# Glutathionylated Products of Radical-Induced Lipid Oxidation in Inflammatory Disease

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $394,272

## Abstract

Limited knowledge of the structures and biological activities of products generated by free
radical-induced lipid oxidation in the retina is a barrier to progress in the development of clinically
useful new disease markers and mechanistically informed therapeutic interventions. Understand-
ing cellular responses to free radical-induced lipid oxidation products is complex owing to their
diversity and ability to mimic enzymatically generated receptor agonists. Their unrecognized
generation and biological activities almost certainly contribute to the mediocre efficacy of currently
available therapeutic measures for age related macular degeneration (AMD). We discovered
glutathione (GSH) derivatives produced from oxidatively truncated arachidonyl phospholipids that
are structural and functional analogues of cysteinyl (Cys) leukotrienes (LTs). We refer to them as
pseudo (ø)LTs. We will test the hypotheses that øLTs contribute to retinal pathology and
physiology in a rat model of light-induced retinal degeneration. Pilot studies show that øLTs are
present in human retina, are produced in vivo consequent to oxidative insult, and exhibit LT-like
biological activities. Therefore, øLTs can elicit cellular responses erroneously presumed to be
induced exclusively by CysLTs. Consequently, they are a confounding factor for interpreting
previous studies on the involvements of LTs in retinal pathology and physiology. The proposed
research will test the hypotheses that øLTs and related GSH derivatives of oxidatively truncated
docosahexaenoyl phospholipids contribute to receptor-dependent inflammatory cytokine signal-
ing, retinal edema, pathological neovascularization, or physiologically important initiation of retinal
pigment epithelium (RPE) autophagy. The potential pathophysiological significance of these
glutathionylated products of lipid oxidation lies in the possibility of their ubiquitous generation in
high levels, e.g., compared to those of CysLTs. We will test the conclusion of preliminary studies
that øLTs are LT receptor agonists and determine if their ability to induce the expression of IL-13
and TGF-b1 promotes LT biosynthesis. Because cross reactivity may confound the interpretation
of immunoassays, we quantitate øLTs and LTs by LC-MS/MS. We will determine signaling path-
ways, e.g., with RNA-Seq studies, activated by glutathionylated products of free radical-induced
lipid oxidation addressing the questions: do they promote inflammation in ocular pathology
or initiate autophagy in RPE cells and how do they do it? Molecular level insights into the role
of oxidative stress in the pathogenesis of inflammatory eye diseases such as AMD can facilitate
development of therapeutic interventions that ameliorate the progression of these common but
disabling diseases.

## Key facts

- **NIH application ID:** 10899606
- **Project number:** 5R01EY034075-02
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Robert Gerd Salomon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $394,272
- **Award type:** 5
- **Project period:** 2023-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10899606

## Citation

> US National Institutes of Health, RePORTER application 10899606, Glutathionylated Products of Radical-Induced Lipid Oxidation in Inflammatory Disease (5R01EY034075-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10899606. Licensed CC0.

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