# Modulation of Lymphatic System Function by LTB4

> **NIH NIH F31** · GEORGIA INSTITUTE OF TECHNOLOGY · 2021 · $17,536

## 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-class
research in...

## Key facts

- **NIH application ID:** 10435118
- **Project number:** 3F31HL145984-02S1
- **Recipient organization:** GEORGIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Matthew Cribb
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $17,536
- **Award type:** 3
- **Project period:** 2019-07-22 → 2021-12-21

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10435118

## Citation

> US National Institutes of Health, RePORTER application 10435118, Modulation of Lymphatic System Function by LTB4 (3F31HL145984-02S1). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10435118. Licensed CC0.

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