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: 8013022
• 负责人: Jeremy Goldman
• 金额: $ 18.9万
• 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/8013022
• 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; 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过表达VEGF-C可以促进淋巴管生成和改善淋巴功能，但我们发现单独过量的淋巴生长因子增加功能性淋巴生长超过生理水平的能力可能是有限的。我们还发现，实验性水肿是能够解决在没有淋巴管生成。临床上，压缩服装已被证明产生显着减少肿胀的人arm. These结果表明，间质流（IF）动力学阻塞部位可能是重要的解决水肿和IF可以增加在水肿的手臂没有事先刺激淋巴生长。因此，直接增加IF的治疗可能对水肿有益。最近已经证明，流体通道是由IF形成的，并且在淋巴管生成的早期阶段，内源性VEGF-C促进淋巴管内皮细胞（LEC）沿流体通道支架沿着迁移。我们假设，压缩负荷可能会增加IF增加流体通道的形成，并结合VEGF-C治疗与压缩负荷可能会改善功能性淋巴管生成通过对流VEGF-C通过流体通道，并建立VEGF-C梯度，可以直接功能性淋巴管生长。我们的目的是确定是否压缩负荷可能会增加IF通过增加形成的流体通道，是否增加流体通道的压缩与外源性VEGF-C蛋白结合可以增强功能性淋巴管生成和改善水肿，以及是否循环压缩负荷可能会增加IF相对于静态压缩负荷。 公共卫生相关性：乳腺癌手术后腋窝淋巴结清扫后常出现淋巴水肿。虽然压迫疗法可以减少水肿，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血流中的作用，并确定联合压迫/淋巴管生成治疗改善水肿的能力。