title: Flavocoxid, a dual inhibitor of COX-2 and 5-LOX of natural origin, attenuates the inflammatory response and protects mice from sepsis.
abstract: BACKGROUND
  Cecal ligation and puncture (CLP) is an inflammatory condition that leads to multisystemic organ failure. Flavocoxid, a dual inhibitor of cyclooxygenase (COX-2) and 5-lipoxygenase (5-LOX), has been shown in vitro to possess antiinflammatory activity in lipopolysaccharide (LPS)-stimulated rat macrophages by reducing nuclear factor (NF)-κB activity and COX-2, 5-LOX and inducible nitric oxide synthase (iNOS) expression. The aim of this study was to evaluate the effects of flavocoxid in a murine model of CLP-induced polymicrobial sepsis.
  
  
  METHODS
  C57BL/6J mice were subjected to CLP or sham operation. In a first set of experiments, an intraperitoneal injection of flavocoxid (20 mg/kg) or vehicle was administered 1 hour after surgery and repeated every 12 hours. Survival rate was monitored every 24 hours throughout 120 hours. Furthermore, additional groups of sham and CLP mice were killed 18 hours after surgical procedures for blood-sample collection and the lung and liver were collected for biomolecular, biochemical and histopathologic studies.
  
  
  RESULTS
  COX-2, 5-LOX, tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-10, extracellular-regulated-kinase 1/2 (ERK), JunN-terminal kinase (JNK), NF-κB, and β-arrestin 2 protein expression were evaluated in lung and liver with Western blot analysis. In addition, leukotriene B4 (LTB4), prostaglandin E2 (PGE2), cytokines, and lipoxin A4 serum content were measured with an enzyme-linked immunosorbent assay (ELISA). Flavocoxid administration improved survival, reduced the expression of NF-κB, COX-2, 5-LOX, TNF-α and IL-6 and increased IL-10 production. Moreover, flavocoxid inhibited the mitogen-activated protein kinases (MAPKs) pathway, preserved β-arrestin 2 expression, reduced blood LTB4, PGE2, TNF-α and IL-6, and increased IL-10 and lipoxin A4 serum levels. The treatment with flavocoxid also protected against the histologic damage induced by CLP and reduced the myeloperoxidase (MPO) activity in the lung and liver.
  
  
  CONCLUSIONS
  Flavocoxid protects mice from sepsis, suggesting that this dual inhibitor may represent a promising approach in such a life-threatening condition.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bitto
authors.forename: Letteria
authors.initials: L
authors.lastname: Minutoli
authors.forename: Antonio
authors.initials: A
authors.lastname: David
authors.forename: Natasha
authors.initials: N
authors.lastname: Irrera
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Rinaldi
authors.forename: Francesco S
authors.initials: FS
authors.lastname: Venuti
authors.forename: Francesco
authors.initials: F
authors.lastname: Squadrito
authors.forename: Domenica
authors.initials: D
authors.lastname: Altavilla
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism; D002392:Catechin / Q000627:therapeutic use*; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use*; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D015232:Dinoprostone / Q000097:blood; D004195:Disease Models, Animal; D004338:Drug Combinations; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007975:Leukotriene B4 / Q000097:blood; D044045:Lipoxins / Q000097:blood; D016859:Lipoxygenase Inhibitors / Q000627:therapeutic use*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000097:blood; D009195:Peroxidase / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605258:Arrb2 protein, mouse; C000605257:Arrb2 protein, rat; D019390:Arrestins; D052246:Cyclooxygenase 2 Inhibitors; D016207:Cytokines; D004338:Drug Combinations; D047908:Intracellular Signaling Peptides and Proteins; D044045:Lipoxins; D016859:Lipoxygenase Inhibitors; C121624:Mapkbp1 protein, mouse; D016328:NF-kappa B; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; C544478:flavocoxid; C040527:lipoxin A4; D007975:Leukotriene B4; D002392:Catechin; D009195:Peroxidase; D048049:Extracellular Signal-Regulated MAP Kinases; D015232:Dinoprostone