# Control of lung permeability by oxidized phospholipids

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $574,522

## Abstract

Project Summary/Abstract
Control of lung permeability by oxidized phospholipids
Oxidative stress during pneumonia or septic lung injury generates a spectrum of bioactive oxidized lipids and
proteins. While terminal products of lipid peroxidation exhibit deleterious effects, other groups, such as
cyclopenthenone-containing products of phosphatidyl choline oxidation (OxPAPC) exhibited anti-inflammatory
and vasoprotective properties in experimental models of inflammation. We have previously described potent
effects of OxPAPC in preventing the lung injury and vascular barrier dysfunction. Products of phospholipid
oxidation are unstable and may convert to barrier disruptive fragmented phospholipids. To overcome this
problem, we developed and successfully tested a new class of synthetic phosholipase-resistant OxPAPC
analogs based on structure-function analysis of barrier protective OxPAPC products. Testing synthetic OxPL
compounds generated on our lab revealed that D-ring prostanoids not only showed barrier-protective and anti-
inflammatory effects, but also effectively attenuated inflammation-associated apoptosis/necroptosis of lung
vascular endothelium. In pilot studies, phospholipase resistant phospholipid containing D-ring prostanoid
(D2PC) showed strong protective effects in the in vitro and in vivo models of Staphylococcus aureus (SA)-
induced ALI. Pilot analysis of anti-inflammatory mechanisms triggered by D2PC revealed increased expression
of KLF2 and KLF4, the two transcription factors regulating anti-inflammatory defense in vascular endothelium.
Our pilot studies also suggest a link between D2PC-induced KLF2/4 upregulation and inhibition of
inflammation-induced expression of thioredoxin interacting protein (TXNIP) involved in activation of NLRP3
inflammasome. In addition, D2PC upregulated guanine nucleotide exchange factor Epac1. Besides the
documented role of Epac1-Rap1 GTPase signaling in the maintenance of lung EC barrier, our pilot studies
show that D2PC suppressed SA-induced EC apoptosis/necroptosis via Epac1-dependent inhibition of death
receptor 5 (DR5) within the caveolin enriched microdomains (CEM). The overall hypothesis of this study is that
synthetic phospholipid D2PC mitigates SA-induced ALI and promotes lung recovery by protecting lung barrier
function, attenuating inflammation and endothelial apoptosis via mechanisms that involve: a) KLF2/4-
dependent downregulation of TXNIP and inactivation of NLRP3 inflammasome; and b) Epac1-mediated
inhibition of DR5-dependent apoptotic/necroptotic signaling caused by SA. Aim-1 will investigate protective
effects of synthetic D2PC in cell and animal models of SA–induced injury and evaluate CEM-associated
receptors mediating D2PC effects. Aim-2 will study the anti-inflammatory mechanism of D2PC via KLF2/4-
dependent suppression of TXNIP/NLRP3 cascade. Aim-3 will investigate anti-apoptotic/necroptotic properties
of D2PC via Epac1-mediated inhibition of DR5 signaling. Characterization of a nove...

## Key facts

- **NIH application ID:** 10205138
- **Project number:** 5R01HL076259-15
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Konstantin Birukov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $574,522
- **Award type:** 5
- **Project period:** 2004-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10205138

## Citation

> US National Institutes of Health, RePORTER application 10205138, Control of lung permeability by oxidized phospholipids (5R01HL076259-15). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10205138. Licensed CC0.

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