Dopaminergic regulation of the immune system

 描述（由申请人提供）：脓毒症仍然是ICU中的主要死亡原因，占美国总死亡人数的9.3%，每年造成约250，000名美国人死亡。FDA尚未批准针对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感染中的疗效和重症监护的重大技术进步，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中的一个重大科学挑战，有超过35个不成功的临床试验。一个关键的考虑是，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成功。一种可能的解释是，大多数实验研究是在健康动物中进行的，并且在脓毒症攻毒前进行了预防性给药。一个典型的例子是，迷走神经刺激抑制血清TNF水平的内毒素血症时，刺激是在健康的动物进行之前，脓毒症的挑战。然而，在脓毒症激发后开始治疗时，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，并且淋巴细胞介导迷走神经的抗炎潜力。我们最近的研究结果表明，神经元刺激改善了实验性脓毒症的生存率，这一机制使我们能够设计新的脓毒症治疗和药理学策略。在实验性脓毒症中，神经元刺激通过激活肾上腺髓质多巴胺的产生来控制全身炎症。从药理学的角度来看，1型多巴胺能激动剂（D1-激动剂）在脓毒症激发后数小时内给药时，可将小鼠从已建立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]控制野生型中细胞因子的产生，但不控制淋巴细胞缺乏的血液或脾细胞的原代培养物中的细胞因子的产生;[2]在脓毒症攻击后数小时内给予时，“拯救”了脓毒症小鼠。在这里，我们试图确定这些淋巴细胞是否可以提供治疗败血症的药理学优势。

 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.