Triptolide Attenuates Transplant Vasculopathy Through Multiple Pathways
Triptolide Attenuates Transplant Vasculopathy Through Multiple Pathways
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雷公藤甲素通过多种途径减轻移植血管病变
DOI：
10.3389/fimmu.2020.00612
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发表时间：
2020-04-21
影响因子：
7.3
通讯作者：
Sun, Qiquan
中科院分区：
文献类型：
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作者：
Luo, Zihuan;Liao, Tao;Sun, Qiquan
移植血管病变（TV）是慢性同种异体移植排斥反应的标志，是器官移植后同种异体移植丧失的主要原因。由于TV的发病机制涉及多种机制，目前尚无有效的治疗方法。在这里，我们确定雷公藤甲素的作用，它具有广泛的免疫抑制活性，在抑制电视发展。建立小鼠主动脉移植模型，分为雷公藤甲素治疗组和未治疗组。我们发现雷公藤甲素通过抑制多种途径显著减轻同种异体移植物内膜增厚。雷公藤甲素可显著降低T淋巴细胞和巨噬细胞的浸润，抑制移植物中促炎因子（TNF-α、IL-2、IL-6）和促纤维化因子（TGF-β、α-SMA、MMP-9）的水平。此外，雷公藤甲素显著降低受体中产生IFN-γ的T淋巴细胞数量，以及IFN-γ和IFN-γ诱导因子（CXCL9和CXCL10）的表达。此外，雷公藤甲素降低了受体B淋巴细胞和浆细胞的数量，以及供体特异性抗体（dsa）的水平。雷公藤甲素不仅能抑制血管平滑肌细胞（VSMC）活力，促进VSMC凋亡，还能显著抑制VSMC在体外的迁移。这些结果强调了雷公藤甲素在抑制TV发展中的作用，为开发新的治疗方法预防TV相关并发症和提高移植受者的长期生存提供了基础。
Transplant vasculopathy (TV), a hallmark of chronic allograft rejection, is the primary cause of allograft loss after organ transplantation. Because multiple mechanisms are involved in TV pathogenesis, effective therapy for it remains elusive. Here, we identify the role of triptolide, which has a wide spectrum of immuno-suppressive activities, in inhibiting TV development. Murine aortic transplants models were constructed and divided into triptolide-treated and untreated groups. We found that triptolide significantly alleviated intima thickening of allografts by inhibiting multiple pathways. Triptolide significantly reduced infiltration of T lymphocytes and macrophages and inhibited the levels of pro-inflammatory (TNF-α, IL-2, and IL-6) and pro-fibrotic factors (TGF-β, α-SMA, and MMP-9) in the graft. Additionally, triptolide significantly decreased the numbers of IFN-γ-producing T lymphocytes, as well as the expression of IFN-γ and IFN-γ-inducing factor (CXCL9 and CXCL10) in recipient. Moreover, triptolide decreased the numbers of B lymphocytes and plasma cells, as well as the levels of donor specific antibodies (DSAs) in recipient. Furthermore, triptolide not only inhibited vascular smooth muscle cell (VSMC) viability and promoted VSMC apoptosis but also significantly inhibited VSMC migration in vitro. These results emphasize the efficacy of triptolide in inhibiting TV development and provide a basis for developing new treatments to prevent TV-related complications and improve the long-term survival of transplant recipients.