Blockade of Transforming Growth Factor-β1 Accelerates Lymphatic Regeneration during Wound Repair
Blockade of Transforming Growth Factor-β1 Accelerates Lymphatic Regeneration during Wound Repair
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DOI：
10.2353/ajpath.2010.100594
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发表时间：
2010-12-01
影响因子：
6
通讯作者：
Mehrara, Babak J.
中科院分区：
文献类型：
--
作者：
Avraham, Tomer;Daluvoy, Sanjay;Mehrara, Babak J.
淋巴水肿是癌症治疗的并发症，约50%的接受淋巴结切除术的患者发生淋巴水肿。这种疾病的病因仍然未知。在这项研究中，我们确定了软组织纤维化对淋巴功能的影响以及转化生长因子（TGF）的作用。β 1在调节这种反应中的作用我们测定了从继发性水肿患者的水肿和正常肢体收集的匹配活检标本中TGF β的表达模式。为了确定TGF β在调节组织纤维化中的作用，我们使用了小鼠水肿模型，并用单克隆抗体全身抑制TGF β功能，或用可溶性缺陷型TGF β受体局部抑制TGF β功能。淋巴水肿组织显示，与对照组相比，TGF β 1染色的细胞数增加近3倍，TGF β抑制显著降低组织纤维化，增加淋巴管生成，改善淋巴功能。此外，抑制TGF β不仅降低了水肿组织中TGF β的表达，而且减少了辅助性T细胞2型（Th 2）的炎症迁移。细胞和促纤维化Th 2细胞因子的表达类似地，全身性T细胞耗竭显著降低尾部组织中TGF β的表达抑制TGF β功能促进淋巴再生减少组织纤维化减少慢性炎症和Th 2细胞这些策略的使用可能代表了预防淋巴结切除术后水肿的新方法（Am J Pathol 2010 177 3202-3214，DOI 10 2353/ajpath 2010 100594）。
Lymphedema is a complication of cancer treatment occurring in approximately 50% of patients who undergo lymph node resection Despite its prevalence, the etiology of this disorder remains unknown In this study we determined the effect of soft tissue fibrosis on lymphatic function and the role of transforming growth factor (TGF)-beta 1 in the regulation of this response We determined TGF beta expression patterns m matched biopsy specimens collected from lymphedematous and normal limbs of patients with secondary lymphedema. To determine the role of TGF beta in regulating tissue fibrosis we used a mouse model of lymphedema and inhibited TGF function either systemically with a monoclonal antibody or locally by using a soluble defective TGF beta receptor Lymphedematous tissue demonstrated a nearly threefold increase in the number of cells that stained for TGF beta 1 TGF beta inhibition markedly decreased tissue fibrosis increased lymphangiogenesis and improved lymphatic function compared with controls In addition inhibition of TGF beta not only decreased TGF beta expression in lymphedematous tissues but also diminished inflammation migration of T helper type 2 (Th2) cells and expression of profibrotic Th2 cytokines Similarly systemic depletion of T cells markedly decreased TGF beta expression in tail tissues Inhibition of TGF beta function promoted lymphatic regeneration decreased tissue fibrosis decreased chronic inflammation and Th2 cell migration and improved lymphatic function The use of these strategies may represent a novel means of preventing lymphedema after lymph node resection (Am J Pathol 2010 177 3202-3214, DOI 10 2353/ajpath 2010 100594)