Department of Plastic Reconstructive and Aesthetic Surgery, Hacettepe University Faculty of Medicine.
Department of Pathology, Hacettepe University Faculty of Medicine.
Ann Plast Surg. 2021 Jun 1;86(6):707-713. doi: 10.1097/SAP.0000000000002479.
Our aim was to create a new rodent hind limb lymphedema model lacking the fibrosis effect induced by radiotherapy and subjected to the inhibition of lymphangiogenesis via sirolimus (rapamycin) to maintain a chronic lymphedema model and investigate its reliability for human treatment modalities.
Forty-two Sprague-Dawley rats were randomly assigned to 7 groups: (1) surgery control, (2) vehicle-surgery control, (3) vehicle control, (4) rapamycin control, (5) surgery with 1 mg/kg per day rapamycin, (6) surgery with 1.5 mg/kg per day rapamycin, and (7) surgery with 2 mg/kg per day rapamycin. All surgeries were performed on the right hind limbs, with the left hind limbs also considered as a control. The drug and its solvent were administered daily into the relevant groups intraperiteonally. The presence of lymphedema was investigated by weekly limb circumference measurements, microcomputed tomography, fluorescence lymphography using indocyanine green dye, and microscopic evaluation at the end of the sixth week to determine any histological changes in the hind limbs.
In group 1, lymphedema was observed for 2 weeks (P = 0.032), whereas in groups 5, 6, and 7, lymphedema lasted for 3 weeks (P < 0.05.) Fluorescence using indocyanine green revealed that the edema was totally resolved after 6 weeks of surgery by a well-developed superficial lymphatic organization instead of the normal distinct vessel structure. Histologically, groups 1, 5, 5, and 7 demonstrated a significant increase in both the number of macrophages (P < 0.001) and newly formed lymphatic vessels in the right side surgically treated hind limb (P < 0.05).
Despite the extreme surgical destruction and lymphangiogenesis inhibition in the rat model, the sustained lymphedema did not last >3 weeks. Because of the rapid neolymphangiogenesis in murines and a different wound healing mechanism, they should not be considered as an appropriate model for research on human lymphedema in first place.
我们的目的是建立一种新的啮齿动物后肢淋巴水肿模型，该模型缺乏放射治疗引起的纤维化作用，并通过西罗莫司（雷帕霉素）抑制淋巴管生成，以维持慢性淋巴水肿模型，并研究其对人类治疗方式的可靠性。
42 只 Sprague-Dawley 大鼠随机分为 7 组：（1）手术对照组，（2）载体手术对照组，（3）载体对照组，（4）雷帕霉素对照组，（5）每天 1mg/kg 雷帕霉素手术组，（6）每天 1.5mg/kg 雷帕霉素手术组，（7）每天 2mg/kg 雷帕霉素手术组。所有手术均在右后肢进行，同时将左后肢也作为对照。将药物及其溶剂每天通过腹膜内给药至相关组。通过每周测量肢体周长、微计算机断层扫描、吲哚菁绿染料荧光淋巴造影和第六周末的显微镜评估来研究淋巴水肿的存在，以确定后肢的任何组织学变化。
在第 1 组中，观察到淋巴水肿持续了 2 周（P=0.032），而在第 5、6 和 7 组中，淋巴水肿持续了 3 周（P<0.05）。吲哚菁绿荧光显示，手术后 6 周，通过发育良好的浅表淋巴管组织而不是正常的明显血管结构，水肿完全消退。组织学上，第 1、5、5 和 7 组均显示右侧手术处理后肢的巨噬细胞数量（P<0.001）和新形成的淋巴管数量显著增加（P<0.05）。
尽管在大鼠模型中进行了极端的手术破坏和淋巴管生成抑制，但持续的淋巴水肿并未持续>3 周。由于鼠类的新生淋巴管生成速度较快，以及不同的伤口愈合机制，它们不应该首先被视为研究人类淋巴水肿的合适模型。
