Modulation of Lymphatic System Function by LTB4

LTB4 对淋巴系统功能的调节

• 批准号: 10435118
• 负责人: Matthew Cribb
• 金额: $ 1.75万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-22 至 2021-12-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10435118
• 关键词: Academia; Acute; Affect; Arachidonic Acids; Arthritis; Asthma; Atherosclerosis; Automobile Driving; Breast Cancer Patient; Breast Cancer Treatment; Cauterize; Cells; Chemotactic Factors; Clinical; Clinical Trials; Deterioration; Development; Disease; Disease Progression; Dose; Drug Targeting; Exhibits; Exposure to; Failure; Fibrosis; Fluid Balance; Genetic; Histologic; Human; Hyperplasia; Imaging Techniques; Immune; Immune response; Impairment; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Injury; Institutes; Insulin Resistance; Intercellular Fluid; Knockout Mice; Knowledge; LTB4R gene; Left; Leukocytes; Leukotriene Antagonists; Leukotriene B4; Ligation; Limb structure; Lymphangiogenesis; Lymphatic; Lymphatic System; Lymphatic function; Lymphedema; Macrophage Activation; Measures; Mediating; Metabolism; Modeling; Mus; Natural regeneration; Near-infrared optical imaging; Nitric Oxide; Obese Mice; Operative Surgical Procedures; Pharmacological Treatment; Phenotype; Physiological; Play; Production; Property; Pump; Research; Research Institute; Research Personnel; Research Training; Resolution; Resources; Role; Site; Structure; Surgical Models; Swelling; System; Tail; Technology; Testing; Therapeutic; Tissues; Ubenimex; VEGFC gene; Work; career; improved; in vivo; lipid mediator; lymphatic circulation; lymphatic insufficiency; lymphatic pump; lymphatic vessel; macrophage; mouse model; novel; receptor; recruit; response; small molecule inhibitor; wound

Lymphedema is a devastating disease that predominantly affects breast cancer patients post- surgery, leading to swelling at the extremities, tissue fibrosis, and general discomfort. There are currently no pharmacological treatments available for lymphedema. However, LTB4, a metabolite of arachidonic acid, has been implicated in the development of lymphedema and identified as a possible drug target. The objective of this study is to determine if LTB4 drives lymphatic collecting vessel failure and identify the direct mechanism of action for LTB4 on lymphatic collecting vessels. The hypothesis is that LTB4 inhibits lymphatic collecting vessel contraction at high concentrations occurring post-injury, leading to lymphatic insufficiency and the extreme swelling found in lymphedema. We predict that this functional effect of LTB4 occurs through two mechanisms; LTB4 directly acts on lymphatic collecting vessels to inhibit pumping, and LTB4 drives macrophage recruitment to the site of injury, further amplifying disease progression through secretion of VEGFC and iNOS, known effectors of lymphatic function. To test how LTB4 concentration affects lymphatic collecting vessel function, we will first use an isolated vessel setup to test the direct effect of varying concentrations of LTB4 on lymphatic vessel tone and contractility. We will also determine if the effect of LTB4 on lymphatic vessel contractility is mediated by its receptors, BLT1 and/or BLT2. Next, an LTB4 antagonist called bestatin will be used in conjunction with a single vessel ligation lymphedema model in mice to study how LTB4 affects collecting vessel function during disease progression. In the single vessel ligation model, the dominant collecting vessel and the surrounding initial lymphatics will be cauterized while one collecting vessel will be left intact. By using NIR imaging techniques to measure contractile function in this collecting vessel after surgery, the effect of LTB4 antagonism on contractile function during disease progression can be determined. This surgical model will be tested in a genetic macrophage depletion mouse model to examine if there is a macrophage-mediated effect of LTB4 on collecting vessel pump function during lymphedema development. VEGFC secretion and iNOS expression by macrophages will be quantified in the context of LTB4 antagonism to determine the mechanism by which macrophages modulate lymphatic function. The results of this study will help elucidate the role of LTB4 in the development of lymphedema, characterize its direct effect on lymphatic system function, and identify multiple mechanisms by which LTB4 drives lymphatic collecting vessel pump failure. These results will be an important step towards a better understanding of lymphedema progression and will inform the use of pharmacotherapeutic treatments for lymphedema targeting LTB4 and its metabolism. The research training will take place at the Georgia Institute of Technology, a world-class research institute with ample facilities and resources to help guide a young researcher towards a career in academia.

淋巴水肿是一种毁灭性的疾病，主要影响乳腺癌后患者