CB2 cannabinoid receptors contribute to bacterial invasion and mortality in polymicrobial sepsis.
CB2 cannabinoid receptors contribute to bacterial invasion and mortality in polymicrobial sepsis.
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DOI：
10.1371/journal.pone.0006409
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发表时间：
2009-07-29
期刊：
影响因子：
3.7
通讯作者：
Haskó G
中科院分区：
文献类型：
--
作者：
Csóka B;Németh ZH;Mukhopadhyay P;Spolarics Z;Rajesh M;Federici S;Deitch EA;Bátkai S;Pacher P;Haskó G
脓毒症是一个主要的医疗保健问题，目前的估计表明，脓毒症的发病率约为每年750，000。脓毒症是由免疫系统无法消除入侵的病原体引起的。最近有人提出，脓毒症过程中产生的内源性介质可能有助于脓毒症中观察到的免疫功能障碍。在脓毒症中过量产生的内源性大麻素是导致免疫功能障碍的潜在因素，因为它们通过与免疫细胞上的G蛋白偶联CB 2受体结合来抑制免疫细胞功能。在这里，我们研究了CB 2受体在调节宿主对脓毒症的反应中的作用。通过使CB 2受体野生型和敲除小鼠经受盲肠结扎和穿刺诱导的细菌性脓毒症来研究CB 2受体的作用。我们报告说，CB 2受体失活基因敲除减少败血症引起的死亡率，和细菌易位到败血症动物的血流。此外，CB 2受体失活减少肾脏和肌肉损伤，抑制脾核因子（NF）-κB活化，并减少IL-10、IL-6和MIP-2的产生。最后，CB 2受体缺乏可防止CLP期间淋巴器官的细胞凋亡，并增加CD 11b+和CD 19+细胞的数量。综上所述，我们的研究结果首次证实了CB 2受体是脓毒症免疫功能障碍和死亡率的重要因素，表明CB 2受体可能是治疗脓毒症患者的靶点。
Sepsis is a major healthcare problem and current estimates suggest that the incidence of sepsis is approximately 750,000 annually. Sepsis is caused by an inability of the immune system to eliminate invading pathogens. It was recently proposed that endogenous mediators produced during sepsis can contribute to the immune dysfunction that is observed in sepsis. Endocannabinoids that are produced excessively in sepsis are potential factors leading to immune dysfunction, because they suppress immune cell function by binding to G-protein-coupled CB2 receptors on immune cells. Here we examined the role of CB2 receptors in regulating the host's response to sepsis. The role of CB2 receptors was studied by subjecting CB2 receptor wild-type and knockout mice to bacterial sepsis induced by cecal ligation and puncture. We report that CB2 receptor inactivation by knockout decreases sepsis-induced mortality, and bacterial translocation into the bloodstream of septic animals. Furthermore, CB2 receptor inactivation decreases kidney and muscle injury, suppresses splenic nuclear factor (NF)-κB activation, and diminishes the production of IL-10, IL-6 and MIP-2. Finally, CB2 receptor deficiency prevents apoptosis in lymphoid organs and augments the number of CD11b+ and CD19+ cells during CLP. Taken together, our results establish for the first time that CB2 receptors are important contributors to septic immune dysfunction and mortality, indicating that CB2 receptors may be therapeutically targeted for the benefit of patients suffering from sepsis.
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DOI：
10.1073/pnas.96.25.14541
发表时间：
1999-12-07
影响因子：
11.1
作者：
Hotchkiss, RS;Tinsley, KW;Karl, IE
通讯作者：
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DOI：
10.1073/pnas.1031788100
发表时间：
2003-05-27
影响因子：
11.1
作者：
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影响因子：
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DOI：
10.1152/ajpregu.00678.2005
发表时间：
2006-03-01
影响因子：
2.8
作者：
Enoh, VT;Fairchild, CD;Sherwood, ER
通讯作者：
Sherwood, ER
影响因子：
--
作者：
Leibovici, L;Drucker, M;Pitlik, SD
通讯作者：
Pitlik, SD