Cholinergic regulation of NF-kB in sepsis

脓毒症中 NF-kB 的胆碱能调节

• 批准号: 8753228
• 负责人: Luis Ulloa
• 金额: $ 15.6万
• 依托单位: RBHS-NEW JERSEY 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 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8753228
• 关键词: Cholinergic; regulation; NF; kB; sepsis

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.

描述（由申请人提供）：目前，脓毒症没有有效、安全的临床治疗方法，每年占美国总死亡人数的9.3%。 败血症不仅与感染有关。休克、创伤、出血和其他重症监护条件导致严重脓毒症，其特征在于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，以抑制全身炎症，提高实验性脓毒症的生存率。 在疾病发作后一天开始用胆碱能激动剂如尼古丁治疗，也减轻全身炎症，并在致死性内毒素血症和盲肠结扎和穿刺中“拯救”小鼠免于“建立的”脓毒症。 尼古丁已经用于炎症性疾病（如溃疡性结肠炎）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。 有两个基本的考虑因素限制了这种机制在重症监护中的转化潜力：（1）鉴定参与该过程的特异性受体;（2）鉴定抑制细胞因子和脓毒症相关病理标志物产生的机制。 我们在RAW 264.7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）的机制调节NF-κ B来抑制促炎细胞因子的产生。 由于我们最近的研究表明，尼古丁减弱全身炎症，并提高生存假手术，但不是在脾切除小鼠，我们建议研究这两个因素在脾脏的影响。 我们的目标是确定胆碱能激动剂是否抑制脾脏中NF-κ B通路的特定步骤，以及胆碱能激动剂是否通过α 7 nAChR介导的机制调节脾脏中NF-κ B。 如果是这样的话，特定的α 7 nAChR激动剂可能代表了一种有前途的药理学策略，以避免尼古丁的毒性，并在感染性和炎症性疾病期间调节特定免疫细胞中的NF-κ B。

项目成果

Anti-inflammatory adjuvant in resuscitation fluids improves survival in hemorrhage.

• DOI: 10.1097/ccm.0b013e31819b8237
• 发表时间: 2009-03
• 期刊: Critical care medicine
• 影响因子: 8.8
• 作者: Cai B;Chen F;Lin X;Miller E;Szabo C;Deitch EA;Ulloa L
• 通讯作者: Ulloa L

Scientific and clinical challenges in sepsis.

• DOI: 10.2174/138161209788453248
• 发表时间: 2009
• 期刊: Current pharmaceutical design
• 影响因子: 3.1
• 作者: Ulloa L;Brunner M;Ramos L;Deitch EA
• 通讯作者: Deitch EA

Mast cell stabilization improves survival by preventing apoptosis in sepsis.

肥大细胞稳定通过预防败血症的凋亡来改善生存。

• DOI: 10.4049/jimmunol.1000273
• 发表时间: 2010-07-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Ramos L;Peña G;Cai B;Deitch EA;Ulloa L
• 通讯作者: Ulloa L

Ethyl pyruvate improves survival in awake hemorrhage.

• DOI: 10.1007/s00109-009-0441-8
• 发表时间: 2009-04
• 期刊: JOURNAL OF MOLECULAR MEDICINE-JMM
• 影响因子: 4.7
• 作者: Cai, Bolin;Brunner, Michael;Wang, Haichao;Wang, Ping;Deitch, Edwin A.;Ulloa, Luis
• 通讯作者: Ulloa, Luis

JAK2 inhibition prevents innate immune responses and rescues animals from sepsis.

• DOI: 10.1007/s00109-010-0628-z
• 发表时间: 2010-08
• 期刊: JOURNAL OF MOLECULAR MEDICINE-JMM
• 影响因子: 4.7
• 作者: Pena, Geber;Cai, Bolin;Deitch, Edwin A.;Ulloa, Luis
• 通讯作者: Ulloa, Luis