# Group V Phospholipase A2 Mediates Acute Lung Injury

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2020 · $399,750

## Abstract

PROJECT SUMMARY
The Acute Lung Injury/Acute Respiratory Distress Syndrome (ALI/ARDS) is a devastating cause of acute
respiratory failure and results in significant morbidity and mortality in critically ill patients. In this proposal we
test the hypothesis that pulmonary endothelial cell (EC) barrier dysfunction in ALI is regulated by the
group V phospholipase A2 (gVPLA2). Lung EC dysfunction induced by disease-related stimuli is a critical
step in ALI. We previously have identified direct effects of gVPLA2 on lung EC as evidenced by disruption of
the EC barrier in vitro. We and others also have demonstrated that gVPLA2 is an important regulator of ALI in
vivo that mediates preclinical models in mice, including endotoxin (LPS)- and high tidal volume mechanical
ventilation-induced lung injury (VILI). In the current proposal, our novel preliminary data suggest that ALI-
relevant stimuli (LPS, mechanical cycle stretch (CS), and pathologic live bacteria (MRSA)) increase expression
of the PLA2G5 gene to upregulate gVPLA2 levels in lung EC to mediate EC dysfunction. Therefore, we
speculate that gVPLA2 represents a promising therapeutic target for ALI/ARDS. To further characterize the
critical role of EC gVPLA2 in ALI, integrated approaches across multiple scientific disciplines will be used to
determine the pathobiological function of gVPLA2 in ALI induced by a highly clinically relevant bacterial
stimulus—MRSA. SA#1 will determine the mechanisms by which gVPLA2 expression is regulated in
pulmonary endothelium in vitro. Regulation of promoter expression for the PLA2G5 gene that encodes
gVPLA2 will be determined in lung EC in response to MRSA, including characterization of the effects of
disease-associated single nucleotide polymorphisms (SNPs) in the PLA2G5 promoter. Similar studies will
determine the epigenetic regulation of expression of the 3’UTR for PLA2G5 by miRNA and SNPs. SA#2 will
determine the mechanisms by which gVPLA2 affects pulmonary EC function in vitro. The functional role
of gVPLA2 on MRSA-induced lung EC permeability will be extensively characterized using multiple
complementary measures of barrier function in vitro, as well as its role in MRSA-induced cytokine production
and epigenetic changes. The novel regulation of gVPLA2 expression and function by autophagy will be
described. SA#3 will explore the therapeutic potential of gVPLA2 inhibition in acute lung injury induced
by MRSA in mice. Studies utilizing gVPLA2 knockout mice, mAb directed against gVPLA2, and pharmacologic
inhibition (pre- and post- injury) of gVPLA2 will determine the functional significance of this enzyme in MRSA-
induced ALI and the potential therapeutic applications in humans. The contribution of EC-derived gVPLA2 will
be determined using a targeted liposomal delivery method to modulate lung EC expression of gVPLA2. Novel
epigenetic effects of MRSA will be characterized. Data derived from these proposed studies will elucidate the
role of gVPLA2 as a critical media...

## Key facts

- **NIH application ID:** 9944665
- **Project number:** 5R01HL133059-04
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** STEVEN M DUDEK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $399,750
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9944665

## Citation

> US National Institutes of Health, RePORTER application 9944665, Group V Phospholipase A2 Mediates Acute Lung Injury (5R01HL133059-04). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9944665. Licensed CC0.

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