Doxorubicin suppression of lymphatic function and therapeutic reversal

阿霉素对淋巴功能的抑制和治疗逆转

• 批准号: 8879914
• 负责人: Nancy J Rusch
• 金额: $ 19.3万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-09 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8879914
• 关键词: Acute; Calcium Channel; Caliber; Cells; Central Vein; Complication; Contractile Proteins; Cytotoxic agent; Development; Dose; Doxorubicin; Duct (organ) structure; Electrophysiology (science); Extracellular Fluid; Extracellular Space; Flow Cytometry; Homeostasis; Hour; Incidence; Inflammation; Injury; L-Type Calcium Channels; Liquid substance; Lymph; Lymphatic; Lymphatic System; Lymphatic vessel; Lymphedema; Lymphocyte; Measurement; Mechanics; Medial; Mediating; Mesentery; Methods; Modeling; Monitor; Muscle Cells; Neoplasm Metastasis; Occupations; Operative Surgical Procedures; Pain; Patch-Clamp Techniques; Peripheral; Pharmaceutical Preparations; Proteins; Pump; Radiation; Radiation therapy; Rattus; Recurrence; Resolution; Severities; Smooth Muscle Myocytes; Solvents; Surface; System; Testing; Therapeutic; Time; Tissues; United States; Venous; Woman; arm; base; cancer surgery; chemotherapy; clinically relevant; cytotoxic; design; in vivo; injured; lymph flow; lymphatic pump; malignant breast neoplasm; medical complication; optical imaging; patch clamp; prevent; public health relevance; response; voltage

 DESCRIPTION (provided by applicant): More than 5 million women in the United States suffer from arm lymphedema after surgery and/or radiation for breast cancer, and the incidence and severity of lymphedema is worsened by doxorubicin (DOX) chemotherapy. The mechanism by which DOX contributes to lymphedema is poorly understood, but it is thought to involve multiple mechanisms of acute and delayed injury to the lymphatic system due to its cytotoxic effects. Alternatively, in this proposal, we will explore the hypothesis that DOX acutely and directly suppresses lymphatic contractile function and DOX-induced suppression of lymphatic flow can be reversed by pharmacological openers of voltage-gated L-type Ca2+ (CaL) channels. Using the rat mesenteric lymphatic system as our model, we will show for the first time that DOX at clinically relevant concentrations directly suppresses the spontaneous contractions ("pumping") of lymph vessels, which propel extracellular fluid from peripheral tissues to the central veins to prevent lymphedema. The spontaneous contractions of lymph vessels rely on Ca2+ influx through CaL channels, and DOX-induced suppression of lymphatic contractions can be partly reversed by CaL channel openers. Based on these findings, we propose to i) define the direct effect of DOX on the contractile activity of isolated lymph vessels, ii) use patch-clamp techniques to determine if DOX blocks CaL channels in lymphatic smooth muscle cells, and iii) use in vivo flow cytometry with high-resolution intravital optical imaging to define the acute effet of DOX chemotherapy on in vivo lymphatic flow.

 描述（由申请人提供）：在美国，超过500万女性在乳腺癌手术和/或放疗后患有手臂水肿，并且多柔比星（DOX）化疗使手臂水肿的发生率和严重程度恶化。DOX导致水肿的机制尚不清楚，但认为其涉及由于其细胞毒性作用而对淋巴系统造成急性和延迟损伤的多种机制。或者，在这个建议中，我们将探讨的假设，DOX急性和直接抑制淋巴收缩功能和DOX诱导的抑制淋巴流量可以逆转的药理开放的电压门控L型钙（CaL）通道。使用大鼠肠系膜淋巴系统作为我们的模型，我们将首次显示临床相关浓度的DOX直接抑制淋巴管的自发收缩（“泵送”），其将细胞外液从外周组织推到中央静脉以防止水肿。淋巴管的自发性收缩依赖于Ca 2+通过CaL通道的内流，并且DOX诱导的淋巴管收缩抑制可被CaL通道开放剂部分逆转。基于这些发现，我们建议i）确定DOX对离体淋巴管的收缩活性的直接作用，ii）使用膜片钳技术来确定DOX是否阻断淋巴平滑肌细胞中的CaL通道，以及iii）使用具有高分辨率活体光学成像的体内流式细胞术来确定DOX化疗对体内淋巴流动的急性作用。