macrophage infiltration, and EndoMT was greatly suppressed in mice administered glycyrrhizin [170].…”

Alternatively activated macrophages are associated with the α2AP production that occurs with the development of dermal fibrosis

“…High-mobility group box 1 (HMGB1) is a multifunctional protein that exerts pro-inflammatory activity by mainly binding to receptor for advanced glycation end products (RAGE). It has been reported that HMGB1 is released from immune cells, and contributes to inflammation, immune responses, myofibroblast differentiation, ECM production, and fibrosis progression [30][31][32][33][34], and the HMGB1 inhibitor, glycyrrhizin, attenuates the development of fibrosis in the belomycin-treated mice [35].…”