title: Age-dependent therapeutic effects of liver X receptor-α activation in murine polymicrobial sepsis.
abstract: The severity of sepsis is significantly affected by advanced age; however, age-dependent molecular mechanisms of this susceptibility are unknown. Nuclear liver X receptor-α (LXRα) is a regulator of lipid metabolism with associated anti-inflammatory properties. Here, we investigated the role of LXRα in age-dependent lung injury and outcome of sepsis. Male C57BL/6, LXRα-deficient (LXRα(-/-)) and wild type (WT) (LXRα(+/+)) mice of different ages were subjected to sepsis by cecal ligation and puncture (CLP). In pharmacological studies, treatment with the LXRα ligand T0901317 reduced lung neutrophil infiltration in C57BL/6 mice aged from 1 to 8 mo when compared with vehicle-treated animals subjected to CLP. The LXRα ligand improved survival in young mice (2-3 mo old) but did not affect survival or neutrophil infiltration in mature adult mice (11-13 mo old). Immunoblotting revealed an age-dependent decrease of lung LXRα levels. Young LXRα(-/-) mice (2-3 mo old) exhibited earlier mortality than age-matched WT mice after CLP. Lung damage and neutrophil infiltration, lung activation of the pro-inflammatory NF-κB and plasma IL-6 levels were higher in LXRα(-/-) mice 18 h after CLP compared with LXRα(+/+) mice. This study suggests that the anti-inflammatory properties of LXRα in sepsis are age-dependent and severely compromised in mature adult animals.
authors.affiliation: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Botez
authors.affiliation: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Piraino
authors.affiliation: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Hake
authors.affiliation: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Ledford
authors.affiliation: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: O'Connor
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Cook
authors.affiliation: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA basilia.zingarelli@cchmc.org.
authors.forename: Basilia
authors.initials: B
authors.lastname: Zingarelli
mesh_terms: D000367:Age Factors; D000818:Animals; D002432:Cecum / Q000601:surgery; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000008:administration & dosage; D015850:Interleukin-6 / Q000097:blood; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D018805:Sepsis / Q000276:immunology*; D013449:Sulfonamides / Q000008:administration & dosage; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D006845:Hydrocarbons, Fluorinated; D015850:Interleukin-6; D000071518:Liver X Receptors; D016328:NF-kappa B; D057093:Orphan Nuclear Receptors; D013449:Sulfonamides; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
keywords: Liver X receptor-α; NF-κB; T0901317; age; lung injury; neutrophil infiltration; sepsis