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Group V Phospholipase A 2 Mediates Endothelial Dysfunction and Acute Lung Injury Caused by Methicillin-Resistant Staphylococcus Aureus

Lung endothelial dysfunction is a key feature of acute lung injury (ALI) and clinical acute respiratory distress syndrome (ARDS). Previous studies have identified the lipid-generating enzyme, group V phospholipase A2 (gVPLA ), as a mediator of lung endothelial barrier disruption and inflammation. Th...

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Bibliographic Details
Published in:Cells (Basel, Switzerland) Switzerland), 2021-07, Vol.10 (7)
Main Authors: Htwe, Yu Maw, Wang, Huashan, Belvitch, Patrick, Meliton, Lucille, Bandela, Mounica, Letsiou, Eleftheria, Dudek, Steven M
Format: Article
Language:English
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Summary:Lung endothelial dysfunction is a key feature of acute lung injury (ALI) and clinical acute respiratory distress syndrome (ARDS). Previous studies have identified the lipid-generating enzyme, group V phospholipase A2 (gVPLA ), as a mediator of lung endothelial barrier disruption and inflammation. The current study aimed to determine the role of gVPLA in mediating lung endothelial responses to methicillin-resistant (MRSA, USA300 strain), a major cause of ALI/ARDS. In vitro studies assessed the effects of gVPLA inhibition on lung endothelial cell (EC) permeability after exposure to heat-killed (HK) MRSA. In vivo studies assessed the effects of intratracheal live or HK-MRSA on multiple indices of ALI in wild-type (WT) and gVPLA -deficient (KO) mice. In vitro, HK-MRSA increased gVPLA expression and permeability in human lung EC. Inhibition of gVPLA with either the PLA2 inhibitor, LY311727, or with a specific monoclonal antibody, attenuated the barrier disruption caused by HK-MRSA. LY311727 also reduced HK-MRSA-induced permeability in mouse lung EC isolated from WT but not gVPLA -KO mice. In vivo, live MRSA caused significantly less ALI in gVPLA KO mice compared to WT, findings confirmed by intravital microscopy assessment in HK-MRSA-treated mice. After targeted delivery of gVPLA plasmid to lung endothelium using ACE antibody-conjugated liposomes, MRSA-induced ALI was significantly increased in gVPLA -KO mice, indicating that lung endothelial expression of gVPLA is critical in vivo. In summary, these results demonstrate an important role for gVPLA in mediating MRSA-induced lung EC permeability and ALI. Thus, gVPLA may represent a novel therapeutic target in ALI/ARDS caused by bacterial infection.
ISSN:2073-4409