title: Mechanical induction of group V phospholipase A(2) causes lung inflammation and acute lung injury.
abstract: Ventilation at high tidal volume may cause lung inflammation and barrier dysfunction that culminates in ventilator-induced lung injury (VILI). However, the mechanisms by which mechanical stimulation triggers the inflammatory response have not been fully elucidated. This study tested the hypothesis that onset of VILI is triggered by activation of secretory group V phospholipase A(2) (gVPLA2) in pulmonary vascular endothelium exposed to excessive mechanical stretch. High-magnitude cyclic stretch (18% CS) increased expression and surface exposure of gVPLA2 in human pulmonary endothelial cells (EC). CS-induced gVPLA2 activation was required for activation of ICAM-1 expression and polymorphonuclear neutrophil (PMN) adhesion to CS-preconditioned EC. By contrast, physiological CS (5% CS) had no effect on gVPLA2 activation or EC-PMN adhesion. CS-induced ICAM-1 expression and EC-PMN adhesion were attenuated by the gVPLA2-blocking antibody (MCL-3G1), general inhibitor of soluble PLA2, LY311727, or siRNA-induced EC gVPLA2 knockdown. In vivo, ventilator-induced lung leukocyte recruitment, cell and protein accumulation in the alveolar space, and total lung myeloperoxidase activity were strongly suppressed in gVPLA2 mouse knockout model or upon administration of MCL-3G1. These results demonstrate a novel role for gVPLA2 as the downstream effector of pathological mechanical stretch leading to an inflammatory response associated with VILI.
authors.affiliation: Section of Pulmonary and Critical Medicine, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Angelo Y
authors.initials: AY
authors.lastname: Meliton
authors.forename: Nilda M
authors.initials: NM
authors.lastname: Muñoz
authors.forename: Lucille N
authors.initials: LN
authors.lastname: Meliton
authors.forename: Anna A
authors.initials: AA
authors.lastname: Birukova
authors.forename: Alan R
authors.initials: AR
authors.lastname: Leff
authors.forename: Konstantin G
authors.initials: KG
authors.lastname: Birukov
mesh_terms: D055371:Acute Lung Injury / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D004790:Enzyme Induction; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007962:Leukocytes / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D054467:Phospholipases A2 / Q000096:biosynthesis*; D011014:Pneumonia / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D013314:Stress, Mechanical; D013990:Tidal Volume / Q000502:physiology; D055397:Ventilator-Induced Lung Injury / Q000201:enzymology / Q000378:metabolism / Q000473:pathology
chemical_list: D018799:Intercellular Adhesion Molecule-1; D054467:Phospholipases A2
keywords: acute lung injury; cyclic stretch; endothelial cells; group V soluble phospholipase A2 inflammation; neutrophil adhesion