Anti-Inflammatory Pharmacotherapy with Ketoprofen Ameliorates Experimental Lymphatic Vascular Insufficiency in Mice

Abstract

BackgroundDisruption 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-α receptor (sTNF-R1) upon tumor necrosis factor (TNF)-α activity in a mouse model of acquired lymphedema.Methods and FindingsLymphedema 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-α gene expression and cytokine levels. Conversely, sTNF-R1 treatment increased tail volume, exacerbated the histopathology, and decreased TNF-α gene expression. Expression of vascular endothelial growth factor-C (VEGF-C), which stimulates lymphangiogenesis, closely correlated with TNF-α expression.ConclusionsKetoprofen therapy reduces experimental post-surgical lymphedema, yet direct TNF-α inhibition does not. Reducing inflammation while preserving TNF-α 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.

Role of COX-2 in lymphangiogenesis and restoration of lymphatic flow in secondary lymphedema

“…14 In a study utilizing a nonselective COX inhibitor in a mouse tail lymphedema model, ketoprofen treatment normalized the histopathology with increased TNF-a expression and VEGF-C expression. 31 The surprising difference between the effect of COX-2 inhibition on VEGF-C expression in that study and ours suggests that the selectivity of COX inhibitors is important.…”

New developments in clinical aspects of lymphatic disease

“…Additionally, enthusiasm for growth factor-mediated therapeutics might be dampened by the cancer-survivor status of a large proportion of the potential recipients (49). Alternative systemic approaches to development of a lymphedema-reversing pharmacology, including targeted antiinflammatory therapy, are beginning to show promise (54)(55)(56).…”

ROCK and cAMP Promote Lymphatic Endothelial Cell Barrier Integrity and Modulate Histamine and Thrombin-Induced Barrier Dysfunction

“…It is worth noting that anti-inflammatory therapy has recently been shown to ameliorate experimentally-induced mouse tail lymphedema. 42 Recognizing the well-defined role of cAMP in enhancing VE-cadherin mediated endothelial adhesions and promoting microvascular barrier function, 14,15 the ability of exogenous 8-Br-cAMP to inhibit histamine and thrombin-induced barrier dysfunction in lymphatic endothelial cells was tested. The results, showing that 8-Br-cAMP enhances barrier function and because of this, limits histamine and thrombin-induced barrier dysfunction, are similar to observations in microvessels and blood endothelial cell models.…”