Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Oct;40(10):4269-4277.
doi: 10.1007/s10067-021-05765-w. Epub 2021 May 19.

Dihydroartemisinin alleviates skin fibrosis and endothelial dysfunction in bleomycin-induced skin fibrosis models

Rui Li  1 , Hanlin Yin  1 , Juan Wang  1 , Dongyi He  2   3 , Qingran Yan  4 , Liangjing Lu  5
Affiliations

Dihydroartemisinin alleviates skin fibrosis and endothelial dysfunction in bleomycin-induced skin fibrosis models

Rui Li et al. Clin Rheumatol. 2021 Oct.

Abstract

Objective: The present study was to investigate whether dihydroartemisinin (DHA), which is a highly effective and safe drug in the treatment of malaria, could be repurposed for the treatment of skin fibrosis and vascular dysfunction in systemic sclerosis (SSc).

Methods: The value of DHA was determined using a bleomycin-induced model of skin fibrosis. mRNA transcriptome analysis was performed, and the targets of DHA on fibroblasts were identified. Immunofluorescence staining was used to identify dermal vessels undergoing endothelial-to-mesenchymal transition (EndoMT). Autophagic flux was detected by western blot and mRFP-GFP-LC3 adenovirus vector transfection.

Results: Both systemic and topical administration of DHA decreased dermal thickness and collagen deposition and alleviated EndoMT in bleomycin-induced skin fibrosis mice model. Treatment of human umbilical vein endothelial cells (HUVECs) with TGF-β1 resulted in the acquisition of the activation marker (α-SMA) and loss of endothelial markers (CD31 and VE-cadherin), a process that was restored by DHA. DHA significantly suppressed skin fibroblast activation and collagen-1 production mainly through regulating PI3K-Akt pathway. DHA also induced fibroblast autophagic flux and that autophagy dependently suppressed collagen-1 production.

Conclusion: The results of the present study revealed that oral and topical DHA administration ameliorated tissue fibrosis and protected dermal blood vessels from bleomycin-induced EndoMT. Our study has elucidated the value of repurposing DHA for the treatment of SSc. Key Points • Oral or topical usage of DHA alleviated dermal fibrosis and EndoMT in bleomycin-induced skin fibrosis mice models. • DHA autophagy dependently inhibited fibroblast activation and collagen deposition via PI3K-ATK pathway. • DHA inhibited EndoMT of HUVECs induced by TGF-β1 by the downregulation of α-SMA and the upregulation of CD31 and VE-cadherin.

Keywords: Dihydroartemisinin; Endothelial-to-mesenchymal transition; Skin fibrosis; Systemic sclerosis.

PubMed Disclaimer

References

    1. Poudel DR, Derk CT (2018) Mortality and survival in systemic sclerosis: a review of recent literature. Curr Opin Rheumatol 30:588–593. https://doi.org/10.1097/bor.0000000000000551 - DOI - PubMed
    1. Denton CP, Khanna D (2017) Systemic sclerosis. Lancet 390:1685–1699. https://doi.org/10.1016/s0140-6736(17)30933-9 - DOI - PubMed
    1. Korman B (2019) Evolving insights into the cellular and molecular pathogenesis of fibrosis in systemic sclerosis. Transl Res 209:77–89. https://doi.org/10.1016/j.trsl.2019.02.010 - DOI - PubMed - PMC
    1. Cutolo M, Soldano S, Smith V (2019) Pathophysiology of systemic sclerosis: current understanding and new insights. Expert Rev Clin Immunol 15:753–764. https://doi.org/10.1080/1744666x.2019.1614915 - DOI - PubMed
    1. Lu X, Gong J, Dennery PA, Yao H (2019) Endothelial-to-mesenchymal transition: pathogenesis and therapeutic targets for chronic pulmonary and vascular diseases. Biochem Pharmacol 168:100–107. https://doi.org/10.1016/j.bcp.2019.06.021 - DOI - PubMed - PMC

LinkOut - more resources