Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia
Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia
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DOI：
10.1073/pnas.0600506103
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发表时间：
2006-03-28
影响因子：
11.1
通讯作者：
Tracey, KJ
中科院分区：
文献类型：
--
作者：
Pavlov, VA;Ochani, M;Tracey, KJ
TNF在炎症中具有重要的中介作用，是重要的治疗靶点。我们最近发现，TNF的产生是由迷走神经的神经信号调节的。激活这种“胆碱能抗炎途径”可以抑制TNF和其他细胞因子的产生，保护动物免受内毒素血症和严重败血症引起的炎症损伤。在这里，我们描述了中枢毒蕈碱乙酰胆碱受体在激活胆碱能抗炎途径中的作用。毒蕈碱、M1受体激动剂McN-A-343和M2受体拮抗剂甲氧曲明激活毒蕈碱中枢胆碱能显著抑制内毒素血症时血清TNF水平。通过测量瞬时心率变异性的变化，中央施用甲氧曲明刺激迷走神经活动。阻断外周毒蕈碱受体并没有消除迷走神经的抗炎信号，这表明免疫细胞上的外周毒蕈碱受体并不是胆碱能抗炎途径中细胞因子调节活性所必需的。中枢毒蕈碱受体在激活胆碱能抗炎途径中的作用，是使用中枢作用毒蕈碱胆碱能增强剂作为抗炎剂的兴趣所在。
TNF has a critical mediator role in inflammation and is an important therapeutic target. We recently discovered that TNF production is regulated by neural signals through the vagus nerve. Activation of this "cholinergic antiinflammatory pathway" inhibits the production of TNF and other cytokines and protects animals from the inflammatory damage caused by endotoxemia and severe sepsis. Here, we describe a role for central muscarinic acetylcholine receptors in the activation of the cholinergic antiinflammatory pathway. Central muscarinic cholinergic activation by muscarine, the M1 receptor agonist McN-A-343, and the M2 receptor antagonist methoctramine inhibited serum TNF levels significantly during endotoxemia. Centrally administered methoctramine stimulated vagus-nerve activity measured by changes in instantaneous heart-rate variability. Blockade of peripheral muscarinic receptors did not abolish antiinflammatory signaling through the vagus nerve, indicating that peripheral muscarinic receptors on immune cells are not required for the cytokine-regulating activities of the cholinergic antiinflammatory pathway. The role of central muscarinic receptors in activating the cholinergic antiinflammatory pathway is of interest for the use of centrally acting muscarinic cholinergic enhancers as antiinflammatory agents.