Imaging sodium and lymphatics in lymphedema

淋巴水肿中钠和淋巴管的成像

• 批准号: 10333317
• 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/10333317
• 关键词: Address; Adipose tissue; Affect; Age; Area; Assisted Circulation; Biological Markers; Blood Pressure; 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; Swelling; Technology; Testing; Therapeutic Intervention; Time; Tissues; Tumor Debulking; Upper Extremity; Work; aggressive therapy; base; blood pressure control; cancer therapy; 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组织钠处理的淋巴管机制。 新型非侵入性成像工具对钠和淋巴管敏感的淋巴病变患者 疾病。这些发现旨在揭示组织钠淋巴清除的机制，并提供新的 淋巴水肿进展和治疗反应的影像生物标志物。最近的证据支持这一点 淋巴管调节间质钠水平。当淋巴清除受损时，高张间质 钠会导致组织肿胀、皮肤钠储存和血压控制不良。当淋巴 在淋巴水肿、淋巴淤积和随后发生炎症的啮齿动物模型中，清除能力受损，导致组织 重塑和纤维化。这些数据表明，但没有证实，淋巴清除受损有助于 组织钠储存和纤维化。然而，这种可能性尚未得到严格的调查，因为 缺乏临床上可行的对人体钠和淋巴管敏感的测量工具。要解决这个问题 需要的是，我们已经开发了非侵入性的在体MRI方法来量化淋巴血管和动力学， 和组织间钠含量的间质测量。我们已经将这些方法的子集(I)应用于患者 单侧上肢淋巴水肿，我们确认为偏侧淋巴淤积和淋巴肿大 收集器横截面积在手动淋巴引流治疗后减少，以及(Ii)在 下肢淋巴功能受损，我们报告皮肤和皮肤钠显著升高。 皮下组织，与年龄、体重指数和种族匹配的对照组相比。在这里提供的初步数据中， 我们的研究表明，在患有晚期下肢淋巴水肿和纤维化的患者中，富钠组织共同定位。 在完全解除充血治疗(CDT)后，皮下纤维化和组织钠减少。这里, 我们将扩展这项工作，以测试关于钠储存、淋巴功能障碍和 淋巴动员疗法。假设(1)：在有继发性淋巴水肿风险的患者中，组织钠 含量(TSC)升高，与淋巴流速呈负相关。假设(2)：皮肤TSC 与淋巴水肿分期呈正相关；皮下深部钠与肝纤维化组织共定位 有淋巴水肿和纤维化的患者。假设(3)：TSC降低，淋巴流速增加 在淋巴水肿的患肢接受CDT一个疗程后，成像指标在类似的时间段内没有变化 在健康的志愿者中。影响：结果将证实TSC与淋巴功能障碍的关系，特别是 手动刺激淋巴通道是否可以降低TSC。这将促使及早干预。 作为减少纤维化发病的候选治疗方法，但更广泛地将概述临床上可行的生物标记物 干预反应，这可能对未来寻求评估影响的临床试验具有意义 关于组织钠储存的新兴淋巴疗法。