title: Mild versus strong anti-inflammatory therapy during early sepsis in mice: a matter of life and death.
abstract: OBJECTIVE
  A recent literature-based study suggested that low-dose corticosteroid treatment has a beneficial effect on mortality in septic patients, whereas high-dose corticosteroid treatment has not. This suggests that mild down-regulation of the inflammatory response during early sepsis may be beneficial while extensive reduction of the inflammatory response is not. To investigate this hypothesis, we examined the effect of dexamethasone in varying doses on cecal ligation and puncture-induced inflammation and mortality.
  
  
  METHODS
  Animal study.
  
  
  METHODS
  University research laboratory.
  
  
  METHODS
  Male C57BL/6 mice.
  
  
  METHODS
  Mice were subjected to cecal ligation and puncture, and dexamethasone was administered intravenously at a dosage of 0.05 (L/DEX), 0.25 (M/DEX), or 2.5 (H/DEX) mg/kg body weight 20 mins postoperatively. Mice receiving phosphate-buffered saline served as controls. Survival was recorded up to 21 days and inflammatory markers were determined in plasma, lungs, liver, and kidney at 6 hrs following cecal ligation and puncture as well as bacterial load in blood and peritoneal fluid.
  
  
  RESULTS
  L/DEX treatment significantly improved survival compared with control mice, whereas treatment with higher concentrations of dexamethasone (M/DEX and H/DEX) did not. Treatment with either M/DEX or H/DEX was associated with significantly (p < .05) reduced cytokine plasma levels as compared with controls at 6 hrs after cecal ligation and puncture. In addition, M/DEX or H/DEX powerfully reduced cytokine messenger RNA expression in the lung, liver, and kidney. In contrast, treatment with L/DEX was associated with a mild, but nonsignificant, reduction of cytokine plasma levels. In addition, L/DEX moderately reduced cytokine messenger RNA expression in lung, liver, and kidney tissue and reduced the occurrence of bacteremia.
  
  
  CONCLUSIONS
  A modest down-regulation of the early sepsis-associated inflammatory response improves survival in a murine cecal ligation and puncture model. We propose that the success of anti-inflammatory therapies in a septic setting fundamentally depends on finding a treatment balance that reduces the hyper-inflammation-induced pathology but still allows adequate defense against pathogens.
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
authors.forename: Jan Willem
authors.initials: JW
authors.lastname: van den Berg
authors.forename: Marten
authors.initials: M
authors.lastname: van der Zee
authors.forename: Ron W F
authors.initials: RW
authors.lastname: de Bruin
authors.forename: Conny
authors.initials: C
authors.lastname: van Holten-Neelen
authors.forename: Jeroen
authors.initials: J
authors.lastname: Bastiaans
authors.forename: Nicole M A
authors.initials: NM
authors.lastname: Nagtzaam
authors.forename: Jan N M
authors.initials: JN
authors.lastname: IJzermans
authors.forename: Robbert
authors.initials: R
authors.lastname: Benner
authors.forename: Willem A
authors.initials: WA
authors.lastname: Dik
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003907:Dexamethasone / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000893:Anti-Inflammatory Agents; D015815:Cell Adhesion Molecules; D016207:Cytokines; D003907:Dexamethasone