Alcohol, the vagus nerve and multi-organ inflammation

描述（由申请人提供）：第十脑神经，迷走神经，分布于全身，包括肠道所有部分和肝脏的主要分支。这种胆碱能神经通过将乙酰胆碱（ACh）紧张性释放到α 7亚型的烟碱受体（nicAChR）上来抑制迷走神经分布的所有器官中的炎症。除了它们存在于炎性细胞上之外，α 7-nicAChR还存在于CNS中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。由于酒精的存在抑制α 7-nicAChR，并且已知的慢性效应是引起迷走神经病变，因此迷走神经的这些抗炎作用在酒精暴露期间严重受损。主要的假设是，这种迷走神经功能的降低有助于氧化应激后的慢性炎症，这是许多器官中酒精诱导损伤的共同特征。如果正确的话，这预示着具有α 7- nicAChR激动剂特性的化合物将防止酒精诱导的组织损伤，特别是如果这些化合物也是抗氧化剂。本提案的第一个具体目的是通过研究酒精和α 7-nicAChR配体对来自野生型和α 7-nicAChR敲除C57 Bl/6 J小鼠的炎性细胞（脾、肺和腹膜巨噬细胞）的内毒素诱导的介质释放的相互作用，在体外检验主要假设。第二个具体目标是通过强迫消费将C57 Bl/6 J小鼠（野生型、迷走神经切断和α 7-nicAChR敲除）长期暴露于酒精，然后评估内毒素诱导的体内炎症介质释放，从而在体内检验该假设。作为这些研究的一部分，我们将评估α 7-nicAChR激动剂胆碱和甲基槲皮素的治疗潜力，甲基槲皮素作为α 7-nicAChR的部分激动剂。后者是最近通过筛选天然植物提取物库发现的，并且除了其对nicAChR的作用之外还具有有效的抗氧化活性，其中它具有与胆碱相当的亲和力。将使用与上述相同的方法在体外和体内研究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。因此，该项目基于以迷走神经为代表的大脑、肠道和肝脏之间的相互作用，测试了酒精引起的器官损伤的新假设，并测试了一种新的治疗方法。 公共卫生相关性：酒精中毒（依赖或滥用）影响了美国8%以上的人口，每年的社会成本接近2000亿美元。其中大约一半是医疗费用，其中大部分是在治疗与酒精有关的器官损伤时积累的。尽管如此，目前还没有公认的方法来防止或扭转这种损害。本申请提出了一种关于器官损伤原因的新假设，其对治疗具有深远的意义。如果成功，该项目将建立一个框架，用于药物发现和评估这一基本上被忽视的治疗目标。

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. PUBLIC HEALTH RELEVANCE: Alcoholism (either dependence or abuse) affects more than 8% of the population of the US, and the societal costs approach $200BN annually. About half of this sum is medical cost, much of which is accrued in treating alcohol-related organ damage. Despite this there are currently no accepted approaches to preventing or reversing this damage. This application proposes a novel hypothesis as to the cause of organ damage which has profound implications for treatment. If successful, the project will establish a framework for drug discovery and evaluation in relation to this largely overlooked therapeutic target.