Dihydroartemisinin alleviates skin fibrosis and endothelial dysfunction in bleomycin-induced skin fibrosis models
Dihydroartemisinin alleviates skin fibrosis and endothelial dysfunction in bleomycin-induced skin fibrosis models
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DOI：
10.1007/s10067-021-05765-w
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发表时间：
2021-05
影响因子：
3.4
通讯作者：
Rui Li;H. Yin;Juan Wang;D. He;Q. Yan;Liangjing Lu
中科院分区：
文献类型：
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作者：
Rui Li;H. Yin;Juan Wang;D. He;Q. Yan;Liangjing Lu
目的探讨双氢青蒿素（DHA）作为一种高效、安全的疟疾治疗药物，是否可用于治疗系统性硬化症（SSc）的皮肤纤维化和血管功能障碍。方法采用博莱霉素致皮肤纤维化模型测定DHA的含量。进行mRNA转录组分析，确定DHA对成纤维细胞的作用靶点。免疫荧光染色用于鉴定真皮血管内皮向间充质转化（EndoMT）。采用western blot和转染mRFP-GFP-LC3腺病毒载体检测自噬通量。结果在博莱霉素诱导的皮肤纤维化模型中，全身和局部给药DHA均可降低真皮厚度和胶原沉积，减轻EndoMT。TGF-β1对人脐静脉内皮细胞（HUVECs）的处理导致激活标记（α-SMA）的获得和内皮标记（CD31和VE-cadherin）的丢失，这一过程被DHA恢复。DHA主要通过调控PI3K-Akt通路显著抑制皮肤成纤维细胞活化和胶原-1生成。DHA还诱导成纤维细胞自噬通量，自噬依赖性地抑制胶原-1的产生。结论口服和外用DHA可改善组织纤维化，保护真皮血管免受博莱霉素诱导的EndoMT。我们的研究阐明了重新利用DHA治疗SSc的价值。•口服或外用DHA可减轻博莱霉素诱导的皮肤纤维化小鼠模型的真皮纤维化和EndoMT。•DHA自噬通过PI3K-ATK途径依赖性地抑制成纤维细胞活化和胶原沉积。•DHA通过下调α-SMA、上调CD31和VE-cadherin抑制TGF-β1诱导的HUVECs EndoMT。
ObjectiveThe 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).MethodsThe 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.ResultsBoth 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.ConclusionThe 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.