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Functional relevance of the cannabinoid receptor 2 - Heme oxygenase pathway: A novel target for the attenuation of portal hypertension

机译：大麻素受体2-血红素加氧酶途径的功能相关性：减轻门脉高压的新目标

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Aims 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. Main methods In 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 findings 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. Significance 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.
机译：目的在肝硬化中，炎症触发门脉高压症。当细菌成分激活时，枯否细胞（KC）产生血管收缩剂。在这里，我们假设大麻素受体2（CB2）激动剂JWH-133和GP 1a的抗炎作用可减轻门脉高压。主要方法在胆管结扎术（BDL）4周后，在大鼠体内进行门静脉压力和非循环肝灌注的测量。在不存在或存在JWH-133（10 mg / kg bw），GP 1a（2.5）的情况下，注入酵母聚糖（150μg/ ml，分离的肝脏灌注）或LPS（4 mg / kg bw，体内）激活KC。毫克/千克体重）或ZnPP IX（1μM）。除JWH-133（5μM）外，分离的KC还用酵母聚糖（0.5 mg / ml）处理。通过ELISA确定灌注液和KC培养基中的血栓烷（TX）B2水平。血红素加氧酶-1（HO-1）和CB2通过蛋白质印迹或共聚焦显微镜分析。在所有实验设置中，JWH-133或GP 1a预处理的主要发现在KC激活后降低了门脉压力。平行地，HO-1表达随着JWH-133预处理而增加。但是，HO-1的抑制增强了门脉高压，表明该新途径的功能作用。在分离的KC中，通过酵母聚糖，LPS和JWH-133处理，CB2和HO-1的表达增加，而通过KWH-133预处理减弱了KC激活后TXB2的产生。意义JWH-133或GP 1a治疗可减轻门静脉高压症。 JWH-133诱导HO-1发挥功能性作用。因此，JWH-133或GP 1a的使用代表了由微生物产品引发的门脉高压的有希望的新治疗选择。

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