Campbell Adana-Christine, Baik Jung Eun, Sarker Ananta, Brown Stav, Park Hyeung Ju, Kuonqui Kevin G, Shin Jinyeon, Pollack Bracha L, Roberts Arielle, Ashokan Gopika, Rubin Jonathan, Kataru Raghu P, Dayan Joseph H, Barrio Andrea V, Mehrara Babak J
Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA; Department of Biotechnology, Levatio Therapeutics, San Diego, California, USA.
J Invest Dermatol. 2025 Jan;145(1):85-97.e4. doi: 10.1016/j.jid.2024.05.017. Epub 2024 Jun 13.
Breast cancer-related lymphedema (BCRL) is characterized by skin changes, swelling, fibrosis, and recurrent skin infections. Clinical studies have suggested that lymphedema results in skin barrier defects; however, the underlying cellular mechanisms and the effects of bacterial contamination on skin barrier function remain unknown. In matched biopsies from patients with unilateral BCRL, we observed decreased expression of FLG and the tight junction protein ZO-1 in skin affected by moderate lymphedema or by subclinical lymphedema in which dermal backflow of lymph was identified by indocyanine green lymphography, relative to those in the controls (areas without backflow and from the unaffected arm). In vitro stimulation of keratinocytes with lymph fluid obtained from patients undergoing lymphedema surgery led to the same changes as well as increased expression of keratin 14, a marker of immature keratinocytes. Finally, using mouse models of lymphedema, we showed that similar to the clinical scenario, the expression of skin barrier proteins was decreased relative to that in normal skin and that colonization with Staphylococcus epidermidis bacteria amplified this effect as well as lymphedema severity. Taken together, our findings suggest that lymphatic fluid stasis contributes to skin barrier dysfunction in lymphedema.
乳腺癌相关淋巴水肿（BCRL）的特征为皮肤改变、肿胀、纤维化和反复皮肤感染。临床研究表明，淋巴水肿会导致皮肤屏障缺陷；然而，其潜在的细胞机制以及细菌污染对皮肤屏障功能的影响仍不清楚。在单侧BCRL患者的配对活检中，我们观察到，与对照组（无淋巴回流区域及未受影响手臂）相比，在中度淋巴水肿或亚临床淋巴水肿（通过吲哚菁绿淋巴造影术确定存在真皮淋巴回流）影响的皮肤中，丝聚蛋白（FLG）和紧密连接蛋白ZO-1的表达降低。用淋巴水肿手术患者的淋巴液对角质形成细胞进行体外刺激，也导致了同样的变化，以及未成熟角质形成细胞标志物角蛋白14表达增加。最后，使用淋巴水肿小鼠模型，我们发现，与临床情况类似，与正常皮肤相比，皮肤屏障蛋白的表达降低，表皮葡萄球菌定植会放大这种效应以及淋巴水肿的严重程度。综上所述，我们的研究结果表明，淋巴液淤滞会导致淋巴水肿中的皮肤屏障功能障碍。
