The Regulation of Interstitial Flow in Experimental Lymphedema by Compression

实验性淋巴水肿压迫对间质血流的调节

• 批准号: 7769809
• 负责人: Jeremy Goldman
• 金额: $ 22.8万
• 依托单位: MICHIGAN TECHNOLOGICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-15 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7769809
• 关键词: Axillary Lymph Node Dissection; Cell Proliferation; Cells; Data; Disease; Drainage procedure; Extracellular Matrix; Goals; Growth; Growth Factor; Human; Implant; Liquid substance; Lymph; Lymphangiogenesis; Lymphatic; Lymphatic Capillaries; Lymphatic Endothelial Cells; Lymphedema; Mediating; Modeling; Mus; Natural regeneration; Obstruction; Physiological; Regulation; Relative (related person); Reporting; Resolution; Role; Scheme; Site; Skin; Staging; Swelling; Tail; Testing; Tissues; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factors; angiogenesis; arm; cancer surgery; cell motility; citrate carrier; clinically significant; compare effectiveness; improved; interstitial; malignant breast neoplasm; mouse model; overexpression; public health relevance; scaffold; wound

DESCRIPTION (provided by applicant): Vascular endothelial growth factor (VEGF)-C has been shown to be necessary for lymphangiogenesis and may be useful for lymphangiogenic therapy in diseases of inadequate lymphatic drainage. Although a number of recent studies have reported that overexpression of VEGF-C can promote lymphangiogenesis and improve lymphatic function, we have found that the ability of excess lymphatic growth factor alone to increase functional lymphatic growth above physiological levels may be limited. We have also found that experimental lymphedema is able to resolve in the absence of lymphangiogenesis. Clinically, compressive garments have been shown to produce significant reductions in the swelling of the edematous human arm. These results suggest that interstitial flow (IF) dynamics across the obstruction site may be important for resolution of lymphedema and that IF can be increased in the edematous arm without prior stimulation of lymphatic growth. Therefore therapies that directly increase IF may be beneficial for lymphedema. It has recently been demonstrated that fluid channels are formed by IF and that endogenous VEGF-C promotes lymphatic endothelial cell (LEC) migration along the fluid channel scaffold during early stages of lymphangiogenesis. We hypothesize that compressive loading may increase IF by increasing fluid channel formation and that combining VEGF-C therapy with compressive loading may improve functional lymphangiogenesis by convecting VEGF-C through fluid channels and establishing VEGF-C gradients that can direct functional lymphatic growth. We aim to determine whether compressive loading may increase IF by increasing the formation of fluid channels, whether an augmentation of fluid channels by compression in conjunction with exogenous VEGF-C protein may enhance functional lymphangiogenesis and improve lymphedema, and whether cyclic compressive loading may increase IF relative to static compressive loading. PUBLIC HEALTH RELEVANCE: Lymphedema often follows axillary lymph node dissection from breast cancer surgery. Although compression therapy reduces lymphedema, the mechanism of action is not clear. We aim to clarify the role of compression in regulating interstitial flow and to determine the ability of combined compression/lymphangiogenesis therapy to improve lymphedema.

描述（由申请人提供）：血管内皮生长因子（VEGF）-C已被证明是淋巴管生成所必需的，并且可用于淋巴引流不足疾病的淋巴管生成治疗。尽管最近的一些研究报道VEGF-C的过度表达可以促进淋巴管生成并改善淋巴功能，但我们发现单独过量的淋巴生长因子将功能性淋巴生长增加到生理水平以上的能力可能是有限的。我们还发现，实验性淋巴水肿能够在没有淋巴管生成的情况下得到缓解。临床上，压力衣已被证明可以显着减少人体手臂水肿的肿胀。这些结果表明，穿过阻塞部位的间质流（IF）动态可能对于解决淋巴水肿很重要，并且可以在不事先刺激淋巴管生长的情况下增加水肿臂中的 IF。因此，直接增加 IF 的疗法可能对淋巴水肿有益。最近已经证明，液体通道是由 IF 形成的，并且内源性 VEGF-C 在淋巴管生成的早期阶段促进淋巴管内皮细胞 (LEC) 沿着液体通道支架迁移。我们假设压缩负荷可以通过增加流体通道的形成来增加 IF，并且将 VEGF-C 治疗与压缩负荷相结合可以通过流体通道对流 VEGF-C 并建立可以指导功能性淋巴管生长的 VEGF-C 梯度来改善功能性淋巴管生成。我们的目的是确定压缩负荷是否可以通过增加流体通道的形成来增加 IF，通过与外源 VEGF-C 蛋白结合压缩来增强流体通道是否可以增强功能性淋巴管生成并改善淋巴水肿，以及相对于静态压缩负荷，循环压缩负荷是否可以增加 IF。 公共卫生相关性：乳腺癌手术后腋窝淋巴结清扫术常常会导致淋巴水肿。尽管压迫疗法可以减轻淋巴水肿，但其作用机制尚不清楚。我们的目的是阐明压迫在调节间质流动中的作用，并确定压迫/淋巴管生成联合疗法改善淋巴水肿的能力。