Dopaminergic regulation of the immune system

免疫系统的多巴胺能调节

基本信息

批准号：
9204839
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
项目类别：
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/9204839
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 Clinical Trials Communicable Diseases Critical Care Critical Illness Developed Countries Developing Countries Dopamine Dopamine Agonists Endotoxemia Evolution Experimental Designs FDA approved Fenoldopam Generations Genetic Goals HMGB1 gene Hour IL2RA gene Immune system Immunologics Infection Inflammation Inflammatory Injury Innate Immune System Intensive Care Knockout Mice Lymphocyte Lymphocyte Subset Mediating Modern Medicine Molecular Mus Nerve Nervous system structure Neurons Nude Mice Null Lymphocytes Organ Parkinson Disease Patients Peripheral Peritonitis Pharmacology 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 experimental study extracellular immunoregulation improved killings macrophage mortality novel novel therapeutics prevent prophylactic public health relevance receptor septic success treatment strategy vagus nerve stimulation

项目摘要

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 尚无批准治疗严重脓毒症的治疗方法。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技术取得了重大进步，但脓毒症仍然是住院患者死亡的主要原因。有超过 35 项不成功的临床试验，一个重要的考虑因素是，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，因为大多数实验研究都是在健康动物中进行的，并且在脓毒症发作之前进行预防性治疗。一个典型的例子是，当在脓毒症攻击之前对健康动物进行刺激时，迷走神经刺激会抑制内毒素血症中的血清 TNF 水平。然而，当感染后开始治疗时，迷走神经刺激不会抑制血清 TNF 水平。这种效应是由于内毒素血症期间淋巴细胞的大量凋亡造成的，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提高了实验性脓毒症的存活率，这种机制使我们能够设计新的。脓毒症的治疗和药理学策略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。 D1 激动剂（D1 激动剂）在脓毒症攻击后数小时内给予小鼠，可挽救已形成的脓毒症。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：[1] 控制细胞因子。在野生型中产生，但在淋巴细胞缺乏的血液或脾细胞原代培养物中不产生；以及[2]在脓毒症攻击后数小时内给予小鼠“拯救”脓毒症。以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。