Leukotriene B4 antagonism ameliorates experimental lymphedema

Abstract

Acquired lymphedema is a cancer sequela and a global health problem currently lacking pharmacologic therapy. We have previously demonstrated that ketoprofen, an anti-inflammatory agent with dual 5-lipoxygenase and cyclooxygenase inhibitory properties, effectively reverses histopathology in experimental lymphedema. We show that the therapeutic benefit of ketoprofen is specifically attributable to its inhibition of the 5-lipoxygenase metabolite leukotriene B₄ (LTB₄). LTB₄ antagonism reversed edema, improved lymphatic function, and restored lymphatic architecture in the murine tail model of lymphedema. In vitro, LTB₄ was functionally bimodal: Lower LTB₄ concentrations promoted human lymphatic endothelial cell sprouting and growth, but higher concentrations inhibited lymphangiogenesis and induced apoptosis. During lymphedema progression, lymphatic fluid LTB₄ concentrations rose from initial prolymphangiogenic concentrations into an antilymphangiogenic range. LTB₄ biosynthesis was similarly elevated in lymphedema patients. Low concentrations of LTB₄ stimulated, whereas high concentrations of LTB₄ inhibited, vascular endothelial growth factor receptor 3 and Notch pathways in cultured human lymphatic endothelial cells. Lymphatic-specific Notch1^-/- mice were refractory to the beneficial effects of LTB₄ antagonism, suggesting that LTB₄ suppression of Notch signaling is an important mechanism in disease maintenance. In summary, we found that LTB₄ was harmful to lymphatic repair at the concentrations observed in established disease. Our findings suggest that LTB₄ is a promising drug target for the treatment of acquired lymphedema.