背景:目前,对于新生血管和淋巴管生成没有完美的治疗方法,每种治疗方法都有其并发症和副作用。本研究旨在探讨大麻二酚的抗血管生成和抗炎作用及其作用机制。
方法:采用缝合法建立体内角膜新生血管(CNV)模型,研究CBD对缝合诱导的角膜炎症的抑制作用,病理性血管形成,和淋巴管生成。此外,研究了CBD对免疫细胞的影响。体外方法学,包括细胞分选和共培养,被用来阐明其作用机制。
结果:与CNV组相比,CBD可以抑制CNV,淋巴管生成,和通过缝合方法诱导的炎症。此外,CBD特异性诱导CD45+CD11b+Gr-1+细胞上调,显着抑制体外CD4+T淋巴细胞的增殖,表现为CD31+表型,证明它们是骨髓来源的抑制细胞(MDSCs)。我们向小鼠施用抗Gr-1以在体内消除MDSCs,并发现抗Gr-1部分逆转了CBD的抗炎和血管生成作用。此外,我们发现,与正常组的MDSCs相比,CBD诱导的MDSCs过表达过氧化物酶体增殖物激活受体γ(PPAR-γ)。在小鼠中施用PPAR-γ抑制剂几乎逆转了CBD对MDSCs的诱导,证明PPAR-γ在CBD功能中的作用。
结论:这项研究表明,CBD可能通过激活核受体PPAR-γ诱导MDSCs上调,发挥抗炎作用,抗血管生成,和淋巴管生成作用,揭示角膜新生血管和淋巴管生成的潜在治疗靶点。
BACKGROUND: Currently, no perfect treatment for neovascularization and lymphangiogenesis exist, and each treatment method has its complications and side effects. This study aimed to investigate the anti-angiogenic and anti-inflammatory effects of cannabidiol and its mechanism of action.
METHODS: An in vivo corneal neovascularization (CNV) model was established using the suture method to investigate the inhibitory effects of CBD on suture-induced corneal inflammation, pathological blood vessel formation, and lymphangiogenesis. Additionally, the impact of CBD on immune cells was studied. In vitro methodologies, including cell sorting and co-culture, were employed to elucidate its mechanism of action.
RESULTS: Compared with the CNV group, CBD can inhibit CNV, lymphangiogenesis, and inflammation induced via the suture method. In addition, CBD specifically induced CD45+CD11b+Gr-1+ cell upregulation, which significantly inhibited the proliferation of CD4+ T lymphocytes in vitro and exhibited a CD31+ phenotype, proving that they were myeloid-derived suppressor cells (MDSCs). We administered anti-Gr-1 to mice to eliminate MDSCs in vivo and found that anti-Gr-1 partially reversed the anti-inflammatory and angiogenic effects of CBD. Furthermore, we found that compared with MDSCs in the normal group, CBD-induced MDSCs overexpress peroxisome proliferator-activated receptor-gamma (PPAR-γ). Administering PPAR-γ inhibitor in mice almost reversed the induction of MDSCs by CBD, demonstrating the role of PPAR-γ in the function of CBD.
CONCLUSIONS: This study indicates that CBD may induce MDSCs upregulation by activating the nuclear receptor PPAR-γ, exerting anti-inflammatory, antiangiogenic, and lymphangiogenic effects, and revealing potential therapeutic targets for corneal neovascularization and lymphangiogenesis.