Cited by 173Lymphatic System and DiseasesParasitic Diseases Research and TreatmentInflammatory mediators and NSAID effects

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Leukotriene B 4 antagonism ameliorates experimental lymphedema

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.·2017·Science Translational Medicine

DOI 10.1126/scitranslmed.aal3920

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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 B 4 (LTB 4 ). LTB 4 antagonism reversed edema, improved lymphatic function, and restored lymphatic architecture in the murine tail model of lymphedema. In vitro, LTB 4 was functionally bimodal: Lower LTB 4 concentrations promoted human lymphatic endothelial cell sprouting and growth, but higher concentrations inhibited lymphangiogenesis and induced apoptosis. During lymphedema progression, lymphatic fluid LTB 4 concentrations rose from initial prolymphangiogenic concentrations into an antilymphangiogenic range. LTB 4 biosynthesis was similarly elevated in lymphedema patients. Low concentrations of LTB 4 stimulated, whereas high concentrations of LTB 4 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 LTB 4 antagonism, suggesting that LTB 4 suppression of Notch signaling is an important mechanism in disease maintenance. In summary, we found that LTB 4 was harmful to lymphatic…

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Authors: Tian, W., Rockson, S. G., Jiang, X., Kim, J., Begaye, A., Shuffle, E. M., Tu, A. B., Cribb, M., Nepiyushchikh, Z., Feroze, A. H., Zamanian, R. T., Dhillon, G. S., Voelkel, N. F., Peters-Golden, M., Kitajewski, J., Dixon, J. B., & Nicolls, M. R.
Affiliations: VA Palo Alto Health Care System (US)
Stanford Medicine (US)
Georgia Institute of Technology (US)
Virginia Commonwealth University (US)
University of Michigan (US)
University of Illinois Chicago (US)
Corresponding author: Tian, Wen
Rockson, Stanley G.
Jiang, Xinguo
Kim, Jeanna
Nicolls, Mark R.
ORCID: Tian, Wen
Rockson, Stanley G.
Jiang, Xinguo
Kim, Jeanna
Shuffle, Eric M.
Tu, Allen B.
Cribb, Matthew
Nepiyushchikh, Zhanna
Feroze, Abdullah H.
Zamanian, Roham T.
Dhillon, Gundeep S.
Peters-Golden, Marc
Kitajewski, Jan
Dixon, J. Brandon
Nicolls, Mark R.
Venue: Science Translational Medicine
Publisher: American Association for the Advancement of Science (AAAS)
Published: 2017-05-10
Volume: 9
Issue: 389
ISSN: 1946-6234 (ISSN-L)
1946-6242
DOI: 10.1126/scitranslmed.aal3920
OpenAlex: W2613046528
Cited by: 173
References: 65
Citations by year: 2026: 17 · 2025: 8 · 2024: 16 · 2023: 17 · 2022: 22 · 2021: 24 · 2020: 22 · 2019: 24 · 2018: 17 · 2017: 6
FWCI: 8.44
Type: journal article
Language: en
Open access: closed
Licence: www.sciencemag.org/about/science-licenses-journal-article-reuse (vor, 365 d)
Locations: Science Translational Medicine (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (award295625)
Topics: Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
Health Sciences › Medicine › Infectious Diseases › Parasitic Diseases Research and Treatment
Health Sciences › Medicine › Pharmacology (medical) › Inflammatory mediators and NSAID effects
Keywords: leukotriene B4, leukotriene receptor antagonism, lymphedema, pathogenesis, therapeutic target
MeSH terms: Animals, Anti-Inflammatory Agents, Humans, Ketoprofen, Leukotriene B4, Lymphedema, Signal Transduction, Endothelial Cells, Mice

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Leukotriene B 4 antagonism ameliorates experimental lymphedema

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