Park GT et al. (2021), Echinochrome A Treatment Alleviates Fibrosis an...

ECB-ART-49207

Mar Drugs 2021 Apr 23;195:. doi: 10.3390/md19050237.

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Echinochrome A Treatment Alleviates Fibrosis and Inflammation in Bleomycin-Induced Scleroderma.

Park GT , Yoon JW , Yoo SB , Song YC , Song P , Kim HK , Han J , Bae SJ , Ha KT , Mishchenko NP , Fedoreyev SA , Stonik VA , Kim MB , Kim JH .

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Scleroderma is an autoimmune disease caused by the abnormal regulation of extracellular matrix synthesis and is activated by non-regulated inflammatory cells and cytokines. Echinochrome A (EchA), a natural pigment isolated from sea urchins, has been demonstrated to have antioxidant activities and beneficial effects in various disease models. The present study demonstrates for the first time that EchA treatment alleviates bleomycin-induced scleroderma by normalizing dermal thickness and suppressing collagen deposition in vivo. EchA treatment reduces the number of activated myofibroblasts expressing α-SMA, vimentin, and phosphorylated Smad3 in bleomycin-induced scleroderma. In addition, it decreased the number of macrophages, including M1 and M2 types in the affected skin, suggesting the induction of an anti-inflammatory effect. Furthermore, EchA treatment markedly attenuated serum levels of inflammatory cytokines, such as tumor necrosis factor-α and interferon-γ, in a murine scleroderma model. Taken together, these results suggest that EchA is highly useful for the treatment of scleroderma, exerting anti-fibrosis and anti-inflammatory effects.

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	Figure 1. Dose-dependent effects of EchA treatment on tissue fibrosis in a scleroderma mice model. (A) Chemical structure of EchA. (B) Dose-dependent effect of Echinochrome A (EchA) on BLM-induced scleroderma. The BLM-induced scleroderma mice (BLM+) were treated with the increasing dose of EchA daily for an additional three weeks, and skin sections were stained using H&E and Massonâs trichrome staining kits. The dermal layer between the epidermalâdermal junction and the dermalâfat junction is indicated by an arrow on H&E-stained sections. Dermal thickness (C) and collagen density (D) were quantified from the H&E and Massonâs trichrome data, respectively. (E) Effect of EchA on the BLM-induced increase in hydroxyproline content in skin. Data represent the mean Â± SD (n = 5 per group). * p < 0.05.
	Figure 2. Effects of EchA treatment on myofibroblast differentiation in scleroderma. (A) EchA-induced inhibition of myofibroblast differentiation in scleroderma. The BLM-induced scleroderma mice were treated with or without 1-ÂµM EchA for three weeks, and the mock-treated (PBS) and the scleroderma (BLM or BLM+EchA) skin specimens were immunostained with antibodies against Î±-SMA and ILB-4. (B) The skin specimens were stained with antibodies against vimentin and phospho-SMAD3. Scale bar = 50 Î¼m. The numbers of Î±-SMA+ILB-4â (C), vimentin+ (D), and vimentin+phospho-SMAD3+ (E) cells were quantified under a high-power field. Data represent the mean Â± SD (n = 4 per group). * p < 0.05, ** p < 0.01 .
	Figure 3. Effects of EchA treatment on the number of macrophages and inflammation in scleroderma. The BLM-induced scleroderma mice were treated with or without EchA for three weeks. The mock-treated (PBS) and scleroderma (BLM or BLM+EchA) skin specimens were stained with anti-CD68 antibody together with anti-NOS2 or anti-TLR2 (A), anti-Arginase-I or CD163 (B) antibodies. Nuclei were stained with DAPI and overlaid images are shown. Scale bar = 50 Î¼m. The numbers of CD68+ macrophages (C), M1 type macrophages ((D); CD68+TLR2+ and CD68+NOS2+ cells), M1 type macrophages ((E); CD68+Arginse-1+ and CD68+CD163+ cells) were counted under high-power field. Data represent the mean Â± SD (n = 4 per group). * p < 0.05.
	Figure 4. The role of EchA-induced immune cytokine resolution in scleroderma. (A,B) EchA-induced inhibition of systemic inflammation in scleroderma. The BLM-induced scleroderma mice were treated with or without EchA for three weeks, and the serum levels of TNF-Î± (A) and INF-Î³ (B) in the mock-treated (PBS) and the scleroderma mice (BLM or BLM+EchA) were determined by ELISA assay. Data represent the mean Â± SD (n =4 per group). * p < 0.05.

References [+] :

Ammitzbøll, Collagen metabolites in urine in localized scleroderma (morphoea). 1984, Pubmed