title: Functional relevance of the cannabinoid receptor 2 - heme oxygenase pathway: a novel target for the attenuation of portal hypertension.
abstract: OBJECTIVE
  In liver cirrhosis, inflammation triggers portal hypertension. Kupffer cells (KC) produce vasoconstrictors upon activation by bacterial constituents. Here, we hypothesize that the anti-inflammatory action of the cannabinoid receptor 2 (CB2) agonists JWH-133 and GP 1a attenuate portal hypertension.
  
  
  METHODS
  In vivo measurements of portal pressures and non-recirculating liver perfusions were performed in rats 4weeks after bile duct ligation (BDL). Zymosan (150μg/ml, isolated liver perfusion) or LPS (4mg/kgb.w., in vivo) was infused to activate the KC in the absence or presence of JWH-133 (10mg/kgb.w.), GP 1a (2.5mg/kgb.w.) or ZnPP IX (1μM). Isolated KC were treated with Zymosan (0.5mg/ml) in addition to JWH-133 (5μM). The thromboxane (TX) B2 levels in the perfusate and KC media were determined by ELISA. Heme oxygenase-1 (HO-1) and CB2 were analyzed by Western blot or confocal microscopy.
  
  
  RESULTS
  JWH-133 or GP 1a pre-treatment attenuated portal pressures following KC activation in all experimental settings. In parallel, HO-1 expression increased with JWH-133 pre-treatment. However, the inhibition of HO-1 enhanced portal hypertension, indicating the functional role of this novel pathway. In isolated KC, the expression of CB2 and HO-1 increased with Zymosan, LPS and JWH-133 treatment while TXB2 production following KC activation was attenuated by JWH-133 pre-treatment.
  
  
  CONCLUSIONS
  JWH-133 or GP 1a treatment attenuates portal hypertension. HO-1 induction by JWH-133 plays a functional role. Therefore, the administration of JWH-133 or GP 1a represents a promising new treatment option for portal hypertension triggered by microbiological products.
authors.affiliation: Department of Medicine II (Gastroenterology and Hepatology), Liver Center Munich, University of Munich, Grosshadern, Munich, Germany. Electronic address: christian.steib@med.uni-muenchen.de.
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Steib
authors.forename: Leonore
authors.initials: L
authors.lastname: Gmelin
authors.forename: Susanne
authors.initials: S
authors.lastname: Pfeiler
authors.forename: Julia
authors.initials: J
authors.lastname: Schewe
authors.forename: Stephan
authors.initials: S
authors.lastname: Brand
authors.forename: Burkhard
authors.initials: B
authors.lastname: Göke
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Gerbes
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D063386:Cannabinoid Receptor Agonists / Q000627:therapeutic use; D002186:Cannabinoids / Q000627:therapeutic use; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis / Q000502:physiology*; D006975:Hypertension, Portal / Q000188:drug therapy* / Q000503:physiopathology*; D007192:Indenes / Q000627:therapeutic use; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D058990:Molecular Targeted Therapy; D047493:PPAR alpha / Q000502:physiology; D017082:Portal Pressure / Q000187:drug effects / Q000502:physiology*; D011720:Pyrazoles / Q000627:therapeutic use; D051381:Rats; D043885:Receptor, Cannabinoid, CB2 / Q000502:physiology*; D013929:Thromboxane B2 / Q000096:biosynthesis; D015054:Zymosan / Q000037:antagonists & inhibitors / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids; D007192:Indenes; D008070:Lipopolysaccharides; C553580:N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-1,4-dihydro-6-methylindeno(1,2-c)pyrazole-3-carboxamide; D047493:PPAR alpha; D011720:Pyrazoles; D043885:Receptor, Cannabinoid, CB2; D013929:Thromboxane B2; D015054:Zymosan; D006419:Heme Oxygenase (Decyclizing); C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC
keywords: (6aR,10aR)-3-(1,1-dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran; 2-Chloro-5-nitro-N-phenylbenzamide; BDL; Bile duct ligation (BDL); CB(2); GW 9662; Gp 1a; HO; Heme oxygenase (HO); JWH-133; KC; Kupffer cell; LDH; LPS; N-(Piperidin-1-yl)-1-(2,4-dichlorop­henyl)-1,4-dihydro-6-methylindeno[1,2-c]pyrazole-3­-carboxamide; TLR; TX; Thromboxane; Zy; Zymosan A; b. w; bile duct ligation; body weight; cannabinoid receptor 2; heme oxygenase; lactate dehydrogenase; lipopolysaccharide; thromboxane; toll like receptor