Dopaminergic regulation of the immune system

 描述(申请人提供)：败血症仍然是ICU的主要死亡原因，占美国总死亡人数的9.3%，每年导致约25万美国人死亡。目前还没有FDA批准的治疗严重脓毒症的方法，而且大多数治疗方法都是支持性的。尽管新一代抗生素对感染有效，在重症监护方面也取得了重大技术进步，但败血症仍然是住院患者死亡的主要原因。败血症仍然是现代医学中的一个重大科学挑战，有超过35项临床试验未获成功。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，大多数实验研究都是在健康动物身上进行的，治疗是在败血症挑战之前预防性给予的。一个典型的例子是，迷走神经刺激抑制了内毒素血症中的血清肿瘤坏死因子水平，而这种刺激是在败血症挑战之前对健康动物进行的。然而，当脓毒症发作后开始治疗时，迷走神经刺激并不抑制血清肿瘤坏死因子水平。这种作用是由于内毒素血症时淋巴细胞的大量凋亡，以及淋巴细胞介导迷走神经的抗炎潜力所致。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，这一机制使我们能够设计新的脓毒症治疗和药物治疗策略。神经元刺激通过激活肾上腺髓质产生的多巴胺来控制实验性脓毒症的全身炎症反应。从药理学的角度来看，如果在脓毒症挑战后的几个小时内给予多巴胺能激动剂1型(d1-激动剂)，可以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-激动剂非诺多巴：[1]控制野生型的细胞因子的产生，但不控制淋巴细胞缺乏的血液或脾细胞的原代培养；和[2]在败血症挑战后的几小时内给药，将小鼠从败血症中“拯救”出来。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。

 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.