The DOI matches its Crossref record; 65 of the 65 references it cites were found in a registry or an index.
Leukotriene B 4 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 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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“The nonsteroidal anti-inflammatory drug ketoprofen (148) and the leukotriene B4 (LTB4) inhibitor bestatin (44) showed promise in their respective mouse studies, but neither clinical trial produced limb volume reduction in lymphedema patients (trial identifiers NCT02257970, NCT02700529).”
From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [44]
Citations
Cites
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Self-citationBlockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis
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Neutrophil swarms require LTB4 and integrins at sites of cell death in vivo
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The Lymphatic Vasculature in the 21st Century: Novel Functional Roles in Homeostasis and Disease
Oliver, G. C., Kipnis, J., Randolph, G. J., & Harvey, N. L. (2020) · Cell · doi:10.1016/j.cell.2020.06.039 · Cited by 701
Lymphatic Vessel Network Structure and Physiology
Breslin, J. W., Yang, Y., Scallan, J. P., Sweat, R. S., Adderley, S., & Murfee, W. L. (2018) · Comprehensive physiology · doi:10.1002/cphy.c180015 · Cited by 420
Cancer-associated secondary lymphoedema
Rockson, S. G., Keeley, V. L., Kilbreath, S. L., Szuba, A., & Towers, A. (2019) · Nature Reviews Disease Primers · doi:10.1038/s41572-019-0072-5 · Cited by 230
Self-citationSurgical Treatment of Lymphedema
Schaverien, M. V., & Coroneos, C. J. (2019) · Plastic & Reconstructive Surgery · doi:10.1097/prs.0000000000005993 · Cited by 208
The Unresolved Pathophysiology of Lymphedema
Azhar, S. H., Lim, H. Y., Tan, B., & Angeli, V. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00137 · Cited by 186
Metadata
- 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
- Venue
- Science Translational Medicine
- Published
- 2017-05-10
- Volume
- 9
- Issue
- 389
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- 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
- 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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