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）：已证明血管内皮生长因子（VEGF）-C对于淋巴管生成是必需的，对于淋巴引流不足的疾病中的淋巴管疗法可能很有用。尽管许多最近的研究报告说，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，仅过量淋巴生长因子单独增加功能性淋巴生长的能力可能受到限制。我们还发现，在没有淋巴管生成的情况下，实验性淋巴水肿能够解决。在临床上，已显示压缩服会在水肿人臂的肿胀中显着减少。这些结果表明，整个阻塞部位的间质性流动（IF）动力学对于淋巴水肿的分辨率可能很重要，并且如果可以在没有事先刺激淋巴生长的情况下增加水肿臂中的增加。因此，如果可能对淋巴水肿有益，可以直接增加的疗法。最近已经证明，在淋巴管生成的早期阶段，内源性VEGF-C促进了淋巴内皮细胞（LEC）沿流体通道支架迁移的淋巴内皮细胞（LEC）迁移。我们假设，如果通过增加流体通道的形成来增加压缩负荷，并且将VEGF-C治疗与压缩负荷结合使用可以通过通过流体通道对流VEGF-C来改善功能性淋巴管生成并建立可以直接功能淋巴生长的VEGF-C梯度来改善功能性淋巴管生成。我们旨在确定如果通过增加流体通道的形成，是否会增加压缩负荷，是否通过与外源性VEGF-C蛋白结合压缩来增加流体通道的增强，是否可以增强功能性淋巴管菌的发生并改善淋巴结和淋巴水肿，以及如果相对于静态压缩载荷增加，是否会增加循环压缩负荷。 公共卫生相关性：淋巴水肿经常跟随乳腺癌手术中的腋窝淋巴结清扫术。尽管压缩疗法降低了淋巴水肿，但作用机理尚不清楚。我们旨在阐明压缩在调节间质流中的作用，并确定组合压缩/淋巴管生成疗法改善淋巴水肿的能力。