Table 1.

Pharmacological interventions for the treatment of lymphedema

Type of intervention	Proposed mechanism for lymphedema treatment	Authors, publication year
Systemic interventions
VEGF-C	Lymphangiogenesis	Szuba et al., 2002
Subcutaneous injection	VEGF-C directly binds VEGFR-3 to activate intracellular signaling pathways that promote LEC growth and survival
VEGF-C Naked plasmid technique	Lymphangiogenesis Transfer of plasmid DNA encoding VEGF-C increases VEGFR-3 expression and activation	Yoon et al., 2003
VEGF-C Viral vectors: Adenovirus ---Lymfactin® Adeno-Associated	Lymphangiogenesis Adenoviral and adeno-associated gene vectors encoding VEGF-C regenerate lymphatic vessels and preserve lymphatic architecture post VLNT	Lai et al., 2002 Tammela et al., 2007 Hartiala et al., 2020
VEGF-C mRNA vectors	Lymphangiogenesis Nucleoside-modified mRNA encoding VEGF-C stimulates site-specific lymphatic growth at low dosages	Pardi et al., 2018 Brown et al., 2020 Szöke et al., 2021
Hepatocyte growth factor (HGF)	Lymphangiogenesis VEGFR-3 independent stimulation of LEC proliferation and migration	Kajiya et al., 2005 Wong et al., 2021
9-cis retinoic acid (RA)	Lymphangiogenesis Indirect activation of PI3K/Akt pathway via fibroblast receptor signaling to stimulate LEC proliferation	Choi et al., 2012 Wong et al., 2021
Adipose-derived stem cells (ADSCs)	Lymphangiogenesis ADSCs release a secretome of bioactive factors that reinforce LEC growth and survival	Hwang et al., 2011 Ahmadzadeh et al., 2020 Yan et al., 2011
Ketoprofen (NSAID)	Anti-inflammatory 5-Lipoxygenase (5-LO) inhibition, $\downarrow$ leukotriene B4 (LTB4) synthesis	Nakamura et al., 2009 Tian et al., 2017 Rockson et al., 2018
Bestatin (NSAID)	Anti-inflammatory Leukotriene A4-hydrolyase (LTA4H) inhibition, $\downarrow$ leukotriene B4 (LTB4) synthesis	Tian et al., 2017 Cribb et al., 2021
Fingolimod (Gilenya®)	Anti-inflammatory Inhibition of activated CD4 + T cell emigration from LNs impairs TH2 differentiation	García Nores et al., 2018
Neutralizing antibodies	Anti-inflammatory Th2 inflammatory cytokine blockade (IL-4/IL-13 inhibition)	Avraham et al., 2013 Savetsky et al., 2015 Mehrara et al., 2021
Doxycycline	Anti-inflammatory Inhibition of Th2 phenotype differentiation, $\downarrow$ monocyte recruitment, $\downarrow$ polarization of alternatively activated M $\varphi$	Debrah et al., 2006 Mand et al., 2012 Furlong-Silva et al., 2021 Brown et al., 2023
Anti-transforming growth factor beta-1 (TGF- β1)	Anti-fibrotic Inhibition of TGF-β1 disrupts fibroblast maturation to myofibroblasts, improving lymphostatic fibrosis	Meng et al., 2016 Yoon et al., 2020
Topical interventions
hADSCs and VEGF-C hydrogel	Lymphangiogenesis hADSC mediated sustained release of VEGF-C	Hwang et al., 2011
Recombinant human fibroblast growth factor 2 (FGF2)	Lymphangiogenesis $\uparrow$ VEGF-C and VEGF-D expression	Onishi et al., 2014
Tacrolimus	Anti-inflammatory Inhibition of IL-2-mediated CD4 + T cell activation/differentiation	Gardenier et al., 2017 Gulmark Hansen et al., 2023
Pirfenidone	Anti-fibrotic Inhibition of TGF-β1	Baik et al., 2022
Captopril	Anti-fibrotic ACE inhibitor—inhibition of intracellular TGF-β1 signaling pathways	Brown et al., 2023

Abbreviations: VEGF vascular endothelial growth factor, VEGFR vascular endothelial growth factor receptor, LEC lymphatic endothelial cell, DNA deoxyribonucleic acid, VLNT vascularized lymph node transplant, mRNA messenger ribonucleic acid, IL interleukin, hADSCs human adipose-derived stem cells