Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China.
Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China.
Front Immunol. 2022 Dec 16;13:1090877. doi: 10.3389/fimmu.2022.1090877. eCollection 2022.
Neovascularization and inflammatory response are two essential features of corneal allograft rejection. Here, we investigated the impact of Piperlongumine (PL) on alleviating corneal allograft rejection, primarily focusing on pathological angiogenesis and inflammation.
A murine corneal allograft transplantation model was utilized to investigate the role of PL in preventing corneal allograft rejection. PL (10 mg/kg) or vehicle was intraperitoneally injected daily into BALB/c recipients from day -3 to day 14. The clinical signs of the corneal grafts were monitored for 30 days. Corneal neovascularization and inflammatory cell infiltration were detected by immunofluorescence staining and immunohistochemistry. The proportion of CD4 T cells and macrophages in the draining lymph nodes (DLNs) was examined by flow cytometry. , HUVECs were cultured under hypoxia or incubated with TNF-α to mimic the hypoxic and inflammatory microenvironment favoring neovascularization in corneal allograft rejection. Multiple angiogenic processes including proliferation, migration, invasion and tube formation of HUVECs in hypoxia with or without PL treatment were routinely evaluated. The influence of PL treatment on TNF-α-induced pro-inflammation in HUVECs was investigated by real-time PCR and ELISA.
, PL treatment effectively attenuated corneal allograft rejection, paralleled by coincident suppression of neovascularization and alleviation of inflammatory response. , PL distinctively inhibited hypoxia-induced angiogenic processes in HUVECs. Two key players in hypoxia-induced angiogenesis, HIF-1α and VEGF-A were significantly suppressed by PL treatment. Also, TNF-α-induced pro-inflammation in HUVECs was hampered by PL treatment, along with a pronounced reduction in ICAM-1, VCAM-1, CCL2, and CXCL5 expression.
The current study demonstrated that PL could exhibit both anti-angiogenic and anti-inflammatory effects in preventing corneal allograft rejection, highlighting the potential therapeutic applications of PL in clinical strategy.
血管新生和炎症反应是角膜移植排斥的两个重要特征。在这里，我们研究了胡椒碱（PL）缓解角膜移植排斥的作用，主要关注病理性血管生成和炎症。
利用小鼠角膜移植模型研究 PL 在预防角膜移植排斥中的作用。PL（10mg/kg）或载体从第-3 天到第 14 天每天腹腔注射到 BALB/c 受者中。监测角膜移植物 30 天的临床体征。通过免疫荧光染色和免疫组织化学检测角膜新生血管和炎症细胞浸润。通过流式细胞术检测引流淋巴结（DLNs）中 CD4 T 细胞和巨噬细胞的比例。在缺氧或用 TNF-α孵育下培养 HUVECs，以模拟有利于角膜移植排斥中血管新生的缺氧和炎症微环境。常规评估缺氧下和缺氧下加或不加 PL 处理的 HUVECs 的增殖、迁移、侵袭和管形成等多种血管生成过程。通过实时 PCR 和 ELISA 研究 PL 处理对 TNF-α诱导的 HUVECs 促炎作用的影响。
PL 治疗有效抑制了角膜移植排斥，同时伴有新生血管化的抑制和炎症反应的减轻。PL 显著抑制了 HUVECs 缺氧诱导的血管生成过程。PL 处理显著抑制了缺氧诱导的血管生成过程中的两个关键因子 HIF-1α和 VEGF-A。此外，PL 处理还抑制了 TNF-α诱导的 HUVECs 促炎作用，同时显著降低了 ICAM-1、VCAM-1、CCL2 和 CXCL5 的表达。
本研究表明，PL 可在预防角膜移植排斥中表现出抗血管生成和抗炎作用，突出了 PL 在临床策略中的潜在治疗应用。
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