Department of Surgery, Plastic and Reconstructive Surgery Service, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Surgery, Plastic and Reconstructive Surgery Service, Memorial Sloan Kettering Cancer Center, New York, New York.
Transl Res. 2023 Jul;257:43-53. doi: 10.1016/j.trsl.2023.01.005. Epub 2023 Feb 1.
Transforming growth factor-beta 1 (TGF-β1)-mediated tissue fibrosis is an important regulator of lymphatic dysfunction in secondary lymphedema. However, TGF-β1 targeting can cause toxicity and autoimmune complications, limiting clinical utility. Angiotensin II (Ang II) modulates intracellular TGF-β1 signaling, and inhibition of Ang II production using angiotensin-converting enzyme (ACE) inhibitors, such as captopril, has antifibrotic efficacy in some pathological settings. Therefore, we analyzed the expression of ACE and Ang II in clinical lymphedema biopsy specimens from patients with unilateral breast cancer-related lymphedema (BCRL) and mouse models, and found that cutaneous ACE expression is increased in lymphedematous tissues. Furthermore, topical captopril decreases fibrosis, activation of intracellular TGF-β1 signaling pathways, inflammation, and swelling in mouse models of lymphedema. Captopril treatment also improves lymphatic function and immune cell trafficking by increasing collecting lymphatic pumping. Our results show that the renin-angiotensin system in the skin plays an important role in the regulation of fibrosis in lymphedema, and inhibition of this signaling pathway may hold merit for treating lymphedema.
转化生长因子-β1（TGF-β1）介导的组织纤维化是继发性淋巴水肿中淋巴功能障碍的重要调节因子。然而，TGF-β1 的靶向治疗可能会引起毒性和自身免疫并发症，限制了其临床应用。血管紧张素 II（Ang II）调节细胞内 TGF-β1 信号转导，使用血管紧张素转换酶（ACE）抑制剂如卡托普利抑制 Ang II 的产生在某些病理情况下具有抗纤维化作用。因此，我们分析了临床淋巴水肿活检标本中 ACE 和 Ang II 在单侧乳腺癌相关淋巴水肿（BCRL）患者和小鼠模型中的表达，发现淋巴水肿组织中皮肤 ACE 的表达增加。此外，局部给予卡托普利可减少小鼠淋巴水肿模型中的纤维化、细胞内 TGF-β1 信号通路的激活、炎症和肿胀。卡托普利治疗还通过增加收集淋巴管的泵血来改善淋巴功能和免疫细胞的迁移。我们的结果表明，皮肤中的肾素-血管紧张素系统在淋巴水肿纤维化的调节中起重要作用，抑制该信号通路可能对治疗淋巴水肿有价值。
