title: PPARα mediates the anti-inflammatory effect of simvastatin in an experimental model of zymosan-induced multiple organ failure.
abstract: OBJECTIVE
  Zymosan-induced non-septic shock is a multi-factorial pathology that involves several organs including the kidneys, liver and lungs. Its complexity and diversity presents a continuing therapeutic challenge. Given their pleiotropic effect, statins could be beneficial in non-septic shock. One of the molecular mechanisms underlying the anti-inflammatory effect of statins involves the peroxisome proliferator-activated receptor (PPAR) α. We used a zymosan-induced non-septic shock experimental model to investigate the role of PPARα in the anti-inflammatory effects of simvastatin.
  
  
  METHODS
  Effects of simvastatin (5 or 10 mg·kg(-1) i.p.) were analysed in PPARα knock-out (KO) and PPARα wild type (WT) mice after zymosan or vehicle administration. Organ injury in lung, liver, kidney and intestine was evaluated by immunohistology. PPARα mRNA expression and nuclear factor-κB activation were evaluated in all experimental groups, 18 h after study onset. Cytokine levels were measured in plasma, and nitrite/nitrate in plasma and peritoneal exudate. Nitric oxide synthase, nitrotyrosine and poly ADP-ribose were localized by immunohistochemical methods.
  
  
  RESULTS
  Simvastatin significantly and dose-dependently increased the zymosan-induced expression of PPARα levels in all tissues analysed. It also dose-dependently reduced systemic inflammation and the organ injury induced by zymosan in lung, liver, intestine and kidney. These effects were observed in PPARαWT mice and in PPARαKO mice.
  
  
  CONCLUSIONS
  Simvastatin protected against the molecular and cellular damage caused by systemic inflammation in our experimental model. Our results also provide new information regarding the role of PPARα in the anti-inflammatory effects of statins.
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology 'L.Donatelli', Excellence Centre for Cardiovascular Diseases, Second University of Naples, Italy. barbara.rinaldi@unina2.it
authors.forename: Barbara
authors.initials: B
authors.lastname: Rinaldi
authors.forename: Maria
authors.initials: M
authors.lastname: Donniacuo
authors.forename: Emanuela
authors.initials: E
authors.lastname: Esposito
authors.forename: Annalisa
authors.initials: A
authors.lastname: Capuano
authors.forename: Loredana
authors.initials: L
authors.lastname: Sodano
authors.forename: Emanuela
authors.initials: E
authors.lastname: Mazzon
authors.forename: Donatella
authors.initials: D
authors.lastname: Di Palma
authors.forename: Irene
authors.initials: I
authors.lastname: Paterniti
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
authors.forename: Francesco
authors.initials: F
authors.lastname: Rossi
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000473:pathology; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009102:Multiple Organ Failure / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D047493:PPAR alpha / Q000235:genetics / Q000502:physiology*; D012769:Shock / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D015054:Zymosan
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D053583:Interleukin-1beta; D016328:NF-kappa B; D047493:PPAR alpha; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D015054:Zymosan; D019821:Simvastatin; D052247:Nitric Oxide Synthase Type II