Department of Plastic and Reconstructive Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
Lymphat Res Biol. 2023 Aug;21(4):372-380. doi: 10.1089/lrb.2022.0071. Epub 2023 Mar 7.
Lymphedema is an intractable disease with no curative treatment available. Conservative treatment is the mainstay, and new drug treatment options are strongly needed. The purpose of this study was to investigate the effect of roxadustat, a prolyl-4-hydroxylase inhibitor, on lymphangiogenesis and its therapeutic effect on lymphedema in a radiation-free mouse hindlimb lymphedema model. Male C57BL/6N mice (8-10 weeks old) were used for the lymphedema model. Mice were randomized to an experimental group receiving roxadustat or a control group. The circumferential ratio of the hindlimbs was evaluated, and lymphatic flow of the hindlimbs was compared by fluorescent lymphography up to 28 days postoperatively. The roxadustat group showed an early improvement in hindlimb circumference and stasis of lymphatic flow. The number and area of lymphatic vessels on postoperative day 7 were significantly larger and smaller, respectively, in the roxadustat group compared with the control group. Skin thickness and macrophage infiltration on postoperative day 7 were significantly reduced in the roxadustat group compared with the control group. The relative mRNA expression of hypoxia-inducible factor-1α (), vascular endothelial growth factor receptor-3 (), vascular endothelial growth factor-C (), and Prospero homeobox 1 () on postoperative day 4 was significantly higher in the roxadustat group compared with the control group. Roxadustat demonstrated a therapeutic effect in a murine model of hindlimb lymphedema through promotion of lymphangiogenesis through the activation of HIF-1α, VEGF-C, VEGFR-3, and Prox1, suggesting the potential of roxadustat as a therapeutic option in lymphedema.
淋巴水肿是一种无法治愈的疾病，目前尚无有效的治疗方法。保守治疗是主要方法，迫切需要新的药物治疗选择。本研究旨在探讨脯氨酰-4-羟化酶抑制剂罗沙司他对无辐射性小鼠后肢淋巴水肿模型淋巴管生成的影响及其对淋巴水肿的治疗作用。雄性 C57BL/6N 小鼠（8-10 周龄）用于建立淋巴水肿模型。将小鼠随机分为实验组（给予罗沙司他）和对照组。评估后肢的周径比，并通过荧光淋巴造影术比较手术后 28 天内后肢的淋巴流量。罗沙司他组后肢周长的改善较早，淋巴淤滞得到缓解。与对照组相比，罗沙司他组术后第 7 天淋巴管的数量和面积分别明显增大和减小。与对照组相比，罗沙司他组术后第 7 天皮肤厚度和巨噬细胞浸润明显减少。与对照组相比，罗沙司他组术后第 4 天缺氧诱导因子-1α（）、血管内皮生长因子受体-3（）、血管内皮生长因子-C（）和 Prox1 的相对 mRNA 表达明显升高。罗沙司他通过激活 HIF-1α、VEGF-C、VEGFR-3 和 Prox1 促进淋巴管生成，在小鼠后肢淋巴水肿模型中显示出治疗作用，提示罗沙司他作为淋巴水肿治疗选择的潜力。
