Leukotriene B 4 antagonism ameliorates experimental lymphedema

• Published in: Science translational medicine 2017-05, Vol.9 (389)
• Main Authors: Tian, Wen, Rockson, Stanley G, Jiang, Xinguo, Kim, Jeanna, Begaye, Adrian, Shuffle, Eric M, Tu, Allen B, Cribb, Matthew, Nepiyushchikh, Zhanna, Feroze, Abdullah H, Zamanian, Roham T, Dhillon, Gundeep S, Voelkel, Norbert F, Peters-Golden, Marc, Kitajewski, Jan, Dixon, J Brandon, Nicolls, Mark R
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents - therapeutic use; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Humans; Ketoprofen - therapeutic use; Leukotriene B4 - antagonists & inhibitors; Leukotriene B4 - metabolism; Lymphedema - drug therapy; Lymphedema - metabolism; Mice; Signal Transduction - drug effects
• ISSN: 1946-6234; 1946-6242
• DOI: 10.1126/scitranslmed.aal3920

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 B (LTB ). LTB antagonism reversed edema, improved lymphatic function, and restored lymphatic architecture in the murine tail model of lymphedema. In vitro, LTB was functionally bimodal: Lower LTB concentrations promoted human lymphatic endothelial cell sprouting and growth, but higher concentrations inhibited lymphangiogenesis and induced apoptosis. During lymphedema progression, lymphatic fluid LTB concentrations rose from initial prolymphangiogenic concentrations into an antilymphangiogenic range. LTB biosynthesis was similarly elevated in lymphedema patients. Low concentrations of LTB stimulated, whereas high concentrations of LTB inhibited, vascular endothelial growth factor receptor 3 and Notch pathways in cultured human lymphatic endothelial cells. Lymphatic-specific mice were refractory to the beneficial effects of LTB antagonism, suggesting that LTB suppression of Notch signaling is an important mechanism in disease maintenance. In summary, we found that LTB was harmful to lymphatic repair at the concentrations observed in established disease. Our findings suggest that LTB is a promising drug target for the treatment of acquired lymphedema.