Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
Mediators Inflamm. 2013;2013:741303. doi: 10.1155/2013/741303. Epub 2013 May 28.
The systemic inflammatory response syndrome can be self-limited or can progress to severe sepsis and septic shock. Despite significant advances in the understanding of the molecular and cellular mechanisms of septic shock, it is still one of the most frequent and serious problems confronting clinicians in the treatments. And the effects of cannabinoid receptor 2 (CB2R) on the sepsis still remain undefined. The present study was aimed to explore the role and mechanism of CB2R in acute sepsis model of mice. Here, we found that mice were more vulnerable for lipopolysaccharide- (LPS-) induced death and inflammation after CB2R deletion (CB2R(-/-)). CB2R agonist, GW405833, could significantly extend the survival rate and decrease serum proinflammatory cytokines in LPS-treated mice. GW405833 dose-dependently inhibits proinflammatory cytokines release in splenocytes and peritoneal macrophages as well as splenocytes proliferation, and these effects were partly abolished in CB2R(-/-) splenocytes but completely abolished in CB2R(-/-) peritoneal macrophages. Further studies showed that GW405833 inhibits LPS-induced phosphorylation of ERK1/2 and STAT3 and blocks I κ B α degradation and NF- κB p65 nuclear translocation in macrophages. All data together showed that CB2R provides a protection and is a potential therapeutic target for the sepsis.
全身炎症反应综合征可以是自限性的，也可以进展为严重脓毒症和感染性休克。尽管在理解脓毒性休克的分子和细胞机制方面取得了重大进展，但它仍然是临床医生在治疗中面临的最常见和最严重的问题之一。大麻素受体 2（CB2R）对脓毒症的影响仍未确定。本研究旨在探讨 CB2R 在小鼠急性脓毒症模型中的作用和机制。在这里，我们发现 CB2R 缺失（CB2R(-/-)）后，小鼠对脂多糖（LPS）诱导的死亡和炎症更为敏感。CB2R 激动剂 GW405833 可显著延长 LPS 处理小鼠的存活率并降低血清促炎细胞因子水平。GW405833 呈剂量依赖性抑制脾细胞和腹腔巨噬细胞中促炎细胞因子的释放以及脾细胞的增殖，而这些作用在 CB2R(-/-)脾细胞中部分被消除，但在 CB2R(-/-)腹腔巨噬细胞中完全被消除。进一步的研究表明，GW405833 抑制 LPS 诱导的 ERK1/2 和 STAT3 磷酸化，并阻断巨噬细胞中 I κ B α 的降解和 NF- κ B p65 的核易位。所有数据表明，CB2R 提供了保护作用，是脓毒症的潜在治疗靶点。
