Cholinergic regulation of NF-kB in sepsis

描述（由申请人提供）：脓毒症每年占美国总死亡人数的9.3%，目前尚无有效、安全的临床治疗方法。败血症不仅与感染有关。休克、创伤、出血和其他重症监护条件可导致严重败血症，其特征是压倒性的全身炎症反应，导致致命的多器官衰竭。我们的目标是开发新的治疗策略来抑制全身性炎症，提高实验性败血症的生存率。在疾病发作后一天开始使用胆碱能激动剂（如尼古丁）治疗，也可以减轻全身炎症，并在致命的内毒素血症和盲肠结扎和穿刺中“拯救”小鼠免受“既定”败血症的“拯救”。尼古丁已经被用于溃疡性结肠炎等炎症性疾病的临床试验，但由于尼古丁的附带毒性，这种机制的治疗潜力被低估了。有两个基本的考虑限制了这种机制在重症监护中的翻译潜力：(1)识别参与该过程的特定受体；(2)确定抑制脓毒症相关细胞因子和病理标志物产生的机制。我们在RAW264.7巨噬细胞样细胞中的研究表明，胆碱能激动剂通过依赖于α - 7烟碱乙酰胆碱受体（nAChR）的机制，通过调节NF-kB来抑制促炎细胞因子的产生。由于我们最近的研究表明，尼古丁减轻全身炎症并提高假手术小鼠的存活率，但在脾切除小鼠中没有，我们建议研究这两个因素在脾脏中的意义。我们的目的是确定胆碱能激动剂是否抑制脾脏NF-kB通路的特定步骤，以及胆碱能激动剂是否通过alpha7nAChR介导的机制调节脾脏NF-kB。如果是这样，特异性alpha7nachr激动剂可能是一种很有前途的药理学策略，可以避免尼古丁的毒性，并在感染和炎症疾病期间调节特异性免疫细胞中的NF-kB。

DESCRIPTION (provided by applicant): Currently, there is no effective, safe clinical treatment for sepsis, which accounts for 9.3% of the overall deaths in the United States annually. Sepsis is not only related to infections. Shock, trauma, hemorrhage, and other conditions of critical care contribute to severe sepsis, which is characterized by an overwhelming systemic inflammatory response that causes lethal multiple organ failure. Our goal is to develop novel therapeutic strategies to restrain systemic inflammation and improve survival in experimental sepsis. Treatment with cholinergic agonists such as nicotine, started one day after the onset of the disease, also attenuate systemic inflammation and "rescue" mice from "established" sepsis both in lethal endotoxemia and cecal ligation and puncture. Nicotine has been already used in clinical trials for inflammatory disorders such as ulcerative colitis, but the therapeutic potential of this mechanism is underestimated due to the collateral toxicity of nicotine. There are two fundamental considerations limiting the translational potential of this mechanism in critical care: (1) identification of the specific receptor(s) involved in the process; and (2) identification of the mechanism inhibiting the production of cytokines and pathological markers associated with sepsis. Our studies in RAW264.7 macrophage-like cells indicate that cholinergic agonists inhibit the production of proinflammartory cytokines by modulating NF-kB through a mechanism dependent on the alpha7 nicotinic acethlcholine receptor (nAChR). Since our most recent studies indicate that nicotine attenuates systemic inflammation and improves survival in sham but not in splenectomized mice, we propose to study the implications of these two factors in the spleen. Our objectives are to determine whether cholinergic agonists inhibit a specific step of the NF-kB pathway in the spleen and whether cholinergic agonists modulate NF-kB in the spleen through a mechanism mediated by the alpha7nAChR. If so, specific alpha7nAChR-agonists may represent a promising pharmacological strategy to avoid the toxicity of nicotine and modulate NF-kB in specific immune cells during infectious and inflammatory disorders.