Xiangya hospital of central south university, Changsha, China.
Changsha Medical University, Changsha, China.
Peptides. 2023 Oct;168:171045. doi: 10.1016/j.peptides.2023.171045. Epub 2023 Jul 26.
Secondary lymphedema often occurs after filariasis, trauma, lymph node dissection and radiation therapy, which is manifested by infiltration of inflammatory cells and fibrosis formation in pathologically. Substance P is a widely used neuropeptide in the field of tissue repair, while the regenerative potential of the substance P has not been proven in the secondary lymphedema. In this study, animal model of secondary lymphedema was constructed by excising the skin and subcutaneous lymphatic network in the tail of mice, and the degree of swelling in the tail of mice was evaluated after 6 weeks under the treatment with substance P. Immunofluorescence staining was also performed to assess immune cell infiltration, subcutaneous fibrosis and lymphangiogenesis. The results revealed that substance P significantly alleviated post-surgical lymphedema in mice. Furthermore, we found that substance P promoted macrophages M2 polarization, a process associated with downregulation of the NF-kB/NLRP3 pathway. After application of disodium clodronate (macrophage scavenger, CLO), the positive effect of substance P in lymphedema is significantly inhibited. In vitro experiments, we further demonstrated the polarizing effect of substance P on bone marrow-derived macrophages (BMDMs), while substance P inhibited the activation of the NF-kB/NLRP3 pathway in BMDMs after the treatment of lipopolysaccharide (LPS). In addition, polarized macrophages were demonstrated to promote the proliferation, tube-forming and migratory functions of human lymphatic endothelial cells (hLEC). In conclusion, our study provides preliminary evidence that substance P alleviates secondary lymphedema by promoting macrophage M2 polarization, and this therapeutic effect may be associated with downregulation of the NF-kB/NLRP3 pathway.
继发性淋巴水肿通常发生在丝虫病、创伤、淋巴结清扫和放射治疗后，其病理表现为炎症细胞浸润和纤维化形成。P 物质是组织修复领域广泛应用的神经肽，而 P 物质在继发性淋巴水肿中的再生潜力尚未得到证实。在这项研究中，通过切除小鼠尾部的皮肤和皮下淋巴管构建继发性淋巴水肿动物模型，在 P 物质治疗 6 周后评估小鼠尾部肿胀程度。还进行了免疫荧光染色，以评估免疫细胞浸润、皮下纤维化和淋巴管生成。结果表明，P 物质显著缓解了小鼠术后淋巴水肿。此外，我们发现 P 物质促进了巨噬细胞 M2 极化，这一过程与 NF-κB/NLRP3 通路的下调有关。应用双氯酸钠（巨噬细胞清除剂，CLO）后，P 物质在淋巴水肿中的积极作用明显受到抑制。在体外实验中，我们进一步证明了 P 物质对骨髓来源的巨噬细胞（BMDMs）的极化作用，而 P 物质在脂多糖（LPS）处理后抑制了 BMDMs 中 NF-κB/NLRP3 通路的激活。此外，极化的巨噬细胞被证明可促进人淋巴管内皮细胞（hLEC）的增殖、管状形成和迁移功能。总之，我们的研究提供了初步证据，表明 P 物质通过促进巨噬细胞 M2 极化来缓解继发性淋巴水肿，这种治疗效果可能与 NF-κB/NLRP3 通路的下调有关。
