Alcohol, the vagus nerve and multi-organ inflammation

描述(申请人提供)：第十个脑神经，迷走神经，分布于全身，包括肠道所有部分的主要分支，以及肝脏。这种胆碱能神经通过将乙酰胆碱(ACh)紧张性释放到α7亚型的烟碱受体(Nicotinic Receptor，NicAChRs)上，在迷走神经分布的所有器官中抑制炎症。除了存在于炎症细胞上，α7-NicAChRs还存在于中枢神经系统迷走神经的细胞体上，在那里它们引起迷走神经激活和神经保护。由于酒精的存在会抑制Alpha7-NicAChRs，而已知的慢性影响是导致迷走神经病变，因此在酒精暴露期间，迷走神经的这些抗炎作用会严重受损。主要的假设是，这种迷走神经功能的降低导致了氧化应激后的慢性炎症，这是酒精诱导的许多器官损伤的共同特征。如果这是正确的，这预测具有α7-NicAChR激动剂特性的化合物将防止酒精引起的组织损伤，特别是如果这些化合物也是抗氧化剂的话。这项建议的第一个具体目的是通过研究酒精和α7-NicAChR配体对内毒素诱导的炎症细胞(脾、肺和腹膜巨噬细胞)释放介质的相互作用，在体外验证第一个假设。第二个具体目的是通过强迫饮酒将C57BL/6J小鼠(野生型、迷走神经切断和alpha7-NicAChR基因敲除)长期暴露于酒精中，然后在体内评估内毒素诱导的炎症介质的释放，从而在体内验证这一假说。作为这些研究的一部分，我们将评估Alpha7-NicAChR激动剂、胆碱和作为Alpha7-NicAChRs部分激动剂的甲基槲皮素的治疗潜力。后者是最近通过筛选天然植物提取物文库发现的，除了对NicAChRs的作用外，还具有强大的抗氧化活性，在NicAChRs中具有与胆碱类似的亲和力。这些化合物抑制酒精暴露后内毒素诱导的炎症介质释放的能力将使用与上述相同的方法在体外和体内进行研究。因此，该项目测试了一种基于迷走神经代表的大脑、肠道和肝脏之间的相互作用的酒精诱导器官损伤的新假说，并测试了一种新的治疗方法。

DESCRIPTION (provided by applicant): The tenth cranial nerve, the vagus, is distributed throughout the body, including major divisions to all parts of the gut, and to the liver. This cholinergic nerve restrains inflammation, in all the organs to which the vagus is distributed, by the tonic release of acetylcholine (ACh) onto nicotinic receptors (nicAChRs) of the alpha7- subtype. In addition to their presence on inflammatory cells, alpha7-nicAChRs are also present on cell bodies of the vagus in the CNS, where they cause vagal activation and neuroprotection. Since the presence of alcohol inhibits alpha7-nicAChRs, and a known chronic effect is to cause vagal neuropathy, these anti-inflammatory effects of the vagus are seriously compromised during alcohol exposure. The primary hypothesis is that this reduced vagal function contributes to the chronic inflammation following oxidative stress, which is a common feature of alcohol-induced damage in many organs. If correct, this predicts that compounds with alpha7- nicAChR agonist properties will protect against alcohol-induced tissue damage, particularly if these compounds are also anti-oxidants. The first specific aim of this proposal is to test the primary hypothesis in vitro by studying the interactions of alcohol and alpha7-nicAChR ligands on endotoxin-induced release of mediators from inflammatory cells (splenic, lung and peritoneal macrophages) from wild-type, and alpha7-nicAChR knock-out, C57Bl/6J mice. The second specific aim is to test the hypothesis in vivo by exposing C57Bl/6J mice (wild-type, vagotomized, and alpha7-nicAChR knockouts) chronically to alcohol by forced consumption, and then evaluating endotoxin-induced release of inflammatory mediators in vivo. As part of these studies we will evaluate the therapeutic potential of the alpha7-nicAChR agonist, choline, and a methylquercetagetin which acts as a partial agonist at alpha7-nicAChRs. The latter was recently discovered by screening a native plant extract library, and has potent anti-oxidant activity in addition to its action at nicAChRs, where it has an affinity comparable to choline. The ability of these compounds to inhibit endotoxin-induced release of inflammatory mediators following alcohol exposure will be studied in vitro and in vivo using the same methods as above. This project therefore tests a novel hypothesis for alcohol-induced organ damage based on the interaction between brain, gut and liver as represented by the vagus nerve, and tests a novel therapeutic approach to this.