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

  • Clin Rheumatol. 2021 Oct;40(10):4269-4277. doi: 10.1007/s10067-021-05765-w.
Rui Li  1 ,  Hanlin Yin  1 ,  Juan Wang  1 ,  Dongyi He  2  3 ,  Qingran Yan  4 ,  Liangjing Lu  5
Affiliations
  • 1. Department of Rheumatology, School of Medicine, Ren Ji Hospital, Shanghai Jiao Tong University, 145 Shandong Middle Road, Shanghai, 2000001, China.
  • 2. Department of Rheumatology, Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200052, China. [email protected].
  • 3. Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, 200052, China. [email protected].
  • 4. Department of Rheumatology, School of Medicine, Ren Ji Hospital, Shanghai Jiao Tong University, 145 Shandong Middle Road, Shanghai, 2000001, China. [email protected].
  • 5. Department of Rheumatology, School of Medicine, Ren Ji Hospital, Shanghai Jiao Tong University, 145 Shandong Middle Road, Shanghai, 2000001, China. [email protected].
PMID: 34013490 DOI: 10.1007/s10067-021-05765-w
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.
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