Doxorubicin suppression of lymphatic function and therapeutic reversal

阿霉素对淋巴功能的抑制和治疗逆转

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：美国乳腺癌手术和/或辐射后，有500万妇女患有手臂淋巴水肿，淋巴水肿的事件和严重程度被阿霉素（DOX）化学疗法所瓦解。 DOX促进淋巴水肿的机制知之甚少，但由于其细胞毒性作用，它涉及急性损伤和延迟损伤的多种机制。另外，在此提案中，我们将探讨以下假设：DOX急性，直接抑制淋巴收缩功能和DOX诱导的淋巴流抑制可以通过电压门控L型CA2+（CAL）通道的药物开瓶器逆转。我们将使用大鼠肠系膜淋巴系统作为模型，我们将首次显示DOX在临床上相关的浓度下直接抑制淋巴血管的赞助收缩（“泵”），这些淋巴血管的赞助收缩（“泵送”）将细胞外液从外周静脉组织到中静脉促进中静脉，以防止淋巴管。赞助商诱导的淋巴管收缩依赖于CA2+通过CAL通道的影响，而DOX诱导的抑制淋巴血管可以通过CAL通道开瓶器部分逆转。 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.