Classically, sympathetic and parasympathetic systems act in opposition to maintain the physiological homeostasis. In this article, we report that both systems work together to restrain systemic inflammation in life-threatening conditions such as sepsis. This study indicates that vagus nerve and cholinergic agonists activate the sympathetic noradrenergic splenic nerve to control systemic inflammation. Unlike adrenalectomy, splenectomy and splenic neurectomy prevent the anti-inflammatory potential of both the vagus nerve and cholinergic agonists, and abrogate their potential to induce splenic and plasma norepinephrine. Splenic nerve stimulation mimics vagal and cholinergic induction of norepinephrine and re-establishes neuromodulation in α7 nicotinic acetylcholine receptor (α7nAChR)-deficient animals. Thus, vagus nerve and cholinergic agonists inhibit systemic inflammation by activating the noradrenergic splenic nerve via the α7nAChR nicotinic receptors. α7nAChR represents a unique molecular link between the parasympathetic and sympathetic system to control inflammation.
The nervous system is classically organized into sympathetic and parasympathetic systems acting in opposition to maintain physiological homeostasis. Here, we report that both systems converge in the activation of β2-adrenoceptors of splenic regulatory lymphocytes to control systemic inflammation. Vagus nerve stimulation fails to control serum TNF levels in either β2-knockout or lymphocyte-deficient nude mice. Unlike typical suppressor CD25(+) cells, the transfer of CD4(+)CD25(-) regulatory lymphocytes reestablishes the anti-inflammatory potential of the vagus nerve and β2-agonists to control inflammation in both β2-knockout and nude mice. β2-Agonists inhibit cytokine production in splenocytes (IC(50)≈ 1 μM) and prevent systemic inflammation in wild-type but not in β2-knockout mice. β2-Agonists rescue wild-type mice from established polymicrobial peritonitis in a clinically relevant time frame. Regulatory lymphocytes reestablish the anti-inflammatory potential of β2-agonists to control systemic inflammation, organ damage, and lethal endotoxic shock in β2-knockout mice. These results indicate that β2-adrenoceptors in regulatory lymphocytes are critical for the anti-inflammatory potential of the parasympathetic vagus nerve, and they represent a potential pharmacological target for sepsis.
Many anti-inflammatory strategies successful in healthy animals fail in clinical trials for sepsis, in part, because sepsis normally involves immunocompromised patients, and massive lymphocyte apoptosis prevents immunomodulation. Here we report a new set of regulatory lymphocytes able to reestablish the cholinergic anti-inflammatory modulation and to provide therapeutic advantages in sepsis. Vagus nerve controls inflammation in healthy, but not in septic mice. Likewise, vagus nerve and cholinergic agonists fail to control inflammation in splenectomized and nude animals. Unlike typical suppressor CD25+ cells, CD4+CD25− lymphocytes reestablish the anti-inflammatory potential of the vagus nerve and cholinergic agonists in immunocompromised and septic animals. These cholinergic lymphocytes reestablish splenic protection and the potential of cholinergic agonists to rescue immunocompromised animals from established sepsis. These results reveal these new regulatory lymphocytes as the first known physiological target for neuromodulation of the innate immune responses, and a potential therapeutic target for sepsis.
BACKGROUND Hemorrhagic shock is known to disrupt the gut barrier leading to end-organ dysfunction. The vagus nerve can inhibit detrimental immune responses that contribute to organ damage in hemorrhagic shock. Therefore, we explored whether stimulation of the vagus nerve can protect the gut and recover lung permeability in trauma-hemorrhagic shock (THS). METHODS Male Sprague-Dawley rats were subjected to left cervical vagus nerve stimulation at 5 V for 10 minutes. The right internal jugular and femoral artery were cannulated for blood withdrawal and blood pressure monitoring, respectively. Animals were then subjected to hemorrhagic shock to a mean arterial pressure between 30 mm Hg and 35 mm Hg for 90 minutes then reperfused with their own whole blood. After observation for 3 hours, gut permeability was assessed with fluorescein dextran 4 in vivo injections in a ligated portion of distal ileum followed by Evans blue dye injection to assess lung permeability. Pulmonary myeloperoxidase levels were measured and compared. RESULTS Vagal nerve stimulation abrogated THS-induced lung injury (mean [SD], 8.46 [0.36] vs. 4.87 [0.78]; p < 0.05) and neutrophil sequestration (19.39 [1.01] vs. 12.83 [1.16]; p < 0.05). Likewise, THS gut permeability was reduced to sham levels. CONCLUSION Neuromodulation decreases injury in the THS model as evidenced by decreased gut permeability as well as decreased lung permeability and pulmonary neutrophil sequestration in a rat model.
Hemorrhage remains a common cause of death despite the recent advances in critical care, in part because conventional resuscitation fluids fail to prevent lethal inflammatory responses. Here, we analyzed whether ethyl pyruvate can provide a therapeutic anti-inflammatory potential to resuscitation fluids and prevent organ damage in porcine hemorrhage. Adult male Yorkshire swine underwent lethal hemorrhage with trauma and received no resuscitation treatment or resuscitation with Hextend alone, or supplemented with ethyl pyruvate. Resuscitation with ethyl pyruvate did not improve early hemodynamics, but prevented hyperglycemia, the intrinsic coagulation pathway, serum aspartate aminotransferase, and myelopyroxidase in the major organs. Resuscitation with ethyl pyruvate provided an anti-inflammatory potential to restrain serum TNF and HMGB1 levels. Ethyl pyruvate inhibited NF-kB in the spleen but not in the other major organs. In contrast, ethyl pyruvate inhibited nitric oxide in all the major organs and it also inhibited TNF production in the major organs but in the lung and heart. The most significant effects were found in the terminal ileum where ethyl pyruvate inhibited cytokine production, restrained myelopyroxidase activity, preserved the intestinal epithelium, and prevented the systemic distribution of bacterial endotoxin. Ethyl pyruvate can provide therapeutic anti-inflammatory benefits to modulate splenic NF-kB, restrain inflammatory responses, and prevent hyperglycemia, the intrinsic coagulation pathway and organ injury in porcine hemorrhage without trauma.
The in vivo data suggest that our fecal peritonitis-induced experimental sepsis model is of clinical relevance, and may play useful roles in the development of novel, sepsis-related therapies.
The alpha7 nicotinic acetylcholine receptors (α7nAChR) play a critical role in modulating systemic inflammation in sepsis (1). However, α7nAChR-agonists have failed to provide significant advantages in several pilot studies with septic patients. Since we recently reported that the vagus nerve prevents sepsis by activating regulatory lymphocytes (2), we reasoned that the massive apoptosis of lymphocytes during sepsis may prevent the therapeutic effects of the α7nAChR-agonists. Our results indicate that α7nAChR-agonists failed to prevent systemic inflammation in lymphocyte-deficient nude mice. The transfer of typical regulatory CD3+CD4+CD25+ suppressor/regulatory lymphocytes failed to reestablish the benefits of α7nAChR-agonists. But, the transfer of CD3+CD4+CD25- modulatory lymphocytes reestablished the anti-inflammatory potential of the α7nAChR-agonists. Likewise, α7nAChR-agonist prevented systemic inflammation in polymicrobial sepsis when administered before sepsis. The anti-inflammatory potential and benefits of the α7nAChR-agonists vanishes as the treatment is delayed after the onset of the infection. However, the adoptive transfer of CD3+CD4+CD25- modulatory lymphocytes reestablished the anti-inflammatory potential of the α7nAChR-agonists, even if the treatment is started long after the infection. These results suggest that a new set of CD25- modulatory lymphocytes can provide clinical advantages for the treatment of infections and inflammatory disorders.
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