# A Critical Role for Leukotriene B4 in Lymphedema

> **NIH NIH R01** · PALO ALTO VETERANS INSTIT FOR RESEARCH · 2021 · $559,566

## Abstract

PROJECT SUMMARY / ABSTRACT
Lymphedema is a chronic and debilitating condition currently without approved medical therapies. Recent
investigations suggest a central role for inflammation in this disease. We discovered that leukotriene B4 (LTB4),
a critical lipid mediator of inflammation, promotes lymphatic endothelial cell (LEC) sprouting and growth at low
concentrations (10nM), and causes LEC injury at high concentrations (200nM) by differentially affecting two
essential lymphatic survival pathways, VEGFR3 and Notch. During pre-clinical lymphedema progression,
lymphatic fluid LTB4 concentrations rise from initial pro-lymphangiogenic concentrations, into an anti-
lymphangiogenic range which may induce pathology. Anti-LTB4 therapy reverses pre-clinical lymphedema.
This finding is the scientific basis for a Phase 2 clinical trial (ULTRA), which is currently testing the efficacy of
LTB4-targeted therapy for lymphedema. New results from a separate proof-of-concept clinical trial are positive,
making this the first effective medicinal therapy for this condition. Even though anti-LTB4 therapy may be
helpful for lymphedema, it is likely not curative, and more information is needed to understand how
inflammatory pathways promote disease. Studies proposed in the grant are designed to address fundamental
mechanistic questions about how LTB4 damages lymphatic capillaries and promotes a proinflammatory
microenvironment. Our global hypothesis is that after lymphatic injury, increased LTB4 exacerbates
lymphedema by inhibiting key lymphatic growth pathways, interfering with the (blood) microvascular circulation,
transforming LECs and redirecting the immune microenvironment.
To address these issues, this proposal is divided into three Specific Aims as follows. Aim 1 is to study the
mechanisms by which LTB4 alters pro-lymphangiogenic signaling pathways, causes blood vascular remodeling
and changes LEC cellular identity. Aim 2 will investigate how LTB4 impacts the immune microenvironment in
lymphedema by influencing the activation and phenotype of proinflammatory dendritic cells and T lymphocytes
and by changing lymphatic immunoregulatory functions. Finally, Aim 3 will use omic technologies to evaluate
clinical lymphedema samples collected by the ULTRA trial to assess the genetic networks built around LTB4
biology in lymphedema.
The goals of these studies are to understand the molecular mechanisms of reparative lymphangiogenesis, the
plasticity of LEC identify and the dynamics of immune regulation in lymphedema. By carefully assessing the
immune microenvironment and the global transcriptome in lymphedema, it should be possible to evolve better
drug therapies for this pervasive and, otherwise, unremitting condition.

## Key facts

- **NIH application ID:** 10072073
- **Project number:** 5R01HL141105-03
- **Recipient organization:** PALO ALTO VETERANS INSTIT FOR RESEARCH
- **Principal Investigator:** Mark Robert Nicolls
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $559,566
- **Award type:** 5
- **Project period:** 2019-01-21 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10072073

## Citation

> US National Institutes of Health, RePORTER application 10072073, A Critical Role for Leukotriene B4 in Lymphedema (5R01HL141105-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10072073. Licensed CC0.

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