# Chlorinated lipids in sepsis

> **NIH NIH R01** · SAINT LOUIS UNIVERSITY · 2020 · $321,934

## Abstract

Sepsis!is a major cause of morbidity and mortality in both adults and children with >1.6 million cases per year
in the United States. Neutrophils are key early responders to infection. Neutrophils eliminate microbes by
phagocytosis and by oxidant-mediated killing. Neutrophil myeloperoxidase (MPO) produces the potent oxidant,
hypochlorous acid (HOCl), which reacts with both microbial and host molecular targets including lipids. PI Dr.
David Ford has shown HOCl targets the vinyl ether bond of plasmalogen lipids, resulting in the production of 2-
chlorofatty aldehyde (2-ClFALD) and other chlorolipids, including 2-chlorofatty acid (2-ClFA), in response to
leukocyte activation. This led our multi-PI team during the previous grant interval to determine chlorolipids elicit
endothelial activation leading to leukocyte and platelet adherence, and to demonstrate chlorolipids associate
with ARDS and 30-day mortality in human sepsis. To further investigate the role of chlorolipids in sepsis
pathophysiology, our multi-PI group has accrued new preliminary data showing that: 1) inhibitors of TLR4,
CD36 and glutathione S-transferase (GST) decrease 2-ClFA-elicited endothelial dysfunction; 2) the TLR4
inhibitor, TAK-242, reduces 2-ClFA-elicited and cecal ligation and puncture (CLP) sepsis-elicited mesenteric
microcirculatory dysfunction using in vivo intravital microscopy; 3) 2-ClFA modifies specific endothelial cell
proteins, which may represent a new paradigm to target for intervention of 2-ClFA-caused endothelial
activation; 4) chlorolipids cause gut epithelial barrier leakiness, including in vivo gut bacterial translocation; 5)
plasma levels of ω-oxidation products of 2-ClFA, 2-chlorodicarboxylic acids (2-ClDCAs), measured on
admission to the intensive care unit (ICU) with sepsis are elevated in patients that develop acute kidney injury
(AKI); and 6) 2-ClDCA causes endothelial cell dysfunction. The role of chlorolipids in sepsis is expanding, and
these preliminary data indicate there are knowledge gaps that need to be addressed in the proposed studies,
which will test our overall hypothesis that chlorolipids produced by activated neutrophils during sepsis
are mediators of severe endothelial dysfunction resulting in multiple organ failure. There are three
specific aims. Specific Aim 1 will test the hypothesis that chlorolipid-mediated dysfunction in human endo-
thelial and epithelial cells can be pharmacologically targeted. Specific Aim 2 will test the hypothesis that in
vivo chlorolipid- and sepsis-elicited microcirculatory dysfunction and gut barrier dysfunction can be
pharmacologically inhibited. Specific Aim 3 will test the hypothesis that plasma 2-ClDCA levels associate with
specific organ dysfunctions and death in human sepsis. Overall, a multi-disciplinary approach with our multi-PI
team and Co-Is will examine chlorolipids produced by activated neutrophils during sepsis as critical mediators
of microcirculatory dysfunction leading to organ failure, and te...

## Key facts

- **NIH application ID:** 9994953
- **Project number:** 5R01GM115553-06
- **Recipient organization:** SAINT LOUIS UNIVERSITY
- **Principal Investigator:** DAVID A. FORD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $321,934
- **Award type:** 5
- **Project period:** 2015-09-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9994953

## Citation

> US National Institutes of Health, RePORTER application 9994953, Chlorinated lipids in sepsis (5R01GM115553-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9994953. Licensed CC0.

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