Anti-inflammatory pharmacotherapy with ketoprofen ameliorates experimental lymphatic vascular insufficiency in mice.
BACKGROUND
Disruption of the lymphatic vasculature causes edema, inflammation, and end-tissue destruction. To assess the therapeutic efficacy of systemic anti-inflammatory therapy in this disease, we examined the impact of a nonsteroidal anti-inflammatory drug (NSAID), ketoprofen, and of a soluble TNF-alpha receptor (sTNF-R1) upon tumor necrosis factor (TNF)-alpha activity in a mouse model of acquired lymphedema.


RESULTS
Lymphedema was induced by microsurgical ablation of major lymphatic conduits in the murine tail. Untreated control mice with lymphedema developed significant edema and extensive histopathological inflammation compared to sham surgical controls. Short-term ketoprofen treatment reduced tail edema and normalized the histopathology while paradoxically increasing TNF-alpha gene expression and cytokine levels. Conversely, sTNF-R1 treatment increased tail volume, exacerbated the histopathology, and decreased TNF-alpha gene expression. Expression of vascular endothelial growth factor-C (VEGF-C), which stimulates lymphangiogenesis, closely correlated with TNF-alpha expression.


CONCLUSIONS
Ketoprofen therapy reduces experimental post-surgical lymphedema, yet direct TNF-alpha inhibition does not. Reducing inflammation while preserving TNF-alpha activity appears to optimize the repair response. It is possible that the observed favorable responses, at least in part, are mediated through enhanced VEGF-C signaling.
Nakamura
Kenta
K
Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA.
Radhakrishnan
Kavita
K
Wong
Yat Man
YM
Rockson
Stanley G
SG
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D018836:Inflammation Mediators / Q000378:metabolism; D007660:Ketoprofen / Q000494:pharmacology / Q000627:therapeutic use*; D042601:Lymphatic Vessels / Q000187:drug effects / Q000473:pathology*; D008209:Lymphedema / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000517:prevention & control*; D051379:Mice; D018448:Models, Immunological; D009928:Organ Specificity; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012995:Solubility / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D018836:Inflammation Mediators; D047888:Receptors, Tumor Necrosis Factor, Type I; D007660:Ketoprofen