Dopaminergic regulation of the immune system

免疫系统的多巴胺能调节

• 批准号: 9038386
• 负责人: Luis Ulloa
• 金额: $ 30.21万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9038386
• 关键词: Accounting; Adoptive Transfer; Adrenal Glands; Adverse effects; Affect; Agonist; American; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotics; Biological; Blood; Cause of Death; Cessation of life; Clinical Trials; Communicable Diseases; Critical Care; Critical Illness; Developed Countries; Dopamine; Dopamine Agonists; Endotoxemia; Evolution; Experimental Designs; FDA approved; Fenoldopam; Generations; Genetic; Goals; HMGB1 gene; Health; Hour; IL2RA gene; Immune; Immune system; Infection; Inflammation; Inflammatory; Injury; Intensive Care; Knockout Mice; Lymphocyte; Lymphocyte Subset; Mediating; Modern Medicine; Molecular; Mus; Nerve; Nervous system structure; Neurons; Nude Mice; Organ; Parkinson Disease; Patients; Peripheral; Peritonitis; Production; Regulation; Regulatory T-Lymphocyte; Reporting; Role; Sepsis; Serum; Splenocyte; Supportive care; System; T-Lymphocyte; TNF gene; Therapeutic; United States; Vagus nerve structure; apoptosis in lymphocytes; cytokine; design; extracellular; improved; killings; macrophage; mortality; novel; novel therapeutics; prevent; receptor; research study; septic; success; treatment strategy; vagus nerve stimulation

 DESCRIPTION (provided by applicant): Sepsis remains the leading cause of death in the ICU accounting for 9.3% of overall deaths in USA, and killing around 250,000 Americans a year. There is no treatment approved by the FDA for severe sepsis, and most of the therapies are supportive. Despite the efficacy of the new generation of antibiotics in infections and major technological advances in critical care, sepsis remains a leading cause of death in hospitalized patients. Sepsis remains a major scientific challenge in modern medicine with more than 35 unsuccessful clinical trials. One critical consideration is that therapeutic approaches successful in experimental sepsis have provided little success in clinical trials. One potential explanation i that most experimental studies are performed in healthy animals and the treatment is given prophylactically before the septic challenge. A typical example is that vagus nerve stimulation inhibits serum TNF levels in endotoxemia when the stimulation is performed in healthy animals before the septic challenge. However, vagus nerve stimulation does NOT inhibit serum TNF levels when the treatment is started after the septic challenge. This effect is due to the massive apoptosis of lymphocytes during endotoxemia, and that lymphocytes mediate the anti-inflammatory potential of the vagus nerve. Our recent results indicate that neuronal stimulation improved survival in experimental sepsis and this mechanism allowed us to design new therapeutic and pharmacological strategies for sepsis. Neuronal stimulation controlled systemic inflammation in experimental sepsis by activating the production of dopamine from the adrenal medulla1. From a pharmacological perspective, dopaminergic agonists type 1 (D1-agonists) rescue mice from established sepsis when given within the hours after the septic challenge. Moreover, D1-agonists control cytokine production in macrophages through a mechanism mediated by T lymphocytes. The D1-agonist fenoldopam: [1] controls cytokine production in wild-type but not in lymphocyte-deficient blood or primary culture of splenocytes; and [2] `rescued' mice from sepsis when given within hours after the septic challenge. Here we seek to determine whether these lymphocytes can provide pharmacological advantages for the treatment of sepsis.

 描述（由申请人提供）：脓毒症仍然是 ICU 死亡的主要原因，占美国总死亡人数的 9.3%，每年导致约 250,000 名美国人死亡。 FDA 还没有批准治疗严重脓毒症的治疗方法，大多数疗法都是支持性的。尽管新一代抗生素在治疗感染方面具有功效，并且重症监护方面也取得了重大技术进步，但脓毒症仍然是住院患者死亡的主要原因。脓毒症仍然是现代医学的一个重大科学挑战，有超过 35 项临床试验不成功。一个关键的考虑因素是，在实验性脓毒症中成功的治疗方法在临床试验中几乎没有取得成功。一种可能的解释是，大多数实验研究都是在健康动物中进行的，并且在脓毒症攻击之前预防性地进行治疗。一个典型的例子是，当健康动物在脓毒症攻击之前进行迷走神经刺激时，迷走神经刺激会抑制内毒素血症中的血清 TNF 水平。然而，在脓毒症攻击后开始治疗时，迷走神经刺激不会抑制血清 TNF 水平。这种作用是由于内毒素血症期间淋巴细胞大量凋亡所致，并且淋巴细胞介导迷走神经的抗炎潜力。我们最近的结果表明，神经元刺激改善了实验性脓毒症的存活率，这种机制使我们能够设计新的脓毒症治疗和药理学策略。神经元刺激通过激活肾上腺髓质产生多巴胺来控制实验性脓毒症的全身炎症。从药理学角度来看，在脓毒症攻击后数小时内给予 1 型多巴胺能激动剂（D1 激动剂）可将小鼠从已形成的脓毒症中拯救出来。此外，D1 激动剂通过 T 淋巴细胞介导的机制控制巨噬细胞中细胞因子的产生。 D1 激动剂非诺多泮：[1] 控制野生型细胞因子的产生，但不控制淋巴细胞缺陷型血液或脾细胞原代培养物中细胞因子的产生； [2] 在败血症攻击后数小时内给予小鼠“拯救”败血症。在这里，我们试图确定这些淋巴细胞是否可以为脓毒症的治疗提供药理学优势。