title: Oxidized phospholipids protect against lung injury and endothelial barrier dysfunction caused by heat-inactivated Staphylococcus aureus.
abstract: Increased endothelial cell (EC) permeability and vascular inflammation along with alveolar epithelial damage are key features of acute lung injury (ALI). Products of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine oxidation (OxPAPC) showed protective effects against inflammatory signaling and vascular EC barrier dysfunction induced by gram-negative bacterial wall lipopolysaccharide (LPS). We explored the more general protective effects of OxPAPC and investigated whether delayed posttreatment with OxPAPC boosts the recovery of lung inflammatory injury and EC barrier dysfunction triggered by intratracheal injection of heat-killed gram-positive Staphylococcus aureus (HKSA) bacteria. HKSA-induced pulmonary EC permeability, activation of p38 MAP kinase and NF-κB inflammatory cascades, secretion of IL-8 and soluble ICAM1, fibronectin deposition, and expression of adhesion molecules ICAM1 and VCAM1 by activated EC were significantly attenuated by cotreatment as well as posttreatment with OxPAPC up to 16 h after HKSA addition. Remarkably, posttreatment with OxPAPC up to 24 h post-HKSA challenge dramatically accelerated lung recovery by restoring lung barrier properties monitored by Evans blue extravasation and protein content in bronchoalveolar lavage (BAL) fluid and reducing inflammation reflected by decreased MIP-1, KC, TNF-α, IL-13 levels and neutrophil count in BAL samples. These studies demonstrate potent in vivo and in vitro protective effects of posttreatment with anti-inflammatory oxidized phospholipids in the model of ALI caused by HKSA. These results warrant further investigations into the potential use of OxPAPC compounds combined with antibiotic therapies as a treatment of sepsis and ALI induced by gram-positive bacterial pathogens.
authors.affiliation: Section of Pulmonary and Critical Care and Lung Injury Center, Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Angelo Y
authors.initials: AY
authors.lastname: Meliton
authors.affiliation: Section of Pulmonary and Critical Care and Lung Injury Center, Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Fanyong
authors.initials: F
authors.lastname: Meng
authors.affiliation: Section of Pulmonary and Critical Care and Lung Injury Center, Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Section of Pulmonary and Critical Care and Lung Injury Center, Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Nicolene
authors.initials: N
authors.lastname: Sarich
authors.affiliation: Section of Pulmonary and Critical Care and Lung Injury Center, Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Gokhan M
authors.initials: GM
authors.lastname: Mutlu
authors.affiliation: Section of Pulmonary and Critical Care and Lung Injury Center, Department of Medicine, University of Chicago, Chicago, Illinois kbirukov@medicine.bsd.uchicago.edu.
authors.forename: Anna A
authors.initials: AA
authors.lastname: Birukova
authors.affiliation: Section of Pulmonary and Critical Care and Lung Injury Center, Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Konstantin G
authors.initials: KG
authors.lastname: Birukov
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D018893:Bronchoalveolar Lavage; D002199:Capillary Permeability / Q000187:drug effects*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D006358:Hot Temperature; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008297:Male; D051379:Mice; D010084:Oxidation-Reduction; D010713:Phosphatidylcholines / Q000378:metabolism / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000737:chemistry*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016207:Cytokines; C573420:ICAM1 protein, human; C090509:Icam1 protein, mouse; D010713:Phosphatidylcholines; D019010:Vascular Cell Adhesion Molecule-1; C472349:oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine; D018799:Intercellular Adhesion Molecule-1; D048051:p38 Mitogen-Activated Protein Kinases
keywords: cytoskeleton; inflammation; oxidized phospholipids; pulmonary endothelium; vascular leak