Dopaminergic regulation of the immune system

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 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.