title: Cannabinoid receptor 2 activation reduces intestinal leukocyte recruitment and systemic inflammatory mediator release in acute experimental sepsis.
abstract: BACKGROUND
  Cannabinoid receptor 2 (CB2R) expression is upregulated during sepsis. However, there are conflicting results regarding the effects of CB2R modulation in the hyperinflammatory phase of the disease. The aim of this study was therefore to investigate the effects of CB2R manipulation on leukocyte activation within the intestinal microcirculation in two acute experimental sepsis models.
  
  
  METHODS
  In the endotoxemia model we studied four groups of Lewis rats: controls, lipopolysaccharide (LPS), LPS + CB2R agonist HU308 (2.5 mg/kg), and LPS + CB2R antagonist AM630 (2.5 mg/kg). In the colon ascendens stent peritonitis (CASP)-induced sepsis model we also studied four groups: sham group, CASP and CASP + CB2R agonist (HU308, 2.5 or 10 mg/kg). Intravital microscopy was performed 2 hours following LPS/placebo administration or 16 hours following CASP/sham surgery to quantify intestinal leukocyte recruitment. Additionally, hemodynamic monitoring, histological examinations and measurements of inflammatory mediators were performed.
  
  
  RESULTS
  HU308 administration significantly reduced intestinal leukocyte adhesion in both acute sepsis models. The systemic levels of inflammatory mediators were significantly reduced by 10 mg/kg HU308 treatment in CASP animals.
  
  
  CONCLUSIONS
  CB2R activation reduces leukocyte activation and systemic release of inflammatory mediators in acute experimental sepsis. Drugs targeting the CB2R pathway may have therapeutic potential in sepsis.
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada, B3H 2Y9. chlehmann@dal.ca
authors.forename: Christian
authors.initials: C
authors.lastname: Lehmann
authors.forename: Mandana
authors.initials: M
authors.lastname: Kianian
authors.forename: Juan
authors.initials: J
authors.lastname: Zhou
authors.forename: Inga
authors.initials: I
authors.lastname: Küster
authors.forename: Rieke
authors.initials: R
authors.lastname: Kuschnereit
authors.forename: Sara
authors.initials: S
authors.lastname: Whynot
authors.forename: Orlando
authors.initials: O
authors.lastname: Hung
authors.forename: Romesh
authors.initials: R
authors.lastname: Shukla
authors.forename: Brent
authors.initials: B
authors.lastname: Johnston
authors.forename: Vladimir
authors.initials: V
authors.lastname: Cerny
authors.forename: Dragan
authors.initials: D
authors.lastname: Pavlovic
authors.forename: Alexander
authors.initials: A
authors.lastname: Spassov
authors.forename: Melanie Em
authors.initials: ME
authors.lastname: Kelly
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000276:immunology; D018836:Inflammation Mediators / Q000276:immunology*; D007422:Intestines / Q000166:cytology / Q000276:immunology*; D007962:Leukocytes / Q000276:immunology*; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D043882:Receptors, Cannabinoid / Q000276:immunology*; D018805:Sepsis / Q000276:immunology*
chemical_list: D018836:Inflammation Mediators; D043882:Receptors, Cannabinoid