title: Endothelial cell peroxisome proliferator-activated receptor γ reduces endotoxemic pulmonary inflammation and injury.
abstract: Bacterial endotoxin (LPS)-mediated sepsis involves severe, dysregulated inflammation that injures the lungs and other organs, often fatally. Vascular endothelial cells are both key mediators and targets of LPS-induced inflammatory responses. The nuclear hormone receptor peroxisome proliferator-activated receptor γ (PPARγ) exerts anti-inflammatory actions in various cells, but it is unknown whether it modulates inflammation through actions within endothelial cells. To determine whether PPARγ acts within endothelial cells to diminish endotoxemic lung inflammation and injury, we measured inflammatory responses and mediators in mice with endothelial-targeted deletion of PPARγ. Endothelial cell PPARγ (ePPARγ) knockout exacerbated LPS-induced pulmonary inflammation and injury as shown by several measures, including infiltration of inflammatory cells, edema, and production of reactive oxygen species and proinflammatory cytokines, along with upregulation of the LPS receptor TLR4 in lung tissue and increased activation of its downstream signaling pathways. In isolated LPS-stimulated endothelial cells in vitro, absence of PPARγ enhanced the production of numerous inflammatory markers. We hypothesized that the observed in vivo activity of the ligand-activated ePPARγ may arise, in part, from nitrated fatty acids (NFAs), a novel class of endogenous PPARγ ligands. Supporting this idea, we found that treating isolated endothelial cells with physiologically relevant concentrations of the endogenous NFA 10-nitro-oleate reduced LPS-induced expression of a wide range of inflammatory markers in the presence of PPARγ, but not in its absence, and also inhibited neutrophil mobility in a PPARγ-dependent manner. Our results demonstrate a key protective role of ePPARγ against endotoxemic injury and a potential ePPARγ-mediated anti-inflammatory role for NFAs.
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Emory University and Atlanta Veterans Affairs Medical Center, Decatur, GA 30033, USA.
authors.forename: Aravind T
authors.initials: AT
authors.lastname: Reddy
authors.forename: Sowmya P
authors.initials: SP
authors.lastname: Lakshmi
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Kleinhenz
authors.forename: Roy L
authors.initials: RL
authors.lastname: Sutliff
authors.forename: C Michael
authors.initials: CM
authors.lastname: Hart
authors.forename: Raju C
authors.initials: RC
authors.lastname: Reddy
mesh_terms: D000818:Animals; D054426:Chemokine CXCL2 / Q000096:biosynthesis / Q000276:immunology; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology; D019446:Endotoxemia / Q000139:chemically induced / Q000150:complications / Q000276:immunology* / Q000378:metabolism; D005227:Fatty Acids / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D007274:Injections, Intraperitoneal; D015850:Interleukin-6 / Q000096:biosynthesis / Q000276:immunology; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008168:Lung; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D009574:Nitro Compounds / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D011014:Pneumonia / Q000139:chemically induced / Q000150:complications / Q000276:immunology* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology
chemical_list: D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D005227:Fatty Acids; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009574:Nitro Compounds; D047495:PPAR gamma; D017382:Reactive Oxygen Species; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha