Table 1.

The impact of current and prospective lymphedema treatments on underlying inflammatory mechanisms that promote lymphedema development and progression.

Current Therapies
Treatment	Description	Reported Impact on Inflammatory Mechanisms
Complete Decongestive Therapy	Manual physical therapies (e.g., compression, massage) that aim to mobilize accumulated interstitial fluid from affected regions back into blood vascular circulation.	Complete Decongestive Therapy (CDT) Decreased circulating levels of TNF-α, IL-10, monocytes [115]. Increased aldosterone, no significant change in hyaluronic acid levels after 3-weeks of CDT [116]. Pneumatic Compression No significant difference (head and neck) in blood levels of IFN-γ, TNF-α, TGFβ-1, IL-1β , IL-6 after 8-weeks of pneumatic compression [117].
Surgical Interventions	Physiologic and reductive techniques, including lymphaticovenous anastomosis, vascularized lymph node transfer, breast reconstruction, combined approaches.	Lymph Node Transfer and Combined Techniques Increased production of IL-10 (after combined lymph node transfer and anastomosis) [118]. Modulation of VEGF-C production, correlation between IL-10, TNF-α, TGFβ-1 and lymphedema-related factors following lymph node transfer [119]. Lymphaticovenous anastomosis Decreased CD4+ cell inflammation, hyperkeratosis, epidermal proliferation, collagen type I deposition and TGFβ-1 expression (biopsy) [120]. One-year post-operative decrease in IFN-γ and IL-17A expression, increased T-cell receptor diversity. Downregulation of PD-1, Tim-3, PD-1+Tim-3+ on CD4+ and CD8+ T cells [121].
Novel Therapies
Treatment	Description	Reported Impact on Inflammatory Mechanisms
5-Lipoxgenase Targeting Medications	Ketoprofen, bestatin (Ubenimex), and Acebilustat are known modifiers of the 5-lipoxygenase pathway that leads to lymphedema progression and worsening.	Ketoprofen Decreased dermal thickness, improved histopathological scores (dermal thickness, collagen thickness, intercellular mucin deposits, perivascular inflammation), decreased plasma G-CSF (human) [122]. Upregulation of VEGF-C, VEGFR-3, PROX-1 expression and paradoxical increase in TNF-α. Normalized histopathological findings of hyperkeratosis, epidermal spongiosis, edema, irregularity of epidermal/dermal junction, elongation of dermal papillae of tail (murine) [123]. Bestatin Improved lymphatic flow, decreased lymphatic permeability, diminished macrophage and neutrophil infiltration in skin sample, decreased IL-6, IL-4, IL-13, and IL-17A, elevated IL-10 (murine) [67].
Antifibrotic Medications	Anti-fibrotic medications target tissue transformation that has been found in later stages of lymphedema.	Neutralizing anti-TGF Antibodies Decreased ECM deposition, increased collateral lymphatic formation, inhibition of T-cell infiltration. Decreased tail edema, fibroadipose tissue deposition, and expression of TGFβ-1 and pSmad3 in skin, decreased expression of all TGF-β isoforms and downstream signaling molecules (Sp1, RhoA, Cfl1, Map3k7, Mapk14, RelA, Nfκb2 and Akt1) and inflammatory mediators (IL-1β, TNF-α, IL-6, -4, -13, -10, -17α) in tail tissue. Decreased skin leukocyte, CD4+, Th1, and Th2 cells, and neutrophils (murine) [107]. EW-7197 Improvements in fibrosis, interstitial flow, lymphangiogenesis, decreased tail diameter (murine) [124].
Tacrolimus	Tacrolimus is an anti-T-cell agent approved for topic treatment of skin inflammation and fibrosis.	Improved lymphatic contractility, swelling, T-cell infiltration, tissue fibrosis. Increased formation of lymphatic collateral vessels, decreased backflow (murine) [125,126,127].