# Modulation of Lymphatic System Function by LTB4

> **NIH NIH F31** · GEORGIA INSTITUTE OF TECHNOLOGY · 2020 · $45,520

## Abstract

Project Abstract
 Lymphedema is a devastating disease that predominantly affects breast cancer patients post-surgery,
leading to swelling at the extremities, tissue fibrosis, and general discomfort. There are currently no
pharmacological treatments available for lymphedema. However, LTB4, a metabolite of arachidonic acid, has
been implicated in the development of lymphedema and identified as a possible drug target. The objective of
this study is to determine if LTB4 drives lymphatic collecting vessel failure and identify the direct mechanism of
action for LTB4 on lymphatic collecting vessels. The hypothesis is that LTB4 inhibits lymphatic collecting vessel
contraction at high concentrations occurring post-injury, leading to lymphatic insufficiency and the extreme
swelling found in lymphedema. We predict that this functional effect of LTB4 occurs through two mechanisms;
LTB4 directly acts on lymphatic collecting vessels to inhibit pumping, and LTB4 drives macrophage recruitment
to the site of injury, further amplifying disease progression through secretion of VEGFC and iNOS, known
effectors of lymphatic function.
 To test how LTB4 concentration affects lymphatic collecting vessel function, we will first use an isolated
vessel setup to test the direct effect of varying concentrations of LTB4 on lymphatic vessel tone and contractility.
We will also determine if the effect of LTB4 on lymphatic vessel contractility is mediated by its receptors, BLT1
and/or BLT2. Next, an LTB4 antagonist called bestatin will be used in conjunction with a single vessel ligation
lymphedema model in mice to study how LTB4 affects collecting vessel function during disease progression. In
the single vessel ligation model, the dominant collecting vessel and the surrounding initial lymphatics will be
cauterized while one collecting vessel will be left intact. By using NIR imaging techniques to measure contractile
function in this collecting vessel after surgery, the effect of LTB4 antagonism on contractile function during
disease progression can be determined. This surgical model will be tested in a genetic macrophage depletion
mouse model to examine if there is a macrophage-mediated effect of LTB4 on collecting vessel pump function
during lymphedema development. VEGFC secretion and iNOS expression by macrophages will be quantified in
the context of LTB4 antagonism to determine the mechanism by which macrophages modulate lymphatic
function. The results of this study will help elucidate the role of LTB4 in the development of lymphedema,
characterize its direct effect on lymphatic system function, and identify multiple mechanisms by which LTB4
drives lymphatic collecting vessel pump failure. These results will be an important step towards a better
understanding of lymphedema progression and will inform the use of pharmacotherapeutic treatments for
lymphedema targeting LTB4 and its metabolism. The research training will take place at the Georgia Institute of
Technology, a world-...

## Key facts

- **NIH application ID:** 9996322
- **Project number:** 5F31HL145984-02
- **Recipient organization:** GEORGIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Matthew Cribb
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2019-07-22 → 2021-12-21

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9996322

## Citation

> US National Institutes of Health, RePORTER application 9996322, Modulation of Lymphatic System Function by LTB4 (5F31HL145984-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9996322. Licensed CC0.

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