Skin Barrier Dysfunction In Lymphedema
Adana Campbell, MD, Adana Campbell, MD, Jungeun Baik, PhD, HyeungJu Park, PhD, Kevin Kuonqui, MS, Raghu Kataru, PhD, Babak J. Mehrara, MD, Ananta Sarker, BS.
Memorial Sloan Kettering Cancer Institute, New York, NY, USA.
Purpose: Lymphedema (LE) is a debilitating condition that can arise following surgical treatment for cancer. Chronic T-helper 2 (TH2) responses contribute to LE pathology, however the initiating factors for disease development remains largely unknown. Here, we investigate the interaction between inflammation and skin barrier impairment as important inciting steps in LE pathogenesis. Methods: Matched, full thickness skin biopsies (5-mm) were obtained from the normal (N) and LE upper extremity of patients with unilateral LE (n=18). Epidermal barrier and tight junction protein expression was assessed by immunohistofluorescense (IHF) and Western Blot (WB) analysis. Epidermal gene expression was compared between LE and normal samples by single-cell RNA-sequencing (RNA-seq). Results: LE samples contain significant reductions in tight junction and epidermal barrier proteins when compared to normal tissue on IHF and WB; zona occludens-1 (ZO-1 (p=0.004)); claudin-1 (CLDN-1 (p=0.058)); claudin-4 (CLDN-4(0.048)); filaggrin (FLG (p=0.049). RNA-seq analysis indicates variation in gene expression of epidermal differentiation markers among LE samples.Conclusion: Skin barrier dysfunction is increased in LE. Alterations in the skin barrier may enhance the inflammatory immune response to external and lymphedema antigens which can perpetuate lymphatic dysfunction. Therefore, therapies aimed at restoring skin barrier integrity may play a critical role in LE management. 
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