Functional relevance of the cannabinoid receptor 2 — heme oxygenase pathway: A novel target for the attenuation of portal hypertension |
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Authors: | Christian J. Steib,Leonore Gmelin,Susanne Pfeiler,Julia Schewe,Stephan Brand,Burkhard Gö ke,Alexander L. Gerbes |
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Affiliation: | 1. Department of Medicine II (Gastroenterology and Hepatology), Liver Center Munich, University of Munich, Grosshadern, Munich, Germany;2. Vascular Biology and Hemostasis, Institute of Laboratory Medicine, University of Munich, Grosshadern, Munich, Germany |
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Abstract: | AimsIn 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.Main methodsIn vivo measurements of portal pressures and non-recirculating liver perfusions were performed in rats 4 weeks after bile duct ligation (BDL). Zymosan (150 μg/ml, isolated liver perfusion) or LPS (4 mg/kg b.w., in vivo) was infused to activate the KC in the absence or presence of JWH-133 (10 mg/kg b.w.), GP 1a (2.5 mg/kg b.w.) or ZnPP IX (1 μM). Isolated KC were treated with Zymosan (0.5 mg/ml) in addition to JWH-133 (5 μM). 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.Key findingsJWH-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.SignificanceJWH-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. |
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Keywords: | BDL, bile duct ligation b. w, body weight CB2, cannabinoid receptor 2 Gp 1a, N-(Piperidin-1-yl)-1-(2,4-dichlorop­ henyl)-1,4-dihydro-6-methylindeno[1,2-c]pyrazole-3­ -carboxamide GW 9662, 2-Chloro-5-nitro-N-phenylbenzamide HO, heme oxygenase JWH-133, (6aR,10aR)-3-(1,1-dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran KC, Kupffer cell LDH, lactate dehydrogenase LPS, lipopolysaccharide TLR, toll like receptor TX, thromboxane Zy, Zymosan A |
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