Imaging sodium and lymphatics in lymphedema

淋巴水肿中钠和淋巴管的成像

• 批准号: 10546461
• 负责人: Rachelle L Crescenzi
• 金额: $ 48.94万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-25 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10546461
• 关键词: Address; Adipose tissue; Affect; Age; Area; Assisted Circulation; Biological Markers; Blood Vessels; Body mass index; Cells; Chronic Disease; Clinical; Clinical Trials; Cross-Sectional Studies; Data; Deposition; Disease; Disease model; Early Intervention; Endometrial Carcinoma; Excision; Fibrosis; Functional Imaging; Functional disorder; Future; Goals; High Prevalence; Human; Image; Imaging Device; Immune; Impairment; Inflammation; Intervention; Knowledge; Leg; Limb structure; Longitudinal Studies; Lower Extremity; Lymphangiogenesis; Lymphangiography; Lymphatic; Lymphatic Diseases; Lymphatic clearance; Lymphatic function; Lymphedema; Lymphoid Tissue; Magnetic Resonance Imaging; Malignant Neoplasms; Manual Lymphatic Drainage; Manuals; Maps; Measurement; Measures; Mediating; Methods; Molecular; National Heart, Lung, and Blood Institute; Operative Surgical Procedures; Patient Triage; Patients; Pharmacologic Substance; Physiology; Procedures; Progressive Disease; Race; Radiology Specialty; Regulation; Reporting; Reproducibility; Risk; Risk Assessment; Rodent; Rodent Model; Role; Severities; Severity of illness; Skin; Skin Tissue; Sodium; Source; Standardization; Subcutaneous Tissue; Suction Lipectomy; Swelling; Technology; Testing; Therapeutic Intervention; Time; Tissues; Tumor Debulking; Upper Extremity; Work; aggressive therapy; blood pressure control; cancer therapy; comparison control; healthy volunteer; human disease; imaging biomarker; imaging modality; in vivo; innovation; interstitial; lymph flow; lymph nodes; lymph stasis; lymphatic circulation; lymphatic dysfunction; lymphatic insufficiency; lymphatic vasculature; lymphatic vessel; non-invasive imaging; novel; novel marker; potential biomarker; response; secondary lymphedema; subcutaneous; subcutaneous fibrosis; tissue biomarkers; tool; treatment response; working group

The overall goal of this work is to investigate lymphatic vascular mechanisms of tissue sodium handling using novel, noninvasive imaging tools sensitive to sodium and lymphatics in patients with well-characterized lymphatic disease. Findings are intended to inform mechanisms of lymphatic clearance of tissue sodium, and provide novel imaging biomarkers of lymphedema progression and treatment response. Recent evidence supports that lymphatics regulate interstitial sodium levels. When lymphatic clearance is impaired, hypertonic interstitial sodium results in tissue swelling, skin sodium storage, and poor blood pressure control. When lymphatic clearance is impaired in rodent models of lymphedema, lymph stasis and inflammation ensues, leading to tissue remodeling and fibrosis. These data suggest, but do not confirm, that impaired lymphatic clearance contributes to tissue sodium storage and fibrosis. However, this possibility has not been investigated rigorously owing to a lack of clinically-feasible measurement tools sensitive to sodium and lymphatics in humans. To address this need, we have developed noninvasive, in vivo MRI approaches to quantify lymphatic vasculature and dynamics, and interstitial measures of tissue sodium content. We have applied a subset of these methods (i) in patients with unilateral upper-extremity lymphedema and we confirmed lateralized lymph stasis and enlarged lymphatic collector cross-sectional area that reduced following manual lymphatic drainage therapy, and (ii) in patients with lower-extremity lymphatic impairment in whom we reported significantly elevated sodium in the skin and subcutaneous tissue, compared to age-, BMI-, and race-matched controls. In preliminary data presented here, we show that in patients with advanced lower-extremity lymphedema and fibrosis, sodium-rich tissue co-localizes with subcutaneous fibrosis, and tissue sodium reduces following complete decongestive therapy (CDT). Here, we will extend this work to test fundamental hypotheses regarding sodium storage, lymphatic dysfunction, and lymphatic mobilization therapy. Hypothesis (1): In patients at-risk for secondary lymphedema, tissue sodium content (TSC) is elevated and inversely correlates with lymphatic flow velocity. Hypothesis (2): Skin TSC positively correlates with lymphedema stage; deep subcutaneous sodium co-localizes with fibrotic tissue in patients with lymphedema and fibrosis. Hypothesis (3): TSC decreases and lymphatic flow velocity increases after a course of CDT in affected limbs with lymphedema; imaging metrics do not change in a similar time-period in healthy volunteers. Impact: Results will confirm how TSC relates to lymphatic dysfunction, and specifically whether TSC can be reduced by manual stimulation of lymphatic channels. This will motivate early intervention as a candidate treatment for reducing fibrosis onset, but more broadly will outline clinically-feasible biomarkers of intervention response which could have significance for future clinical trials that seek to evaluate the impact of emerging lymphatic therapies on tissue sodium storage.

这项工作的总体目标是研究淋巴管机制的组织钠处理使用 新型、非侵入性成像工具，在特征明确的淋巴结转移患者中对钠和抗生素敏感， 疾病这些发现旨在告知组织钠的淋巴清除机制，并提供新的 水肿进展和治疗反应的成像生物标志物。最近的证据表明， 利尿剂调节间质钠水平。当淋巴清除功能受损时，高渗性间质 钠导致组织肿胀、皮肤钠储存和血压控制不良。当淋巴 在啮齿类动物的水肿、淋巴淤滞和炎症增强模型中， 重塑和纤维化。这些数据表明，但不能证实，受损的淋巴清除有助于 组织钠储存和纤维化。然而，由于一个原因，这种可能性尚未得到严格调查。 缺乏临床上可行的测量工具，对人体中的钠和维生素敏感。为了解决这个 需要，我们已经开发了非侵入性的，在体内MRI方法来量化淋巴血管和动力学， 和组织钠含量的间质测量。我们已经应用了这些方法的子集（i）在患者中 单侧上肢水肿，我们证实了单侧淋巴淤滞和淋巴结肿大 收集器横截面积减少后，手动淋巴引流治疗，和（ii）在患者 下肢淋巴损伤，我们报告了皮肤中的钠显著升高， 皮下组织，与年龄，BMI和种族匹配的对照组相比。在这里提供的初步数据中， 我们发现，在晚期下肢水肿和纤维化患者中， 皮下纤维化，组织钠在完全减充血治疗（CDT）后降低。在这里， 我们将扩展这项工作，以测试有关钠储存，淋巴功能障碍， 淋巴动员疗法假设（1）：在继发性水肿风险患者中，组织钠 总干细胞含量（TSC）升高，并与淋巴流速呈负相关。假设（2）：皮肤TSC 与水肿分期呈正相关;深层皮下钠与纤维化组织共定位， 水肿和纤维化患者。假设（3）：TSC减少，淋巴流速增加 在患肢水肿的CDT疗程后;成像指标在相似的时间段内没有变化 健康志愿者。影响：结果将证实TSC与淋巴功能障碍的关系， 是否可以通过手动刺激淋巴通道来减少TSC。这将促进早期干预 作为减少纤维化发作的候选治疗，但更广泛地将概述临床可行的生物标志物 这可能对未来的临床试验具有重要意义， 关于组织钠储存的新兴淋巴疗法。