New therapeutic targets in treatment of post-traumatic lymphedema

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Abstract Post-traumatic lymphedema is often managed as a mechanical drainage problem. We asked whether the chronic condition reflects a selectively sustained inflammatory–fibrotic state. Skin from patients with manifest post-traumatic lymphedema ( n = 23, typically 1–2 years post-injury) and controls ( n = 10) underwent quantitative immunohistochemistry (% marker-positive cells per standardized dermal ROI) and Luminex multiplex profiling (technical duplicates; two-tailed statistics after Shapiro–Wilk). Lymphedema tissue showed depressed lymphatic endothelial signaling: lower LYVE-1 and podoplanin (each q < 0.001) and reduced VEGFR-3 ( q < 0.001) versus controls; myeloperoxidase was also lower ( q < 0.05), while lipoxygenase was unchanged. Luminex revealed a selective pro-inflammatory core (IL-1β q < 0.05, IL-6 q < 0.01, TNF-α q < 0.01), with no differences in IL-4, IL-10, IL-12p40, IL-13, IL-17A, or RANTES/CCL5. Chemotactic cues were increased (MCP-1 q < 0.01, MIP-1α q < 0.01), aligning with monocyte/macrophage recruitment. Fibrosis-linked growth factors were upregulated (TGF-β1/β2/β3 each q < 0.01; PDGF-AA q < 0.05), while PDGF-BB was unchanged. Together, histology and soluble profiling converge on three axes—innate inflammatory drive, myeloid chemotaxis, and fibrotic remodeling—co-existing with suppressed lymphangiogenic tone. In this cohort, integrated human tissue profiling supports the view that chronic post-traumatic lymphedema is a selectively sustained inflammatory–fibrotic state rather than a purely mechanical disorder, suggesting stage-adapted therapeutic avenues that are prospectively testable.