Cholinergic regulation of NF-kB in sepsis

脓毒症中 NF-kB 的胆碱能调节

• 批准号: 8270539
• 负责人: Luis Ulloa
• 金额: $ 13.74万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-05 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8270539
• 关键词: Accounting; Acetylcholine; Acute; Affect; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotics; Apoptosis; Attenuated; Cause of Death; Cell Line; Cells; Cessation of life; Cholinergic Agonists; Clinical Treatment; Clinical Trials; Critical Care; Disease; Endotoxemia; Goals; Health; Hemorrhage; Immune; Infection; Inflammation; Inflammatory; Inflammatory Response; Intensive Care; Knockout Mice; Ligation; MAP Kinase Gene; Mediating; Molecular; Multiple Organ Failure; Mus; Myocardial; NF-kappa B; Nicotine; Nicotinic Agonists; Nicotinic Receptors; Onset of illness; Organ; Pathway interactions; Patients; Physiological Processes; Process; Production; Puncture procedure; Regulation; STAT3 gene; Sepsis; Shock; Societies; Spleen; Therapeutic; Time; Toxic effect; Trauma; Ulcerative Colitis; United States; alpha-bungarotoxin receptor; cholinergic; cytokine; design; human morbidity; improved; in vivo; macrophage; mortality; novel; novel therapeutics; prevent; receptor

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. PUBLIC HEALTH RELEVANCE Currently, there is no effective, safe clinical treatment for sepsis, which accounts for 9.3% of the overall deaths in the United States annually. Our goal is to determine the molecular mechanism by which cholinergic agonists restrain systemic inflammation in sepsis. These studies will allow the design of novel pharmacological strategies to improve survival in sepsis

描述（由申请人提供）：目前，败血症没有有效的，安全的临床治疗，占美国每年总死亡人数的9.3％。 败血症不仅与感染有关。休克，创伤，出血和重症护理的其他条件导致严重的败血症，其特征是导致致命的多器官衰竭的压倒性全身性炎症反应。 我们的目标是制定新的治疗策略来抑制系统性炎症并改善实验性败血症的生存。 疾病发作后一天开始，用胆碱能激动剂（如尼古丁）进行治疗，还减轻了全身性炎症，并从致命性内毒素血症和盲肠结扎和穿刺的“已建立”败血症中“营救”小鼠。 尼古丁已经用于炎症性疾病（例如溃疡性结肠炎）的临床试验中，但是由于尼古丁的核心毒性，该机制的治疗潜力被低估了。 有两个基本考虑因素限制了这种机制在重症监护中的翻译潜力：（1）鉴定该过程中涉及的特定受体； （2）鉴定抑制与败血症相关的细胞因子和病理标记的机制。 我们在RAW264.7巨噬细胞样细胞中的研究表明，胆碱能激动剂通过根据α7烟碱酸乙醇胆碱受体（NACHR）调节NF-KB来抑制促炎性细胞因子的产生。 由于我们最近的研究表明尼古丁会减轻系统性炎症并改善假小鼠的生存，但在脾切除小鼠中却不能，我们建议研究这两个因素在脾脏中的含义。 我们的目标是确定胆碱能激动剂是否抑制脾脏中NF-KB途径的特定步骤，以及胆碱能激动剂是否通过α7nAchr介导的机制调节脾脏中的NF-KB。 如果是这样，特定的α7NACHR激动剂可能代表了一种有希望的药理学策略，以避免在传染性和炎症性疾病期间调节特定免疫细胞中NF-KB的毒性。目前，公共卫生相关性，败血症没有有效的安全临床治疗，占美国总死亡人数的9.3％。 我们的目标是确定胆碱能激动剂抑制败血症全身炎症的分子机制。 这些研究将允许设计新型药理策略以提高败血症的生存