Department of Respiratory and Intensive Care Unit, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Institute of Respiratory Diseases, Jinan, 250014, China; Institute of Microvascular Medicine, Medical Research Center, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China; School of Public Health and Health Management, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250014, China.
Institute of Microvascular Medicine, Medical Research Center, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China.
Biomed Pharmacother. 2024 Jun;175:116741. doi: 10.1016/j.biopha.2024.116741. Epub 2024 May 13.
Cadmium (Cd) is a widespread environmental toxicant that poses significant threat to public health. After intake, Cd is distributed throughout the body via blood and lymphatic circulation. However, the effect of Cd on lymphatic vessels has not been revealed. In this study, mice were exposed to 10 μM cadmium chloride through drinking water immediately after corneal alkali burn. In vivo analyses showed that Cd treatment enhances the alkali burn-induced corneal lymphangiogenesis, which is characterized by increased expression of lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), prospero-related homeobox 1 (PROX-1) and vascular endothelial growth factor receptor 3 (VEGFR3). In vitro, the proliferation and migration of human dermal lymphatic endothelial cells (HDLECs) are increased by 1 μM Cd treatment, while inhibited by 10 μM Cd treatment. At a concentration of 1 μM, Cd specifically induces phosphorylation of signal transducer and activator of transcription 3 (STAT3), but has no effect on the MAPK, AKT, or NF-κB signaling pathway. In the presence of the STAT3 inhibitor STATTIC, Cd fails to induce HDLECs proliferation and migration. In addition, Cd upregulates VEGFR3 expression and its gene promoter activity in a STAT3-dependent manner. Our study suggests that low-dose Cd promotes lymphangiogenesis through activation of the STAT3 signaling pathway.
镉 (Cd) 是一种广泛存在的环境毒物，对公众健康构成重大威胁。摄入后，Cd 通过血液和淋巴循环分布到全身。然而，Cd 对淋巴管的影响尚未被揭示。在这项研究中，小鼠在角膜碱烧伤后立即通过饮用水暴露于 10µM 氯化镉。体内分析表明，Cd 处理增强了碱烧伤诱导的角膜淋巴管生成，其特征是淋巴管内皮透明质酸受体 1 (LYVE-1)、同源盒蛋白 1 (PROX-1) 和血管内皮生长因子受体 3 (VEGFR3) 的表达增加。在体外，1µM Cd 处理可增加人真皮淋巴管内皮细胞 (HDLEC) 的增殖和迁移，而 10µM Cd 处理则抑制其增殖和迁移。在 1µM 浓度下，Cd 特异性诱导信号转导和转录激活因子 3 (STAT3) 的磷酸化，但对 MAPK、AKT 或 NF-κB 信号通路没有影响。在 STAT3 抑制剂 STATTIC 的存在下，Cd 无法诱导 HDLEC 的增殖和迁移。此外，Cd 以 STAT3 依赖性方式上调 VEGFR3 的表达及其基因启动子活性。我们的研究表明，低剂量 Cd 通过激活 STAT3 信号通路促进淋巴管生成。
