Group v phospholipase a2 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 en-zyme, group V phospholipase A2 (gVPLA2), as a mediator of lung endothelial barrier disruption and inflammation. The current study aimed to determine the role of gVPLA2 in mediating lung endothelial responses to methicillin‐resistant Staphylococcus aureus (MRSA, USA300 strain), a major cause of ALI/ARDS. In vitro studies assessed the effects of gVPLA2 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 gVPLA2‐defi-cient (KO) mice. In vitro, HK‐MRSA increased gVPLA2 expression and permeability in human lung EC. Inhibition of gVPLA2 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 gVPLA2‐KO mice. In vivo, live MRSA caused significantly less ALI in gVPLA2 KO mice compared to WT, findings confirmed by intravital microscopy assessment in HK‐MRSA‐treated mice. After targeted delivery of gVPLA2 plasmid to lung endothelium using ACE antibody‐conjugated liposomes, MRSA‐induced ALI was significantly increased in gVPLA2‐KO mice, indicating that lung endothelial expression of gVPLA2 is critical in vivo. In summary, these results demonstrate an important role for gVPLA2 in mediating MRSA‐induced lung EC permeability and ALI. Thus, gVPLA2 may represent a novel therapeutic target in ALI/ARDS caused by bacterial infection.