Experimental assessment of pro-lymphangiogenic growth factors in the treatment of post-surgical lymphedema following lymphadenectomy
Experimental assessment of pro-lymphangiogenic growth factors in the treatment of post-surgical lymphedema following lymphadenectomy
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DOI：
10.1186/bcr2638
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发表时间：
2010-01-01
影响因子：
7.4
通讯作者：
Johnston, Miles
中科院分区：
文献类型：
--
作者：
Baker, Amy;Kim, Harold;Johnston, Miles
前言：淋巴水肿是乳腺癌手术中淋巴结切除的常见后果。目前的治疗选择主要局限于外按压疗法，以限制水肿的发展。我们之前在一个绵羊模型中研究了切除单个淋巴结后的淋巴水肿，并确定自体淋巴结移植有可能减少或防止水肿的发展。方法：将淋巴管生成因子(血管内皮生长因子C(VEGF-C)和血管生成素-2(Ang-2))负载到基于凝胶的药物释放系统(HAMC；透明质酸和甲基纤维素的混合物)中。体外测定靶血管内皮细胞的药物释放率和淋巴管生成信号，并进行体内血管通透性生物相容性试验。切除一个窝窝淋巴结后，在切除部位注射HAMC和生长因子。6周后，通过将(125)碘标记的牛血清白蛋白(I-125-BSA)注入结前血管并测量其在血浆中的回收率来评估淋巴功能。结果：生长因子在体外两周内通过HAMC的扩散释放，其中50%在前24小时内释放。该系统在目标内皮细胞中诱导淋巴管生成信号，而在绵羊中仅诱导最小的炎症反应。与完整组(3.2+/-0.7)相比，淋巴结切除组的淋巴功能显著降低(1.9+/-0.9，仅HAMC为1.7+/-0.8)。相反，生长因子治疗组(2.3+/-0.73)与完整组之间无显著差异，表明分子因子的功能得到改善。透视下观察到治疗部位再生淋巴管的数量增加。与未治疗组(结节切除219.8+/-118.7和单纯使用HAMC 162.6+/-141后)相比，HAMC+生长因子治疗组的水肿明显减轻(107.4+/-51.3)。结论：在淋巴水肿动物模型中，生长因子治疗具有提高淋巴功能和降低水肿程度的潜力。这一概念在淋巴水肿患者中的应用值得进一步研究。
Introduction: Lymphedema is a frequent consequence of lymph node excision during breast cancer surgery. Current treatment options are limited mainly to external compression therapies to limit edema development. We investigated previously, postsurgical lymphedema in a sheep model following the removal of a single lymph node and determined that autologous lymph node transplantation has the potential to reduce or prevent edema development. In this report, we examine the potential of lymphangiogenic therapy to restore lymphatic function and reduce postsurgical lymphedema.Methods: Lymphangiogenic growth factors (vascular endothelial growth factor C (VEGF-C)) and angiopoietin-2 (ANG-2) were loaded into a gel-based drug delivery system (HAMC; a blend of hyaluronan and methylcellulose). Drug release rates and lymphangiogenic signaling in target endothelial cells were assessed in vitro and vascular permeability biocompatibility tests were examined in vivo. Following, the removal of a single popliteal lymph node, HAMC with the growth factors was injected into the excision site. Six weeks later, lymphatic functionality was assessed by injecting (125)Iodine radiolabeled bovine serum albumin (I-125-BSA) into prenodal vessels and measuring its recovery in plasma. Circumferential leg measurements were plotted over time and areas under the curves used to quantify edema formation.Results: The growth factors were released over a two-week period in vitro by diffusion from HAMC, with 50% being released in the first 24 hr. The system induced lymphangiogenic signaling in target endothelial cells, while inducing only a minimal inflammatory response in sheep. Removal of the node significantly reduced lymphatic functionality (nodectomy 1.9 +/- 0.9, HAMC alone 1.7 +/- 0.8) compared with intact groups (3.2 +/- 0.7). In contrast, there was no significant difference between the growth factor treatment group (2.3 +/- 0.73) and the intact group indicating improved function with the molecular factors. An increase in the number of regenerated lymphatic vessels at treatment sites was observed with fluoroscopy. Groups receiving HAMC plus growth factors displayed significantly reduced edema (107.4 +/- 51.3) compared with nontreated groups (nodectomy 219.8 +/- 118.7 and HAMC alone 162.6 +/- 141).Conclusions: Growth factor therapy has the potential to increase lymphatic function and reduce edema magnitude in an animal model of lymphedema. The application of this concept to lymphedema patients warrants further examination.