Inflammation and immunity are regulated by neural reflexes. Recent basic science research has demonstrated that a neural reflex, termed the inflammatory reflex, modulates systemic and regional inflammation in a multiplicity of clinical conditions encountered in perioperative medicine and critical care. In this review, the authors describe the anatomic and physiologic basis of the inflammatory reflex and review the evidence implicating this pathway in the modulation of sepsis, ventilator-induced lung injury, postoperative cognitive dysfunction, myocardial ischemia–reperfusion injury, and traumatic hemorrhage. The authors conclude with a discussion of how these new insights might spawn novel therapeutic strategies for the treatment of inflammatory diseases in the context of perioperative and critical care medicine.

Neural reflexes modulate systemic inflammation in clinical conditions encountered in perioperative and critical care. This review discusses how recent studies in this area are leading to new therapeutic strategies for the treatment of inflammatory diseases.

NEURAL reflex circuits are the basic organizational units of the nervous system, capable of rapid and precise responses to a myriad of physiologic challenges in both health and disease. In particular, homeostatic autonomic reflexes regulate body temperature, heart rate, blood pressure, and a wide range of other organ functions.1  Patients in perioperative or critical care are to variable extents unable to maintain homeostasis and fine-tune their internal physiology due to combinations of therapeutic interventions (e.g., surgery and anesthesia) and disease.1  When homeostatic reflexes fail, clinicians are tasked with replacing neural reflex control with biochemical monitoring and therapeutic interventions to support normal physiology.

Autonomic reflex circuits are composed of a sensory (afferent) arc that report to the central nervous system (CNS) and a motor (efferent) arc that project regulatory signals to target tissues. CNS integration of a multitude of sensory information allows for purposeful and rapid adaptation to changing demands. For example, the baroreflex regulates heart rate and blood pressure to optimize organ perfusion and adjust exchange of oxygen, carbon dioxide, and nutrients according to need2  (fig. 1A). Detailed understanding of this cardiovascular reflex has enabled clinicians to diagnose and treat hemodynamic instability effectively.

Fig. 1.

Reflex structure and function. (A) The baroreflex is a well-characterized reflex that maintains blood pressure. Like other reflexes, its anatomy consists of a sensory branch coupled with a motor output. The sensory component includes baroreceptors within the aortic arch and carotid sinus, which send information about blood pressure to the central nervous system via the glossopharyngeal (CN IX) and vagus nerves (CN X), respectively. Hypertension activates the reflex leading to cholinergic activation and adrenergic inhibition. This manifests as decreased heart rate and peripheral resistance and ultimately decreased blood pressure. Hypotension has the opposite effect and thereby increases blood pressure. (B) The inflammatory reflex similarly contains sensory and motor branches. In this case, vagus nerve sensory afferents are activated by the products of inflammatory and infectious stimuli. This information is conveyed to the brainstem. After integration by the central nervous system, the reflex is completed by sending vagus motor signals to the celiac ganglion where the splenic nerve arises. (C) The splenic nerve terminates in close proximity to a specialized acetylcholine-producing T cell in the spleen. This T cell behaves similarly to an interneuron: norepinephrine (NE) released by the splenic nerve activates β2 adrenergic receptors (β2ARs) on the T cell, which in turn releases acetylcholine (ACh). The ACh engages the α7 nicotinic acetylcholine receptor (α7nAChR) on splenic macrophages and down-regulates their production of tumor necrosis factor (TNF) resulting in an antiinflammatory effect. The intracellular mechanism for α7nAChR-mediated regulation of cytokine production in immune cells may involve Janus Kinase (Jak) 2 and signal transducer and activator of transcription (STAT) 3 signaling. Pharmacologic α7nAChR agonists (yellow circles) that activate the inflammatory reflex are being developed as potential antiinflammatory therapies. CN = cranial nerve; IL-1β = interleukin-1β.

Fig. 1.

Reflex structure and function. (A) The baroreflex is a well-characterized reflex that maintains blood pressure. Like other reflexes, its anatomy consists of a sensory branch coupled with a motor output. The sensory component includes baroreceptors within the aortic arch and carotid sinus, which send information about blood pressure to the central nervous system via the glossopharyngeal (CN IX) and vagus nerves (CN X), respectively. Hypertension activates the reflex leading to cholinergic activation and adrenergic inhibition. This manifests as decreased heart rate and peripheral resistance and ultimately decreased blood pressure. Hypotension has the opposite effect and thereby increases blood pressure. (B) The inflammatory reflex similarly contains sensory and motor branches. In this case, vagus nerve sensory afferents are activated by the products of inflammatory and infectious stimuli. This information is conveyed to the brainstem. After integration by the central nervous system, the reflex is completed by sending vagus motor signals to the celiac ganglion where the splenic nerve arises. (C) The splenic nerve terminates in close proximity to a specialized acetylcholine-producing T cell in the spleen. This T cell behaves similarly to an interneuron: norepinephrine (NE) released by the splenic nerve activates β2 adrenergic receptors (β2ARs) on the T cell, which in turn releases acetylcholine (ACh). The ACh engages the α7 nicotinic acetylcholine receptor (α7nAChR) on splenic macrophages and down-regulates their production of tumor necrosis factor (TNF) resulting in an antiinflammatory effect. The intracellular mechanism for α7nAChR-mediated regulation of cytokine production in immune cells may involve Janus Kinase (Jak) 2 and signal transducer and activator of transcription (STAT) 3 signaling. Pharmacologic α7nAChR agonists (yellow circles) that activate the inflammatory reflex are being developed as potential antiinflammatory therapies. CN = cranial nerve; IL-1β = interleukin-1β.

Close modal

The inflammatory response is crucial for proper antimicrobial defense and healing after an aseptic injury; however, an excessive inflammatory response or failure to resolve the proinflammatory phase may lead to exaggerated tissue injury, circulatory shock, and death.3,4  The available therapy for treatment of this unbalanced inflammatory reaction remains limited: steroidal and nonsteroidal antiinflammatory drugs, small-molecule compounds, and specific anticytokine drugs in clinical use are not selective to particular tissues and often produce serious undesirable side effects. For example, systemic anti-tumor necrosis factor (TNF) therapy, which has revolutionized the treatment of several chronic inflammatory conditions, may increase the risk of opportunistic bacterial, viral, and fungal infections.5,6  The need for new, selective treatment options in inflammation is, therefore, pressing.7 

In this context, the identification of the so-called “inflammatory reflex” provided the first description of a neural circuit capable of providing information in real time to the brain about the body’s inflammatory status to allow for rapid neural regulatory responses.8,9  Yet, the neural reflexes that monitor and respond to inflammatory stimuli in real time remain oftentimes overlooked. Recent research on how peripheral neural networks both sense and respond to inflammation is providing a possible framework on which to build and implement novel clinical therapies based on the neural control of inflammation.10 

In this review, we elaborate the anatomic and physiologic basis of the inflammatory reflex as the prototype of inflammation-regulating neural circuits (section “The Inflammatory Reflex”) and review the evidence implicating this reflex in modulating clinical conditions (section “Clinical Implications of the Inflammatory Reflex”). We conclude with a discussion of active areas of research into the neuroimmune interface that aim to develop new therapeutics that exploit the nervous system to control dysregulated and nonresolving inflammation (sections “Cholinergic Antiinflammatory Pharmacologic Intervention and Bioelectronic Medicine” and “Other Neural Reflexes that Regulate Immunity”).

The vagus nerve (“the wandering nerve”) is the longest of the cranial nerves and innervates the majority of the visceral organs including the lungs, liver, and intestine with both sensory and motor fibers. The majority of vagus nerve fibers are sensory, detect a broad spectrum of mechanical and chemical stimuli, and send the information to the brain stem.11  Notably, these same fibers monitor peripheral inflammatory responses.

The work delineating the interplay between immune mediators and the sensory vagus nerve began with studies by Watkins et al., demonstrating that subdiaphragmatic vagotomies prevent the normal stress and febrile responses elicited by systemic administration of interleukin-1β.12–14  These physiologic responses were corroborated by direct electrophysiologic recordings from the afferent fibers of the hepatic branch of the vagus nerve in rats, where intraportal injection of interleukin-1β lead to a dose-dependent increase in afferent fiber activity.15,16  Moreover, bacterial products may also elicit reflex activity mediated by the vagus nerve. Recently, Fairchild et al.17  observed bradydysrhythmias within minutes of administering bacteria or fungi to mice and implicated the vagus nerve by demonstrating simultaneous activation of vagus nuclei in the brain stem. Together, these data suggest that the sensory arm of the vagus nerve can detect immune and inflammatory signals within viscera and convey that information to the brain (fig. 1B). It remains unclear, however, whether the vagus nerve itself is able to directly sense cytokines and bacterial products, if intermediate players are involved, or if both direct and indirect activation pathways are at play. An intriguing possibility is that the afferent fibers of the vagus nerve convey cytokine-specific information to the brain stem, conceivably allowing the CNS to engage differential neurophysiologic responses depending on the immunologic challenge.

In line with this postulate, recent studies of the carotid body suggest that this multimodal sensory organ also serves as a peripheral monitor of inflammation in addition to oxygen, carbon dioxide, and pH, relaying information via the carotid sinus nerve and the glossopharyngeal nerve to the brain stem.18,19  Furthermore, specific sensory nerves have a capacity to directly detect the presence of bacteria to modulate inflammation.20  Primary sensory neurons in the dorsal root and trigeminal ganglia of the peripheral nervous system express functional toll-like receptors, innate immune receptors that recognize structurally conserved microbial motifs and regulate sensory function including pain and pruritus.21–24  Interestingly, the selective deletion from nociceptive sensory neurons of myeloid differentiation primary response gene 88, a downstream signaling molecule in the toll-like receptor activation pathway, results in impaired innate and adaptive immunity.25  These results suggest that bacterial products could directly modulate neuronal excitability in certain sensory neuron populations.

The efferent arc of the inflammatory reflex (fig. 1, B and C) was first defined by Borovikova et al., who observed that electrical vagus nerve stimulation (VNS) reduced systemic levels of TNF in experimental models of severe systemic inflammation.26–28  They also found that acetylcholine—the principal neurotransmitter of the vagus nerve—decreased proinflammatory cytokine production in stimulated macrophages.26  Efferent fibers of the vagus nerve travel to the celiac ganglion where the splenic nerve originates. Splenic nerve axons terminate in close proximity to an acetylcholine-releasing subset of T cells.29,30  Norepinephrine, the transmitter released by splenic nerve terminals, promotes acetylcholine release from these T cells. This cholinergic signal activates the homomeric neuronal subtype α7 nicotinic acetylcholine receptor (α7nAChR) on immune cells, including macrophages resident within the spleen, and reduces their secretion of TNF.29,31  The intracellular mechanism for α7nAChR-mediated regulation of cytokine production in immune cells is, however, not entirely clear, but it has been described to involve phosphatidylinositol-4,5-bisphosphate 3-kinase activation, Janus Kinase 2/signal transducer and activator of transcription 3 signaling, and inhibition of the assembly of the nuclear factor κB complex in cells outside the CNS32–34  (fig. 1C). Furthermore, α7nAChR in mitochondrial membranes may regulate interleukin-1β and high-mobility group box 1 in macrophages by inhibiting inflammasome activation through a mechanism involving mitochondrial DNA release.35  Further studies of the intracellular mechanisms after α7nAChR activation in immune cells are clearly warranted. The physiologic effects, in cell culture and in vivo, are better known.9  Mice devoid of α7nAChR do not respond to α7 nicotinic acetylcholine (α7nACh) agonists or to electrical VNS with reduced TNF release, and higher levels of systemic TNF were observed in α7nAChR-deficient mice subjected to endotoxemia.31,36,37  The α7nAChR subunit in immune cells is, therefore, a key component of the cholinergic antiinflammatory pathway and an essential regulator of inflammation. Disruption of the integrity of the inflammatory reflex conversely inhibits resolution of inflammation.38  Taken together, these data suggest that the inflammatory reflex tonically balances the production and release of inflammatory mediators and plays an important role in the resolution of inflammation.39 

Given these important effects of neural signaling on inflammation and immune system activity, it is conceivable that modulation of signals in the inflammatory reflex can be used to regulate inflammation and treat disease. In fact, the inflammatory reflex has already been implicated as a potential therapeutic target across a variety of clinical conditions of regional and systemic inflammation26,34,39–59  (fig. 2). In this context, a series of pharmacologic studies in experimental animals have demonstrated a key role for this neuronal pathway in inflammation and, in particular, the essential regulatory role of α7nAChR. Pharmacologic interventions using selective or nonselective α7nAChR agonists improve survival in experimental sepsis, reduce acute neuroinflammation, and result in improved cognitive performance after aseptic surgical injury.46,60–62  Moreover, there are ongoing trials of the potential benefits from pharmacologic interventions using nicotinic agonists as well as clinical trials evaluating electrical VNS as treatment for chronic inflammatory disorders such as rheumatoid arthritis and inflammatory bowel disease (clinicaltrials.gov: NCT01552941, NCT01569503, and NCT02311660).63  These trials will evaluate the efficacy of α7nAChR agonists or VNS in these chronic conditions; the extensive preclinical and preliminary clinical data suggest promise with this approach.59,64  Recent research indicates that selective pharmacologic intervention of the α7nAChR or direct electrical stimulation of the cervical vagus nerve may serve as novel treatment strategies in the management of sepsis, ventilator-induced lung injury (VILI), postoperative cognitive dysfunction (POCD), myocardial ischemia–reperfusion injury (IRI), and hemorrhage.

Fig. 2.

Experimental disease models that respond to pharmacologic or electrical stimulation of the inflammatory reflex. A more detailed discussion of vagus nerve stimulation (VNS) in sepsis, ventilator-induced lung injury (VILI), postoperative cognitive dysfunction myocardial ischemia–reperfusion injury (IRI), and hemorrhage is provided in the main text. ICH = intracranial hemorrhage; POCD = postoperative cognitive dysfunction; α7nAChR = α7 nicotinic acetylcholine receptor.

Fig. 2.

Experimental disease models that respond to pharmacologic or electrical stimulation of the inflammatory reflex. A more detailed discussion of vagus nerve stimulation (VNS) in sepsis, ventilator-induced lung injury (VILI), postoperative cognitive dysfunction myocardial ischemia–reperfusion injury (IRI), and hemorrhage is provided in the main text. ICH = intracranial hemorrhage; POCD = postoperative cognitive dysfunction; α7nAChR = α7 nicotinic acetylcholine receptor.

Close modal

Sepsis

Sepsis is a leading cause of worldwide morbidity and mortality and refers to a syndrome of florid systemic inflammatory response as triggered by a microbial infection. Its incidence continues to rise and it has a persistently high mortality.65  At present, there are no specific therapies available targeting the inflammatory response to infection, and current treatment in sepsis is primarily based on early administration of antibiotics and mechanical removal of damaged tissues, typically combined with aggressive supportive intensive care therapy.66  The paucity of therapeutic options that directly target the septic inflammatory syndrome partly reflects not only its heterogeneous etiology but also the lack of a more comprehensive understanding of its underlying pathophysiology. A dysregulated inflammatory response and impaired neuroendocrine signaling contribute to disease progression including multiorgan failure with subsequently increased morbidity and mortality.67 

An association between changes in vagus nerve activity and systemic inflammatory responses has been observed. Analysis of heart rate variability, an indicator of vagus nerve activity, indicates that vagus nerve signals change before severe sepsis68  and are associated with compromised cardiac function.69–71  In line with these observations, early changes in heart rate variability recorded at admission in the emergency department have been associated with an increased risk of developing severe sepsis, septic shock, and death,69,72,73  further implicating a potential role for the vagus nerve in septic patients.

In agreement with these clinical and experimental observations, vagotomy increases mortality in experimental models of sepsis42,60,74,75  as does genetic ablation of the α7nAChR.37  Reciprocally, activation of the inflammatory reflex by pharmacologic interventions using selective α7nAChR agonists or direct electrical stimulation of the vagus nerve is protective, yielding not only decreased proinflammatory cytokine burden but also increased survival,42,60,74  a therapeutic benefit lost in α7nAChR-deficient mice.37  Sepsis survivors commonly suffer from long-lasting organ dysfunction, including cognitive impairment, which can be reduced by antiinflammatory therapy after recovery from the acute episode in mice.76  Interestingly, activation of the a7nAChR reduces microglial activation and cytokine release in CNS inflammation.77,78  Hence, it is conceivable that activation of cholinergic signaling and the inflammatory reflex might be beneficial for mitigating organ dysfunction in sepsis survivors, although this remains to be studied. Notably, in a human trial, nicotine (a nonselective α7nAChR agonist) attenuated the inflammatory response in individuals exposed to intravenous endotoxin.79  Hence, the α7nAChR is a key component of the inflammatory reflex, serves as a physiologic break on inflammation, and is an attractive pharmacologic target for the development of novel immunomodulatory pharmacologic therapeutics against systemic inflammatory disease and organ injury in acute inflammation due to sepsis and surgical trauma.

Ventilator-induced Lung Injury

Mechanical ventilation in the perioperative or critical care setting renders patients susceptible to VILI through cycles of stretch and overinflation concomitant to damaging inflammatory responses, so-called biotrauma.80,81  Multiple strategies to prevent VILI have focused on reducing the amount of mechanical damage to the lung tissue, while optimizing ventilation and gas exchange regimens, yet the clinical burden remains high.82  Low-tidal volume as part of lung-protective ventilation strategies may still lead to increased release of inflammatory mediators83,84  with subsequent risk for pulmonary edema and impaired gas exchange. This suggests that even with the development of novel lung-protective techniques, the inflammatory response needs to be addressed to fully abrogate the additional burden of VILI.

Experimental studies suggest that activation of the inflammatory reflex is beneficial in lung injury. For example, in burn-induced or hemorrhagic shock–induced acute lung injury mouse models, VNS reduced neutrophil infiltration into the lung as well as histologic lung injury.85,86  Similarly, nicotine, choline, or a selective α7nAChR agonist, agents that activate target receptors in the inflammatory reflex, significantly reduce acid-induced lung injury.87  Surgical vagotomy before the initiation of VILI, in contrast, lead to worsening of pulmonary inflammation and lung function, corroborating that the inflammatory reflex is a modulator of mechanical ventilation-induced biotrauma.53  In reciprocal experiments, both pharmacologic and electrical stimulation of the efferent vagus nerve was protective in a model of VILI after hemorrhagic shock and resuscitation.53  Similarly, stimulation of α7nAChR through the systemic administration of a partial agonist reduced TNF release and the alveolar–arterial gradient at clinically appropriate ventilation parameters.52  In a recent study using a two-hit rodent lung model combining acute lung injury with barotrauma, neither pharmacologic intervention with nicotine nor VNS improved lung function, yet vagotomy lead to a worsening of the pulmonary cytokine response.88  These results underscore the importance of further mechanistic studies aimed at delineating the involvement of the cholinergic system and the vagus nerve in modulating regional pulmonary and systemic inflammation. VILI offers a unique opportunity for intervention and study as the causative injury is initiated at a well-defined moment of patient care with the prescription of mechanical ventilation.

Postoperative Cognitive Dysfunction

Surgery and trauma impair cognitive functions and affect a considerable proportion of the surgical population worldwide.89,90  In surgical care, POCD is one of the most common long-term complications involving memory, learning, and attention capacity, which, when it occurs, impair postoperative rehabilitation and quality of life.91 

Postoperative cognitive dysfunction develops within the first week after surgery and may remain for several months. POCD is distinct from acute postoperative delirium, which lasts for hours or days, and from postoperative dementia, which represents a permanent reduction in higher cognitive functions. While reversible, POCD affects up to 30% of middle-aged and elderly patients at 1 week after surgery and 10% of elderly surgical patients at 3 months or even later.90,92,93  Notably, the incidence of POCD is similar after regional or general anesthesia, indicating that general anesthesia per se has minimal direct influence on long-term deficits in cognition after surgery.

The pathophysiology of surgery-induced memory decline remains unclear although preclinical models suggest a role for surgery-induced systemic inflammation leading to activation of immune cells in the CNS with subsequent neuroinflammation94,95  and neuronal dysfunction.96  Surgery and tissue damage trigger an innate immune response via release of damage-associated molecular patterns such as high-mobility group box 1 and canonical proinflammatory cytokines (TNF, interleukin-1β, interleukin-6). This systemic inflammatory milieu leads to transient endothelial dysfunction and an impairment of the blood–brain barrier (BBB) integrity, which is associated with infiltration of peripheral immune cells into the brain parenchyma and later cognitive dysfunction.97,98  In this context, activated peripheral macrophages appear to play a pivotal role by orchestrating a systemic release of inflammatory biomarkers combined with short-lasting BBB disintegration, ultimately resulting in macrophage migration into the CNS and distinct hippocampal neuroinflammation with neuronal impairment and ensuing cognitive dysfunction.46,99  Recent experimental studies have demonstrated that prophylactic administration of α7nAChR agonists before surgery prevents trauma-induced neuroinflammation, BBB disruption, and subsequent cognitive decline by inhibiting TNF release and nuclear factor κB activation in monocyte-derived peripheral macrophages.46  Efforts to translate these findings into surgical patients by analysis of cerebrospinal fluid have revealed a timely increase in pro- and antiinflammatory molecules after major cardiac and orthopedic surgery,100–103  suggesting that immune activation in the brain is present within 24 h in surgical patients. These findings demonstrate that therapeutics targeting cholinergic signaling within the inflammatory reflex pathway have the potential to provide a novel prevention and treatment strategy for POCD in humans.

Myocardial Ischemia–Reperfusion Injury

Ischemic heart disease, common in perioperative and critical care patient populations, is typically treated with reperfusion therapies. A patient presenting emergently with an acute myocardial infarction may undergo reperfusion by thrombolytic therapy or primary percutaneous coronary intervention. Alternatively, stable ischemic heart disease may be treated by coronary artery bypass surgery. Timely intervention limits infarct size, preserves systolic function, and prevents the development of heart failure. Paradoxically, however, the reperfusion process itself independently damages the myocardium, contributing up to 50% of the final infarct size.104,105  The full extent of the cardiomyocyte death constitutes the IRI.

The pathophysiology of myocardial IRI is complex, involving oxidative stress, cardiomyocyte calcium overload, and mitochondrial dysfunction.106,107  A robust inflammatory response accompanies an acute myocardial infarction, although the degree to which it is a direct contributor to the development of myocardial injury is unclear.106  At minimum, the ischemic event and subsequent reperfusion lead to reactive oxygen species production and initiate a local and systemic inflammatory response and the release of proteases, TNF, and other cytokines.107–109 

Advances directed at improving timely and effective reperfusion along with maintaining the patency of the diseased coronary vessel do not address the full extent of myocardial IRI.110  To this end, VNS has emerged as a possible therapeutic strategy in the treatment of IRI, with multiple preclinical studies demonstrating that VNS is cardioprotective, improves ventricular function, and decreases arrhythmia in the setting of IRI.50,111–116  Nevertheless, these animal studies have not been uniformly beneficial. Continuously applied right-sided VNS in a rabbit model of IRI produced increased infarct size, which was suspected to be due to increased sympathetic activation and catecholamine release.117  Intermittent VNS, in contrast, decreased infarct size in an atropine-dependent fashion.118  Similar results were observed in a swine IRI model, where left-sided intermittent VNS had a greater cardioprotective effect than a continuous stimulation protocol.119 

The observed variability likely reflects important differences in the VNS protocols. For example, the decision to stimulate the right or left cervical vagus nerves, intermittently or continuously, may significantly influence the efficacy of the therapy. The right cervical vagus nerve has more efferent cardiac fibers than the left and is thought to have a greater influence on cardiac function.119  More recently, noninvasive VNS strategies have been tried in IRI. Low-level transcutaneous stimulation of the auricular branch of the vagus nerve in a canine model of cardiac remodeling postmyocardial ischemia produced decreased infarct size and heart remodeling, improved systolic and diastolic function, and decreased systemic C-reactive protein and N-terminal probrain-type natriuretic peptide levels.120 

Mechanistically, VNS during ischemia appears to decrease infarct size through nicotinic receptor activation112 ; however, the specific molecular pathways that are activated remain poorly defined. It has been postulated that VNS can induce a cardioprotective ischemic preconditioning-like state that includes activation of the phosphatidylinositol-4,5-bisphosphate 3-kinase pathway and inhibition of glycogen synthase kinase-3β by phosphorylation.118,121,122  These signaling pathways ultimately reduce interstitial myoglobin, norepinephrine, and matrix metalloprotease levels important in tissue remodeling.123–125  The detailed molecular mechanisms by which these VNS-activated pathways preserve cardiac function remains an active area of research and will likely continue to inform the design of future experimental VNS protocols in IRI management.

Hemorrhage and Coagulopathy

Coagulopathy and hemorrhage are frequently encountered in high-energy blunt or penetrating trauma and in the critically ill patient populations. Traumatic hemorrhage remains one of the most common causes of preventable death,126  with a notable morbidity and mortality burden in younger adults. Within the operating room, the ability to maintain hemostasis has benefitted from improvements in surgical approach; however, control of intraoperative bleeding can readily deteriorate in the setting of coagulopathy.

While surgical technique, coagulation factors, and blood products remain central to the management of hemorrhage, clinical best practices continue to evolve. Given the magnitude of this perioperative challenge, the development of so-called neural tourniquet approaches based on animal experiments has been proposed.127  In particular, recent studies have mapped the effects of VNS and cholinergic agonists in experimental models of bleeding. VNS reduces bleeding time and blood loss in porcine traumatic injury by approximately 50%.47  Notably, this was not a function of hemodynamic effects resulting from activation of vagus nerve cardiac fibers. In fact, the investigators found that the electrical stimulation as compared to sham controls had increased thrombin-antithrombin complex concentration at the site of injury, suggestive of a bona fide biochemical mechanism to the effect.47  It is tempting to speculate that specific pharmacologic treatment or nerve stimulation strategies that physiologically facilitate coagulation might be used therapeutically pre-, intra-, and postoperatively to reduce blood loss and aid surgical hemostasis. We eagerly await future reports that will provide a greater mechanistic understanding of these observations in animal studies and inform possible novel clinical therapeutic interventions for the treatment of coagulopathies, traumatic injury, and intraoperative hemorrhage.

With the cholinergic inflammatory reflex and the vagus nerve as a prototype, the role of neural control of inflammation is becoming increasingly recognized as a therapeutic target in clinical medicine. The animal studies discussed in the section “Clinical Implications of the Inflammatory Reflex” offer a framework for designing clinical trials that employ pharmacologic or electrical interventions to treat inflammatory conditions through cholinergic pathways.

Pharmacologic Interventions of the Cholinergic System

Pharmacologically, the neuronal control of inflammation can be modulated by stimulation or inhibition of the cholinergic system using nicotinic α7nAChR agonists or antagonists, respectively. Since the initial demonstration of the role of the α7nACh receptor subtype for the regulation of inflammation, in particular peripheral macrophages,37  a series of experimental studies on acute inflammation as triggered by either infection or trauma in animals and humans have demonstrated promising effects on outcomes.

Anesthesiologists and critical care physicians have a longstanding familiarity with medications that target the cholinergic system, such as acetylcholinesterase inhibitors for the reversal of nondepolarizing neuromuscular blockade. Yet, the approved agents used routinely in the perioperative setting have not been shown to have clinically significant antiinflammatory effects. Moreover, given the pleiotropic effects of direct and indirect cholinergic agonists, it is unlikely that these agents, used in isolation, will be at the forefront of pharmacologic interventions that target inflammation through the neuroimmune interface. Targeting the α7nAChR specifically will avoid the untoward side effects affecting locomotor activity and autonomic dysfunction that result from stimulation of other nicotinic receptors such as α3nACh, α4nACh, α5nACh, and β2nAChR. To this end, investigators have been developing an array of specific small-molecule modulators of the α7nAChR activity.

GTS-21 (3-[2,4-dimethoxybenzylidene] anabaseine) was one of the first such α7nAChR agonists to be studied for its immune-modulating capacity. GTS-21 was found to suppress proinflammatory cytokine production in human macrophages stimulated by endotoxin128  as well as improve survival in animal models of sepsis60  and hemorrhage.129  To extend these findings toward patient care, a double-blind placebo-controlled pilot human study was conducted in healthy volunteers exposed to intravenous endotoxin.130  This study did not show any effect of the drug on proinflammatory cytokine serum levels compared with the placebo group; however, high plasma levels of the drug correlated with lower levels of TNF and interleukin-6.130  The study was largely underpowered and limited by the considerable intersubject variability in cytokine levels and the achieved levels of GTS-21 or its active metabolite. It was further complicated by the incomplete information on the specificity of GTS-21 for human α7nAChR.131 

The inflammatory reflex can likewise be activated by cholinergic agents that act at the level of the CNS. For example, galantamine, a Federal Drug Agency–approved drug for the treatment of Alzheimer disease, is a centrally acting acetylcholinesterase inhibitor that activates the efferent arm of the inflammatory reflex.132  In an experimental model of endotoxemia in mice, galantamine decreased TNF levels and improved survival, an effect dependent on α7nAChR. Although galantamine acts centrally, the α7nAChR dependence presumably reflects the importance of this receptor in completing the antiinflammatory efferent arc at the level of the spleen.132  Galantamine has been shown to be similarly beneficial in animal models of experimental colitis133  and obesity-associated inflammation.134  In the latter study, treatment of obese mice with galantamine decreased circulating levels of proinflammatory cytokines, such as interleukin-6, as well as decreased food intake and body weight while alleviating impaired glucose tolerance.134  These encouraging preclinical data have since informed the design of a phase 4 clinical trial investigating the efficacy of galantamine in the treatment of patients with metabolic syndrome (clinicaltrials.gov: NCT02283242).

The overall strength of the preclinical findings and accumulating human data maintain the ongoing enthusiasm for pharmacologically targeting antiinflammatory cholinergic pathways. Moving forward, researchers are working toward specific neuronal nicotinic AChR agonists, including for the α7nAChR. To the best of our knowledge, as of yet, no clinical trials of these agents in perioperative or critical care have started but are greatly anticipated.

Bioelectronic Medicine

Another approach to modulate the inflammatory reflex and the neural control of inflammation is by electrical nerve stimulation. Bioelectronic medicine63,135,136  is the interdisciplinary field that brings together molecular medicine, neuroscience, engineering, and clinical medicine. The field holds great promise for targeted and specific therapy in the treatment of inflammatory diseases, for example, by modulating signals in neural reflexes (fig. 3). A current objective in the field at large is to develop electrical recording devices that interrogate the neural activity moving through the nerve and translate the neural code into an interpretable physiologic readout. While the field remains in its infancy, the confluence of improved electrical recording hardware, wireless technologies, and data analytics brings our ability to decipher an immunologic code within the realm of possibility. Ultimately, the goal is to develop either implantable or transcutaneous devices capable of recording and interpreting sensory information that inform ensuing modulatory signals in efferent nerves to support homeostasis and treat diseases.

Fig. 3.

Bioelectronic medicine. Bioelectronic medicine treats disease through the use of electricity to activate or inhibit neural circuits. This therapeutic modality can interface with both the afferent and efferent branches of a neural reflex to modulate the amount of information propagating down the nerve fibers. The long-term objective of this therapeutic approach is to allow clinicians to record the electrical activity in the nerve so as to extract real-time information about patient status. This information can be incorporated into diagnosis and monitoring algorithms as well as inform therapeutic delivery of either electrical or pharmacologic treatment in a patient-specific fashion.

Fig. 3.

Bioelectronic medicine. Bioelectronic medicine treats disease through the use of electricity to activate or inhibit neural circuits. This therapeutic modality can interface with both the afferent and efferent branches of a neural reflex to modulate the amount of information propagating down the nerve fibers. The long-term objective of this therapeutic approach is to allow clinicians to record the electrical activity in the nerve so as to extract real-time information about patient status. This information can be incorporated into diagnosis and monitoring algorithms as well as inform therapeutic delivery of either electrical or pharmacologic treatment in a patient-specific fashion.

Close modal

The therapeutic use of electricity has a well-established precedence within the CNS. Deep brain stimulation is approved for treatment of Parkinson disease and depression. It was in fact within the context of illnesses of the CNS that VNS became recognized as a therapeutic modality. First used clinically nearly 30 yr ago, VNS was introduced for the treatment of epilepsy in 1988137  and eventually approved in both the United States and Canada in 1997. In VNS, a bipolar helical electrode is surgically placed around the cervical vagus nerve, and an implanted stimulator similar to a conventional pacemaker delivers electrical charges that directly activate the vagus nerve. The efficacy of VNS in epilepsy is well defined across adult and pediatric populations with significant reductions in seizure frequency and duration along with improved postictal recovery.138–140  The clinical indication for VNS has expanded to include chronic treatment–resistant depression,141–144  and VNS is being explored in other diseases involving the CNS, such as migraine and eating disorders.145,146 

More recently, clinical trials are exploiting the vagus nerve’s control of chronic inflammatory responses in the context of autoimmune diseases, including inflammatory bowel disease and rheumatoid arthritis.64,147  In a pilot, open-label study, eight patients with active rheumatoid arthritis were implanted with a commercially available vagus nerve stimulator and received 6 weeks of daily stimulation. According to preliminary data, the VNS-treated patients showed improved clinical symptoms, with the therapy being well tolerated by study participants.64,147 

During the implantation procedure, the vagus nerve is stimulated to test device functionality. In less than 0.1% of patients, the test can elicit a bradyarrhythmia or transient asystole, although this adverse event has only been reported at the time of the intraoperative stimulation and resolves when stimulation is stopped.148  Postoperative surgical site infection and vocal cord paresis are rare, occurring in approximately 3 to 6% and less than 1% of patients, respectively.148  With use of the vagus nerve stimulator, the reported side effects include hoarseness, throat pain, and coughing and are largely limited to the periods of actual stimulation and commonly alleviate with time.148–150  Importantly, a 1-min-long daily electrical stimulation of the vagus nerve is sufficient to alleviate experimental inflammatory disease, with more recent findings indicating that even stimulation times of as little as 500 μs, may be sufficient to significantly reduce an inflammatory response in animal models.151  Treatment strategies with very low-stimulation duty cycles may allow for innovative, smaller stimulator designs with longer service intervals and fewer side effects in patients with chronic inflammation.

Although extensive experimental data in animal models indicate that VNS is effective for the treatment of acute inflammation, the effect on human acute inflammation has not been evaluated in clinical trials. At present, the only available data come from a few small studies in patients with VNS-treated epilepsy and demonstrate variable changes in serum cytokine levels associated with VNS.152–155  These data are limited and largely inconclusive given that the patients studied had epilepsy but not inflammatory conditions per se. In another small study of 10 patients with treatment-resistant depression, both pro- and antiinflammatory cytokines increased in the 3 months after VNS device implantation.156 

While medical device technology continues to evolve, VNS has yet to be adapted for temporary, preferably noninvasive, stimulation. Several initiatives are underway, and access to safe and reliable noninvasive methods for specific VNS would significantly facilitate clinical studies of the potential efficacy of VNS in perioperative and intensive care medicine.

In addition to the inflammatory reflex, multiple other peripheral neural circuits that regulate inflammation have been described157,158  (fig. 4). These include modulation of inflammatory pulmonary airway hyperresponsiveness and nociceptive neuron modulation of infection.

Fig. 4.

Examples of neural control of inflammatory processes. (A) Stimulation of the hypothalamic–pituitary–adrenal (HPA) axis initiates a neuroendocrine sequence resulting in glucocorticoid release and suppression of the inflammatory response. (B) Activation of the sciatic nerve by electroacupuncture inhibits cytokine release and improves survival in a mouse model of sepsis. The neural circuit maps from the sensory sciatic nerve to the efferent fibers of the vagus nerve. In this case, the vagus nerve signal results in the release of dopamine from the adrenal medulla. The dopamine engages dopaminergic type 1 receptors to suppress the inflammatory response. (C) After stroke, noradrenergic innervation of the liver signal to hepatic invariant natural killer T (iNKT) promotes immunosuppression. Blockade of adrenergic signaling (e.g., β-blockade with propranolol) reduces immunosuppression, protects against infection, and improves survival. (D) Infection with the bacterium Staphylococcus aureus results in an acute pain response caused by the direct activation of peripheral nociceptors by bacterial products. In addition to transducing a signal toward the central nervous system, receptor stimulation at the nerve terminal generates an antidromic axon–axon reflex that results in the release of neuropeptides that impair the recruitment and activation of locally infiltrating immune cells. (E) In an imiquimod-induced model of skin inflammation, a subset of nociceptors that express TRPV1 and Nav1.8 promote local inflammation through the induction of interleukin (IL)-23 production by skin-resident dendritic cells. In turn, the IL-23 activates other immune cells within the skin to secrete the IL-17 and IL-22 that ultimately propel psoriasiform skin inflammation. CNS = central nervous system; NE = norepinephrine; TH2 = T helper cell type 2.

Fig. 4.

Examples of neural control of inflammatory processes. (A) Stimulation of the hypothalamic–pituitary–adrenal (HPA) axis initiates a neuroendocrine sequence resulting in glucocorticoid release and suppression of the inflammatory response. (B) Activation of the sciatic nerve by electroacupuncture inhibits cytokine release and improves survival in a mouse model of sepsis. The neural circuit maps from the sensory sciatic nerve to the efferent fibers of the vagus nerve. In this case, the vagus nerve signal results in the release of dopamine from the adrenal medulla. The dopamine engages dopaminergic type 1 receptors to suppress the inflammatory response. (C) After stroke, noradrenergic innervation of the liver signal to hepatic invariant natural killer T (iNKT) promotes immunosuppression. Blockade of adrenergic signaling (e.g., β-blockade with propranolol) reduces immunosuppression, protects against infection, and improves survival. (D) Infection with the bacterium Staphylococcus aureus results in an acute pain response caused by the direct activation of peripheral nociceptors by bacterial products. In addition to transducing a signal toward the central nervous system, receptor stimulation at the nerve terminal generates an antidromic axon–axon reflex that results in the release of neuropeptides that impair the recruitment and activation of locally infiltrating immune cells. (E) In an imiquimod-induced model of skin inflammation, a subset of nociceptors that express TRPV1 and Nav1.8 promote local inflammation through the induction of interleukin (IL)-23 production by skin-resident dendritic cells. In turn, the IL-23 activates other immune cells within the skin to secrete the IL-17 and IL-22 that ultimately propel psoriasiform skin inflammation. CNS = central nervous system; NE = norepinephrine; TH2 = T helper cell type 2.

Close modal

Airway Hyperresponsiveness

The lung contains a dense network of nociceptive neurons that respond to inhaled noxious chemical stimuli via transient receptor potential (TRP) channels, including TRP vanilloid 1 (TRPV1) and TRP ankyrin 1. When activated, these nociceptors initiate protective coughing reflexes and mucus secretion.159  Airway hyperresponsiveness in the setting of chronic inflammation and increased mucus secretion are hallmarks of asthma. These features, including local inflammation, reflect activation of pulmonary airway afferent neural pathways. For example, in allergic and nonallergic mouse models of asthma, genetic ablation or pharmacologic inhibition of TRPV1 and TRP ankyrin 1 channels eliminates airway hyperresponsiveness,160,161  which appears to be driven primarily by a subset of TRPV1-positive vagus nerve neurons.162 

Stimulation of pulmonary nociceptors with capsaicin results in increased neuropeptide release and immune cell infiltration, whereas genetic ablation or pharmacologic inhibition of NaV1.8-positive neurons was protective against airway inflammation and hyperresponsiveness in murine models of allergic asthma.163  Notably, interleukin-5, an important cytokine in eosinophil activation, was shown to directly stimulate nociceptors to release vasoactive intestinal peptide, which in turn activates resident immune cells and promotes the allergic response.163  These data are consistent with earlier work that demonstrated that allergic asthma is diminished in mice with systemic denervation. In this case, denervation resulted in decreased interleukin-5 release and chemokine production, thereby limiting the number of eosinophils that infiltrated into the tissue.158,164,165  Accordingly, current work is being directed toward whether pharmacologic inhibitors of pulmonary nociceptive pathways represent a new therapeutic target for asthma and inflammatory pulmonary disease.

Infection

While chemical irritants and sterile inflammatory pathways are modulated by peripheral neural networks, the same appears true for infectious inflammation. The dense network of peripheral nociceptive neurons ensures that invading microorganisms will encounter neural tissue independent of their point of entry. In turn, the peripheral nervous system interfaces with the immune system to modulate the inflammatory response to invading microorganisms. For instance, chemical ablation of sensory neurons in Mycoplasma infection increases tissue damage, tracheal thickness, and disease severity.166  Similarly, genetic deletion of TRPV1 in mice subjected to experimental sepsis impairs bacterial clearance, worsens end-organ damage, and exacerbates a detrimental cytokine production.167 

Recent work suggests that this relationship stems from direct activation of nociceptive neurons by bacterial toxins so as to initiate a rapid response to infection,20,168  in part through the production of neuropeptides.169  Ablation of NaV1.8-positive neurons before Staphylococcus aureus inoculation in mice lead to increased leukocyte infiltration to the site of infection and draining lymphadenopathy.20  In this model, bacterial products, including N-formylated peptides and α-hemolysin toxin, directly activate axon–axon reflexes via formyl peptide receptors and a disintegrin and metalloprotease 10, respectively, and thereby result in the release of antiinflammatory neuropeptide, such as calcitonin gene–related peptide (CGRP).20  NaV1.8 neuron ablation prevents CGRP release and thus promotes the inflammatory phenotype. Conversely, administration of exogenous CGRP is protective against otherwise lethal endotoxemia, decreasing pro- and increasing antiinflammatory cytokines.170 

Further examples of peripheral neural networks that modulate inflammatory processes continue to be described171–174  and have been reviewed elsewhere.157,158  It is likely that a large number of additional neural reflex circuits that regulate inflammation and immunity yet remain to be discovered. As our mechanistic understanding of these physiologic processes increase, we predict that measuring and modulating activity of specific neural circuits using bioelectronic medicine will eventually become part of patient care in many diseases with an inflammatory component.

The immune system, similar to other organ systems, is regulated by the CNS through neural reflexes, with the inflammatory reflex involving α7nACh-dependent chemical neurotransmission and the vagus nerve being the most highly studied pathway. As inflammation is part of the pathogenesis of a diverse and important set of diseases commonly encountered in perioperative and critical care patients, this neural regulation may allow for new treatment possibilities. Approaching the neural control mechanisms of inflammation by novel pharmacologic and technical principles provides a new and exciting possibility for prevention and treatment of acute and chronic inflammation.

Future research and clinical trials should focus on introducing pharmacologic interventions applying α7nAChR agonists in clinical practice and work to improve technology for recording nerve activity and delivering specific electrical signals to targeted nerves in order to ultimately mitigate the physiologic trespass of an acute traumatic or chronic inflammatory insult and improve patient health.

This study was supported by a Clinician Investigator Program fellowship from the Ministry of Health (Ontario, Canada; to Dr. Steinberg), Svenska Läkaresällskapet (Stockholm, Sweden; to Dr. Olofsson), the Knut and Alice Wallenberg Foundation (Stockholm, Sweden; to Dr. Olofsson), and the Heart-Lung Foundation (Stockholm, Sweden; to Dr. Olofsson).

The authors declare no competing interests.

1.
Glick
DB
:
The autonomic nervous system
in
Miller’s Anesthesia
, 8th edition. Edited by
Miller
RD
,
Cohen
NH
,
Eriksson
LI
,
Fleisher
LA
,
Wiener-Kronish
JP
,
Young
WL
.
Philadelphia
,
Elsevier Saunders
,
2014
, pp
pp 346
86
2.
Thomas
GD
:
Neural control of the circulation.
Adv Physiol Educ
2011
;
35
:
28
32
3.
Hotchkiss
RS
,
Monneret
G
,
Payen
D
:
Immunosuppression in sepsis: A novel understanding of the disorder and a new therapeutic approach.
Lancet Infect Dis
2013
;
13
:
260
8
4.
Tracey
KJ
,
Beutler
B
,
Lowry
SF
,
Merryweather
J
,
Wolpe
S
,
Milsark
IW
,
Hariri
RJ
,
Fahey
TJ
III
,
Zentella
A
,
Albert
JD
:
Shock and tissue injury induced by recombinant human cachectin.
Science
1986
;
234
:
470
4
5.
Ramiro
S
,
Gaujoux-Viala
C
,
Nam
JL
,
Smolen
JS
,
Buch
M
,
Gossec
L
,
van der Heijde
D
,
Winthrop
K
,
Landewé
R
:
Safety of synthetic and biological DMARDs: A systematic literature review informing the 2013 update of the EULAR recommendations for management of rheumatoid arthritis.
Ann Rheum Dis
2014
;
73
:
529
35
6.
Ali
T
,
Kaitha
S
,
Mahmood
S
,
Ftesi
A
,
Stone
J
,
Bronze
MS
:
Clinical use of anti-TNF therapy and increased risk of infections.
Drug Healthc Patient Saf
2013
;
5
:
79
99
7.
Nathan
C
,
Ding
A
:
Nonresolving inflammation.
Cell
2010
;
140
:
871
82
8.
Tracey
KJ
:
The inflammatory reflex.
Nature
2002
;
420
:
853
9
9.
Olofsson
PS
,
Rosas-Ballina
M
,
Levine
YA
,
Tracey
KJ
:
Rethinking inflammation: Neural circuits in the regulation of immunity.
Immunol Rev
2012
;
248
:
188
204
10.
Steinberg
BE
,
Tracey
KJ
,
Slutsky
AS
:
Bacteria and the neural code.
N Engl J Med
2014
;
371
:
2131
3
11.
Berthoud
HR
,
Neuhuber
WL
:
Functional and chemical anatomy of the afferent vagal system.
Auton Neurosci
2000
;
85
:
1
17
12.
Watkins
LR
,
Goehler
LE
,
Relton
JK
,
Tartaglia
N
,
Silbert
L
,
Martin
D
,
Maier
SF
:
Blockade of interleukin-1 induced hyperthermia by subdiaphragmatic vagotomy: Evidence for vagal mediation of immune-brain communication.
Neurosci Lett
1995
;
183
:
27
31
13.
Watkins
LR
,
Wiertelak
EP
,
Goehler
LE
,
Smith
KP
,
Martin
D
,
Maier
SF
:
Characterization of cytokine-induced hyperalgesia.
Brain Res
1994
;
654
:
15
26
14.
Hansen
MK
,
O’Connor
KA
,
Goehler
LE
,
Watkins
LR
,
Maier
SF
:
The contribution of the vagus nerve in interleukin-1beta-induced fever is dependent on dose.
Am J Physiol Regul Integr Comp Physiol
2001
;
280
:
R929
34
15.
Niijima
A
,
Hori
T
,
Katafuchi
T
,
Ichijo
T
:
The effect of interleukin-1 beta on the efferent activity of the vagus nerve to the thymus.
J Auton Nerv Syst
1995
;
54
:
137
44
16.
Niijima
A
:
The afferent discharges from sensors for interleukin 1 beta in the hepatoportal system in the anesthetized rat.
J Auton Nerv Syst
1996
;
61
:
287
91
17.
Fairchild
KD
,
Srinivasan
V
,
Moorman
JR
,
Gaykema
RP
,
Goehler
LE
:
Pathogen-induced heart rate changes associated with cholinergic nervous system activation.
Am J Physiol Regul Integr Comp Physiol
2011
;
300
:
R330
9
18.
Zapata
P
,
Larraín
C
,
Reyes
P
,
Fernández
R
:
Immunosensory signalling by carotid body chemoreceptors.
Respir Physiol Neurobiol
2011
;
178
:
370
4
19.
Shu
HF
,
Wang
BR
,
Wang
SR
,
Yao
W
,
Huang
HP
,
Zhou
Z
,
Wang
X
,
Fan
J
,
Wang
T
,
Ju
G
:
IL-1beta inhibits IK and increases [Ca2+]i in the carotid body glomus cells and increases carotid sinus nerve firings in the rat.
Eur J Neurosci
2007
;
25
:
3638
47
20.
Chiu
IM
,
Heesters
BA
,
Ghasemlou
N
,
Von Hehn
CA
,
Zhao
F
,
Tran
J
,
Wainger
B
,
Strominger
A
,
Muralidharan
S
,
Horswill
AR
,
Bubeck Wardenburg
J
,
Hwang
SW
,
Carroll
MC
,
Woolf
CJ
:
Bacteria activate sensory neurons that modulate pain and inflammation.
Nature
2013
;
501
:
52
7
21.
Liu
T
,
Gao
YJ
,
Ji
RR
:
Emerging role of Toll-like receptors in the control of pain and itch.
Neurosci Bull
2012
;
28
:
131
44
22.
Liu
T
,
Berta
T
,
Xu
ZZ
,
Park
CK
,
Zhang
L
,
N
,
Liu
Q
,
Liu
Y
,
Gao
YJ
,
Liu
YC
,
Ma
Q
,
Dong
X
,
Ji
RR
:
TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice.
J Clin Invest
2012
;
122
:
2195
207
23.
Liu
T
,
Xu
ZZ
,
Park
CK
,
Berta
T
,
Ji
RR
:
Toll-like receptor 7 mediates pruritus.
Nat Neurosci
2010
;
13
:
1460
2
24.
Li
Y
,
Zhang
H
,
Zhang
H
,
Kosturakis
AK
,
Jawad
AB
,
Dougherty
PM
:
Toll-like receptor 4 signaling contributes to paclitaxel-induced peripheral neuropathy.
J Pain
2014
;
15
:
712
25
25.
Liu
XJ
,
Zhang
Y
,
Liu
T
,
Xu
ZZ
,
Park
CK
,
Berta
T
,
Jiang
D
,
Ji
RR
:
Nociceptive neurons regulate innate and adaptive immunity and neuropathic pain through MyD88 adapter.
Cell Res
2014
;
24
:
1374
7
26.
Borovikova
LV
,
Ivanova
S
,
Zhang
M
,
Yang
H
,
Botchkina
GI
,
Watkins
LR
,
Wang
H
,
Abumrad
N
,
Eaton
JW
,
Tracey
KJ
:
Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin.
Nature
2000
;
405
:
458
62
27.
Borovikova
LV
,
Ivanova
S
,
Nardi
D
,
Zhang
M
,
Yang
H
,
Ombrellino
M
,
Tracey
KJ
:
Role of vagus nerve signaling in CNI-1493-mediated suppression of acute inflammation.
Auton Neurosci
2000
;
85
:
141
7
28.
Bernik
TR
,
Friedman
SG
,
Ochani
M
,
DiRaimo
R
,
Susarla
S
,
Czura
CJ
,
Tracey
KJ
:
Cholinergic antiinflammatory pathway inhibition of tumor necrosis factor during ischemia reperfusion.
J Vasc Surg
2002
;
36
:
1231
6
29.
Rosas-Ballina
M
,
Olofsson
PS
,
Ochani
M
,
Valdés-Ferrer
SI
,
Levine
YA
,
Reardon
C
,
Tusche
MW
,
Pavlov
VA
,
Andersson
U
,
Chavan
S
,
Mak
TW
,
Tracey
KJ
:
Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit.
Science
2011
;
334
:
98
101
30.
Rosas-Ballina
M
,
Ochani
M
,
Parrish
WR
,
Ochani
K
,
Harris
YT
,
Huston
JM
,
Chavan
S
,
Tracey
KJ
:
Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia.
Proc Natl Acad Sci USA
2008
;
105
:
11008
13
31.
Olofsson
PS
,
Katz
DA
,
Rosas-Ballina
M
,
Levine
YA
,
Ochani
M
,
Valdés-Ferrer
SI
,
Pavlov
VA
,
Tracey
KJ
,
Chavan
SS
:
α7 nicotinic acetylcholine receptor (α7nAChR) expression in bone marrow-derived non-T cells is required for the inflammatory reflex.
Mol Med
2012
;
18
:
539
43
32.
Arredondo
J
,
Chernyavsky
AI
,
Jolkovsky
DL
,
Pinkerton
KE
,
Grando
SA
:
Receptor-mediated tobacco toxicity: Cooperation of the Ras/Raf-1/MEK1/ERK and JAK-2/STAT-3 pathways downstream of alpha7 nicotinic receptor in oral keratinocytes.
FASEB J
2006
;
20
:
2093
101
33.
Sugano
N
,
Shimada
K
,
Ito
K
,
Murai
S
:
Nicotine inhibits the production of inflammatory mediators in U937 cells through modulation of nuclear factor-kappaB activation.
Biochem Biophys Res Commun
1998
;
252
:
25
8
34.
de Jonge
WJ
,
van der Zanden
EP
;
The FO
Bijlsma
MF
,
van Westerloo
DJ
,
Bennink
RJ
,
Berthoud
HR
,
Uematsu
S
,
Akira
S
,
van den Wijngaard
RM
,
Boeckxstaens
GE
;
The FO
:
Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway.
Nat Immunol
2005
;
6
:
844
51
35.
Lu
B
,
Kwan
K
,
Levine
YA
,
Olofsson
PS
,
Yang
H
,
Li
J
,
Joshi
S
,
Wang
H
,
Andersson
U
,
Chavan
SS
,
Tracey
KJ
:
α7 nicotinic acetylcholine receptor signaling inhibits inflammasome activation by preventing mitochondrial DNA release.
Mol Med
2014
;
20
:
350
8
36.
Parrish
WR
,
Rosas-Ballina
M
,
Gallowitsch-Puerta
M
,
Ochani
M
,
Ochani
K
,
Yang
LH
,
Hudson
L
,
Lin
X
,
Patel
N
,
Johnson
SM
,
Chavan
S
,
Goldstein
RS
,
Czura
CJ
,
Miller
EJ
,
Al-Abed
Y
,
Tracey
KJ
,
Pavlov
VA
:
Modulation of TNF release by choline requires alpha7 subunit nicotinic acetylcholine receptor-mediated signaling.
Mol Med
2008
;
14
:
567
74
37.
Wang
H
,
Yu
M
,
Ochani
M
,
Amella
CA
,
Tanovic
M
,
Susarla
S
,
Li
JH
,
Wang
H
,
Yang
H
,
Ulloa
L
,
Al-Abed
Y
,
Czura
CJ
,
Tracey
KJ
:
Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation.
Nature
2003
;
421
:
384
8
38.
Mirakaj
V
,
Dalli
J
,
Granja
T
,
Rosenberger
P
,
Serhan
CN
:
Vagus nerve controls resolution and pro-resolving mediators of inflammation.
J Exp Med
2014
;
211
:
1037
48
39.
Andersson
U
,
Tracey
KJ
:
Reflex principles of immunological homeostasis.
Annu Rev Immunol
2012
;
30
:
313
35
40.
Huston
JM
,
Ochani
M
,
Rosas-Ballina
M
,
Liao
H
,
Ochani
K
,
Pavlov
VA
,
Gallowitsch-Puerta
M
,
Ashok
M
,
Czura
CJ
,
Foxwell
B
,
Tracey
KJ
,
Ulloa
L
:
Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis.
J Exp Med
2006
;
203
:
1623
8
41.
Hofer
S
,
Eisenbach
C
,
Lukic
IK
,
Schneider
L
,
Bode
K
,
Brueckmann
M
,
Mautner
S
,
Wente
MN
,
Encke
J
,
Werner
J
,
Dalpke
AH
,
Stremmel
W
,
Nawroth
PP
,
Martin
E
,
Krammer
PH
,
Bierhaus
A
,
Weigand
MA
:
Pharmacologic cholinesterase inhibition improves survival in experimental sepsis.
Crit Care Med
2008
;
36
:
404
8
42.
Huston
JM
,
Gallowitsch-Puerta
M
,
Ochani
M
,
Ochani
K
,
Yuan
R
,
Rosas-Ballina
M
,
Ashok
M
,
Goldstein
RS
,
Chavan
S
,
Pavlov
VA
,
Metz
CN
,
Yang
H
,
Czura
CJ
,
Wang
H
,
Tracey
KJ
:
Transcutaneous vagus nerve stimulation reduces serum high mobility group box 1 levels and improves survival in murine sepsis.
Crit Care Med
2007
;
35
:
2762
8
43.
Boland
C
,
Collet
V
,
Laterre
E
,
Lecuivre
C
,
Wittebole
X
,
Laterre
PF
:
Electrical vagus nerve stimulation and nicotine effects in peritonitis-induced acute lung injury in rats.
Inflammation
2011
;
34
:
29
35
44.
Lee
ST
,
Chu
K
,
Jung
KH
,
Kang
KM
,
Kim
JH
,
Bahn
JJ
,
Jeon
D
,
Kim
M
,
Lee
SK
,
Roh
JK
:
Cholinergic anti-inflammatory pathway in intracerebral hemorrhage.
Brain Res
2010
;
1309
:
164
71
45.
Su
X
,
Feng
X
,
Terrando
N
,
Yan
Y
,
Chawla
A
,
Koch
LG
,
Britton
SL
,
Matthay
MA
,
Maze
M
:
Dysfunction of inflammation-resolving pathways is associated with exaggerated postoperative cognitive decline in a rat model of the metabolic syndrome.
Mol Med
2012
;
18
:
1481
90
46.
Terrando
N
,
Eriksson
LI
,
Ryu
JK
,
Yang
T
,
Monaco
C
,
Feldmann
M
,
Jonsson Fagerlund
M
,
Charo
IF
,
Akassoglou
K
,
Maze
M
:
Resolving postoperative neuroinflammation and cognitive decline.
Ann Neurol
2011
;
70
:
986
95
47.
Czura
CJ
,
Schultz
A
,
Kaipel
M
,
Khadem
A
,
Huston
JM
,
Pavlov
VA
,
Redl
H
,
Tracey
KJ
:
Vagus nerve stimulation regulates hemostasis in swine.
Shock
2010
;
33
:
608
13
48.
Guarini
S
,
Altavilla
D
,
Cainazzo
MM
,
Giuliani
D
,
Bigiani
A
,
Marini
H
,
Squadrito
G
,
Minutoli
L
,
Bertolini
A
,
Marini
R
,
Adamo
EB
,
Venuti
FS
,
Squadrito
F
:
Efferent vagal fibre stimulation blunts nuclear factor-kappaB activation and protects against hypovolemic hemorrhagic shock.
Circulation
2003
;
107
:
1189
94
49.
Xiong
J
,
Yuan
YJ
,
Xue
FS
,
Wang
Q
,
Cheng
Y
,
Li
RP
,
Liao
X
,
Liu
JH
:
Postconditioning with α7nAChR agonist attenuates systemic inflammatory response to myocardial ischemia–reperfusion injury in rats.
Inflammation
2012
;
35
:
1357
64
50.
Mioni
C
,
Bazzani
C
,
Giuliani
D
,
Altavilla
D
,
Leone
S
,
Ferrari
A
,
Minutoli
L
,
Bitto
A
,
Marini
H
,
Zaffe
D
,
Botticelli
AR
,
Iannone
A
,
Tomasi
A
,
Bigiani
A
,
Bertolini
A
,
Squadrito
F
,
Guarini
S
:
Activation of an efferent cholinergic pathway produces strong protection against myocardial ischemia/reperfusion injury in rats.
Crit Care Med
2005
;
33
:
2621
8
51.
Brégeon
F
,
Xeridat
F
,
Andreotti
N
,
Lepidi
H
,
Delpierre
S
,
Roch
A
,
Ravailhe
S
,
Jammes
Y
,
Steinberg
JG
:
Activation of nicotinic cholinergic receptors prevents ventilator-induced lung injury in rats.
PLoS One
2011
;
6
:
e22386
52.
Kox
M
,
Pompe
JC
,
Peters
E
,
Vaneker
M
,
van der Laak
JW
,
van der Hoeven
JG
,
Scheffer
GJ
,
Hoedemaekers
CW
,
Pickkers
P
:
α7 nicotinic acetylcholine receptor agonist GTS-21 attenuates ventilator-induced tumour necrosis factor-α production and lung injury.
Br J Anaesth
2011
;
107
:
559
66
53.
dos Santos
CC
,
Shan
Y
,
Akram
A
,
Slutsky
AS
,
Haitsma
JJ
:
Neuroimmune regulation of ventilator-induced lung injury.
Am J Respir Crit Care Med
2011
;
183
:
471
82
54.
Song
XM
,
Li
JG
,
Wang
YL
,
Liang
H
,
Huang
Y
,
Yuan
X
,
Zhou
Q
,
Zhang
ZZ
:
Effect of vagus nerve stimulation on thermal injury in rats.
Burns
2010
;
36
:
75
81
55.
Costantini
TW
,
Bansal
V
,
Peterson
CY
,
Loomis
WH
,
Putnam
JG
,
Rankin
F
,
Wolf
P
,
Eliceiri
BP
,
Baird
A
,
Coimbra
R
:
Efferent vagal nerve stimulation attenuates gut barrier injury after burn: Modulation of intestinal occludin expression.
J Trauma
2010
;
68
:
1349
54; discussion 1354–6
56.
Meregnani
J
,
Clarençon
D
,
Vivier
M
,
Peinnequin
A
,
Mouret
C
,
Sinniger
V
,
Picq
C
,
Job
A
,
Canini
F
,
Jacquier-Sarlin
M
,
Bonaz
B
:
Anti-inflammatory effect of vagus nerve stimulation in a rat model of inflammatory bowel disease.
Auton Neurosci
2011
;
160
:
82
9
57.
van Westerloo
DJ
,
Giebelen
IA
,
Florquin
S
,
Bruno
MJ
,
Larosa
GJ
,
Ulloa
L
,
Tracey
KJ
,
van der Poll
T
:
The vagus nerve and nicotinic receptors modulate experimental pancreatitis severity in mice.
Gastroenterology
2006
;
130
:
1822
30
58.
The FO
Boeckxstaens
GE
,
Snoek
SA
,
Cash
JL
,
Bennink
R
,
Larosa
GJ
,
van den Wijngaard
RM
,
Greaves
DR
,
de Jonge
WJ
;
The FO
:
Activation of the cholinergic anti-inflammatory pathway ameliorates postoperative ileus in mice.
Gastroenterology
2007
;
133
:
1219
28
59.
Levine
YA
,
Koopman
FA
,
Faltys
M
,
Caravaca
A
,
Bendele
A
,
Zitnik
R
,
Vervoordeldonk
MJ
,
Tak
PP
:
Neurostimulation of the cholinergic anti-inflammatory pathway ameliorates disease in rat collagen-induced arthritis.
PLoS One
2014
;
9
:
e104530
60.
Pavlov
VA
,
Ochani
M
,
Yang
LH
,
Gallowitsch-Puerta
M
,
Ochani
K
,
Lin
X
,
Levi
J
,
Parrish
WR
,
Rosas-Ballina
M
,
Czura
CJ
,
Larosa
GJ
,
Miller
EJ
,
Tracey
KJ
,
Al-Abed
Y
:
Selective alpha7-nicotinic acetylcholine receptor agonist GTS-21 improves survival in murine endotoxemia and severe sepsis.
Crit Care Med
2007
;
35
:
1139
44
61.
Han
Z
,
Li
L
,
Wang
L
,
Degos
V
,
Maze
M
,
Su
H
:
Alpha-7 nicotinic acetylcholine receptor agonist treatment reduces neuroinflammation, oxidative stress, and brain injury in mice with ischemic stroke and bone fracture.
J Neurochem
2014
;
131
:
498
508
62.
Han
Z
,
Shen
F
,
He
Y
,
Degos
V
,
Camus
M
,
Maze
M
,
Young
WL
,
Su
H
:
Activation of α-7 nicotinic acetylcholine receptor reduces ischemic stroke injury through reduction of pro-inflammatory macrophages and oxidative stress.
PLoS One
2014
;
9
:
e105711
63.
Olofsson
PS
:
A stimulating concept: bioelectronic medicine in inflammatory disease.
Bioelectron Med
2014
;
2014
:
30
3
64.
Koopman
FA
,
Schuurman
PR
,
Vervoordeldonk
MJ
,
Tak
PP
:
Vagus nerve stimulation: A new bioelectronics approach to treat rheumatoid arthritis?
Best Pract Res Clin Rheumatol
2014
;
28
:
625
35
65.
Dombrovskiy
VY
,
Martin
AA
,
Sunderram
J
,
Paz
HL
:
Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: A trend analysis from 1993 to 2003.
Crit Care Med
2007
;
35
:
1244
50
66.
Angus
DC
,
van der Poll
T
:
Severe sepsis and septic shock.
N Engl J Med
2013
;
369
:
840
51
67.
Deutschman
CS
,
Tracey
KJ
:
Sepsis: Current dogma and new perspectives.
Immunity
2014
;
40
:
463
75
68.
Thayer
JF
,
Lane
RD
:
Claude Bernard and the heart-brain connection: Further elaboration of a model of neurovisceral integration.
Neurosci Biobehav Rev
2009
;
33
:
81
8
69.
Buchan
CA
,
Bravi
A
,
Seely
AJ
:
Variability analysis and the diagnosis, management, and treatment of sepsis.
Curr Infect Dis Rep
2012
;
14
:
512
21
70.
Frasure-Smith
N
,
Lespérance
F
,
Irwin
MR
,
Talajic
M
,
Pollock
BG
:
The relationships among heart rate variability, inflammatory markers and depression in coronary heart disease patients.
Brain Behav Immun
2009
;
23
:
1140
7
71.
Werdan
K
,
Schmidt
H
,
Ebelt
H
,
Zorn-Pauly
K
,
Koidl
B
,
Hoke
RS
,
Heinroth
K
,
Müller-Werdan
U
:
Impaired regulation of cardiac function in sepsis, SIRS, and MODS.
Can J Physiol Pharmacol
2009
;
87
:
266
74
72.
Barnaby
D
,
Ferrick
K
,
Kaplan
DT
,
Shah
S
,
Bijur
P
,
Gallagher
EJ
:
Heart rate variability in emergency department patients with sepsis.
Acad Emerg Med
2002
;
9
:
661
70
73.
Chen
WL
,
Kuo
CD
:
Characteristics of heart rate variability can predict impending septic shock in emergency department patients with sepsis.
Acad Emerg Med
2007
;
14
:
392
7
74.
Wang
H
,
Liao
H
,
Ochani
M
,
Justiniani
M
,
Lin
X
,
Yang
L
,
Al-Abed
Y
,
Wang
H
,
Metz
C
,
Miller
EJ
,
Tracey
KJ
,
Ulloa
L
:
Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis.
Nat Med
2004
;
10
:
1216
21
75.
Rosas-Ballina
M
,
Valdés-Ferrer
SI
,
Dancho
ME
,
Ochani
M
,
Katz
D
,
Cheng
KF
,
Olofsson
PS
,
Chavan
SS
,
Al-Abed
Y
,
Tracey
KJ
,
Pavlov
VA
:
Xanomeline suppresses excessive pro-inflammatory cytokine responses through neural signal-mediated pathways and improves survival in lethal inflammation.
Brain Behav Immun
2015
;
44
:
19
27
76.
Chavan
SS
,
Huerta
PT
,
Robbiati
S
,
Valdes-Ferrer
SI
,
Ochani
M
,
Dancho
M
,
Frankfurt
M
,
Volpe
BT
,
Tracey
KJ
,
Diamond
B
:
HMGB1 mediates cognitive impairment in sepsis survivors.
Mol Med
2012
;
18
:
930
7
77.
Shytle
RD
,
Mori
T
,
Townsend
K
,
Vendrame
M
,
Sun
N
,
Zeng
J
,
Ehrhart
J
,
Silver
AA
,
Sanberg
PR
,
Tan
J
:
Cholinergic modulation of microglial activation by alpha 7 nicotinic receptors.
J Neurochem
2004
;
89
:
337
43
78.
Thomsen
MS
,
Mikkelsen
JD
:
The α7 nicotinic acetylcholine receptor ligands methyllycaconitine, NS6740 and GTS-21 reduce lipopolysaccharide-induced TNF-α release from microglia.
J Neuroimmunol
2012
;
251
:
65
72
79.
Wittebole
X
,
Hahm
S
,
Coyle
SM
,
Kumar
A
,
Calvano
SE
,
Lowry
SF
:
Nicotine exposure alters in vivo human responses to endotoxin.
Clin Exp Immunol
2007
;
147
:
28
34
80.
Tremblay
LN
,
Slutsky
AS
:
Ventilator-induced injury: From barotrauma to biotrauma.
Proc Assoc Am Physicians
1998
;
110
:
482
8
81.
Santos
CC
,
Zhang
H
,
Liu
M
,
Slutsky
AS
:
Bench-to-bedside review: Biotrauma and modulation of the innate immune response.
Crit Care
2005
;
9
:
280
6
82.
Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network.
N Engl J Med
2000
;
342
:
1301
8
83.
Vaneker
M
,
Halbertsma
FJ
,
van Egmond
J
,
Netea
MG
,
Dijkman
HB
,
Snijdelaar
DG
,
Joosten
LA
,
van der Hoeven
JG
,
Scheffer
GJ
:
Mechanical ventilation in healthy mice induces reversible pulmonary and systemic cytokine elevation with preserved alveolar integrity: An in vivo model using clinical relevant ventilation settings.
Anesthesiology
2007
;
107
:
419
26
84.
Wolthuis
EK
,
Vlaar
AP
,
Choi
G
,
Roelofs
JJ
,
Juffermans
NP
,
Schultz
MJ
:
Mechanical ventilation using non-injurious ventilation settings causes lung injury in the absence of pre-existing lung injury in healthy mice.
Crit Care
2009
;
13
:
R1
85.
Krzyzaniak
MJ
,
Peterson
CY
,
Cheadle
G
,
Loomis
W
,
Wolf
P
,
Kennedy
V
,
Putnam
JG
,
Bansal
V
,
Eliceiri
B
,
Baird
A
,
Coimbra
R
:
Efferent vagal nerve stimulation attenuates acute lung injury following burn: The importance of the gut-lung axis.
Surgery
2011
;
150
:
379
89
86.
Reys
LG
,
Ortiz-Pomales
YT
,
Lopez
N
,
Cheadle
G
,
de Oliveira
PG
,
Eliceiri
B
,
Bansal
V
,
Costantini
TW
,
Coimbra
R
:
Uncovering the neuroenteric-pulmonary axis: Vagal nerve stimulation prevents acute lung injury following hemorrhagic shock.
Life Sci
2013
;
92
:
783
92
87.
Su
X
,
Lee
JW
,
Matthay
ZA
,
Mednick
G
,
Uchida
T
,
Fang
X
,
Gupta
N
,
Matthay
MA
:
Activation of the alpha7 nAChR reduces acid-induced acute lung injury in mice and rats.
Am J Respir Cell Mol Biol
2007
;
37
:
186
92
88.
Kox
M
,
Vaneker
M
,
van der Hoeven
JG
,
Scheffer
GJ
,
Hoedemaekers
CW
,
Pickkers
P
:
Effects of vagus nerve stimulation and vagotomy on systemic and pulmonary inflammation in a two-hit model in rats.
PLoS One
2012
;
7
:
e34431
89.
Abildstrom
H
,
Rasmussen
LS
,
Rentowl
P
,
Hanning
CD
,
Rasmussen
H
,
Kristensen
PA
,
Moller
JT
:
Cognitive dysfunction 1-2 years after non-cardiac surgery in the elderly. ISPOCD group. International Study of Post-Operative Cognitive Dysfunction.
Acta Anaesthesiol Scand
2000
;
44
:
1246
51
90.
Moller
JT
,
Cluitmans
P
,
Rasmussen
LS
,
Houx
P
,
Rasmussen
H
,
Canet
J
,
Rabbitt
P
,
Jolles
J
,
Larsen
K
,
Hanning
CD
,
Langeron
O
,
Johnson
T
,
Lauven
PM
,
Kristensen
PA
,
Biedler
A
,
van Beem
H
,
Fraidakis
O
,
Silverstein
JH
,
Beneken
JE
,
Gravenstein
JS
:
Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators. International Study of Post-Operative Cognitive Dysfunction.
Lancet
1998
;
351
:
857
61
91.
Steinmetz
J
,
Christensen
KB
,
Lund
T
,
Lohse
N
,
Rasmussen
LS
;
ISPOCD Group
ISPOCD Group
:
Long-term consequences of postoperative cognitive dysfunction.
Anesthesiology
2009
;
110
:
548
55
92.
Johnson
T
,
Monk
T
,
Rasmussen
LS
,
Abildstrom
H
,
Houx
P
,
Korttila
K
,
Kuipers
HM
,
Hanning
CD
,
Siersma
VD
,
Kristensen
D
,
Canet
J
,
Ibañaz
MT
,
Moller
JT
;
ISPOCD2 Investigators
ISPOCD2 Investigators
:
Postoperative cognitive dysfunction in middle-aged patients.
Anesthesiology
2002
;
96
:
1351
7
93.
Price
CC
,
Garvan
CW
,
Monk
TG
:
Type and severity of cognitive decline in older adults after noncardiac surgery.
Anesthesiology
2008
;
108
:
8
17
94.
Terrando
N
,
Monaco
C
,
Ma
D
,
Foxwell
BM
,
Feldmann
M
,
Maze
M
:
Tumor necrosis factor-alpha triggers a cytokine cascade yielding postoperative cognitive decline.
Proc Natl Acad Sci USA
2010
;
107
:
20518
22
95.
Cibelli
M
,
Fidalgo
AR
,
Terrando
N
,
Ma
D
,
Monaco
C
,
Feldmann
M
,
Takata
M
,
Lever
IJ
,
Nanchahal
J
,
Fanselow
MS
,
Maze
M
:
Role of interleukin-1beta in postoperative cognitive dysfunction.
Ann Neurol
2010
;
68
:
360
8
96.
Terrando
N
,
Gómez-Galán
M
,
Yang
T
,
Carlström
M
,
Gustavsson
D
,
Harding
RE
,
Lindskog
M
,
Eriksson
LI
:
Aspirin-triggered resolvin D1 prevents surgery-induced cognitive decline.
FASEB J
2013
;
27
:
3564
71
97.
Li
RL
,
Zhang
ZZ
,
Peng
M
,
Wu
Y
,
Zhang
JJ
,
Wang
CY
,
Wang
YL
:
Postoperative impairment of cognitive function in old mice: A possible role for neuroinflammation mediated by HMGB1, S100B, and RAGE.
J Surg Res
2013
;
185
:
815
24
98.
Vacas
S
,
Degos
V
,
Tracey
KJ
,
Maze
M
:
High-mobility group box 1 protein initiates postoperative cognitive decline by engaging bone marrow-derived macrophages.
Anesthesiology
2014
;
120
:
1160
7
99.
Degos
V
,
Vacas
S
,
Han
Z
,
van Rooijen
N
,
Gressens
P
,
Su
H
,
Young
WL
,
Maze
M
:
Depletion of bone marrow-derived macrophages perturbs the innate immune response to surgery and reduces postoperative memory dysfunction.
Anesthesiology
2013
;
118
:
527
36
100.
Reinsfelt
B
,
Ricksten
SE
,
Zetterberg
H
,
Blennow
K
,
Fredén-Lindqvist
J
,
Westerlind
A
:
Cerebrospinal fluid markers of brain injury, inflammation, and blood-brain barrier dysfunction in cardiac surgery.
Ann Thorac Surg
2012
;
94
:
549
55
101.
Bromander
S
,
Anckarsäter
R
,
Kristiansson
M
,
Blennow
K
,
Zetterberg
H
,
Anckarsäter
H
,
Wass
CE
:
Changes in serum and cerebrospinal fluid cytokines in response to non-neurological surgery: An observational study.
J Neuroinflammation
2012
;
9
:
242
102.
Yeager
MP
,
Lunt
P
,
Arruda
J
,
Whalen
K
,
Rose
R
,
DeLeo
JA
:
Cerebrospinal fluid cytokine levels after surgery with spinal or general anesthesia.
Reg Anesth Pain Med
1999
;
24
:
557
62
103.
Buvanendran
A
,
Kroin
JS
,
Berger
RA
,
Hallab
NJ
,
Saha
C
,
Negrescu
C
,
Moric
M
,
Caicedo
MS
,
Tuman
KJ
:
Upregulation of prostaglandin E2 and interleukins in the central nervous system and peripheral tissue during and after surgery in humans.
Anesthesiology
2006
;
104
:
403
10
104.
Braunwald
E
,
Kloner
RA
:
Myocardial reperfusion: A double-edged sword?
J Clin Invest
1985
;
76
:
1713
9
105.
Yellon
DM
,
Hausenloy
DJ
:
Myocardial reperfusion injury.
N Engl J Med
2007
;
357
:
1121
35
106.
Hausenloy
DJ
,
Yellon
DM
:
Myocardial ischemia-reperfusion injury: A neglected therapeutic target.
J Clin Invest
2013
;
123
:
92
100
107.
Álvarez
P
,
Tapia
L
,
Mardones
LA
,
Pedemonte
JC
,
Farías
JG
,
Castillo
RL
:
Cellular mechanisms against ischemia reperfusion injury induced by the use of anesthetic pharmacological agents.
Chem Biol Interact
2014
;
218
:
89
98
108.
Ahn
J
,
Kim
J
:
Mechanisms and consequences of inflammatory signaling in the myocardium.
Curr Hypertens Rep
2012
;
14
:
510
6
109.
Zhang
M
,
Chen
L
:
Status of cytokines in ischemia reperfusion induced heart injury.
Cardiovasc Hematol Disord Drug Targets
2008
;
8
:
161
72
110.
Fröhlich
GM
,
Meier
P
,
White
SK
,
Yellon
DM
,
Hausenloy
DJ
:
Myocardial reperfusion injury: Looking beyond primary PCI.
Eur Heart J
2013
;
34
:
1714
22
111.
Katare
RG
,
Ando
M
,
Kakinuma
Y
,
Arikawa
M
,
Handa
T
,
Yamasaki
F
,
Sato
T
:
Vagal nerve stimulation prevents reperfusion injury through inhibition of opening of mitochondrial permeability transition pore independent of the bradycardiac effect.
J Thorac Cardiovasc Surg
2009
;
137
:
223
31
112.
Calvillo
L
,
Vanoli
E
,
Andreoli
E
,
Besana
A
,
Omodeo
E
,
Gnecchi
M
,
Zerbi
P
,
Vago
G
,
Busca
G
,
Schwartz
PJ
:
Vagal stimulation, through its nicotinic action, limits infarct size and the inflammatory response to myocardial ischemia and reperfusion.
J Cardiovasc Pharmacol
2011
;
58
:
500
7
113.
Katare
RG
,
Ando
M
,
Kakinuma
Y
,
Arikawa
M
,
Yamasaki
F
,
Sato
T
:
Differential regulation of TNF receptors by vagal nerve stimulation protects heart against acute ischemic injury.
J Mol Cell Cardiol
2010
;
49
:
234
44
114.
Li
M
,
Zheng
C
,
Sato
T
,
Kawada
T
,
Sugimachi
M
,
Sunagawa
K
:
Vagal nerve stimulation markedly improves long-term survival after chronic heart failure in rats.
Circulation
2004
;
109
:
120
4
115.
Uemura
K
,
Zheng
C
,
Li
M
,
Kawada
T
,
Sugimachi
M
:
Early short-term vagal nerve stimulation attenuates cardiac remodeling after reperfused myocardial infarction.
J Card Fail
2010
;
16
:
689
99
116.
Mastitskaya
S
,
Marina
N
,
Gourine
A
,
Gilbey
MP
,
Spyer
KM
,
Teschemacher
AG
,
Kasparov
S
,
Trapp
S
,
Ackland
GL
,
Gourine
AV
:
Cardioprotection evoked by remote ischaemic preconditioning is critically dependent on the activity of vagal pre-ganglionic neurones.
Cardiovasc Res
2012
;
95
:
487
94
117.
Buchholz
B
,
Donato
M
,
Perez
V
,
Ivalde
FC
,
Höcht
C
,
Buitrago
E
,
Rodríguez
M
,
Gelpi
RJ
:
Preischemic efferent vagal stimulation increases the size of myocardial infarction in rabbits. Role of the sympathetic nervous system.
Int J Cardiol
2012
;
155
:
490
1
118.
Buchholz
B
,
Donato
M
,
Perez
V
,
Deutsch
AC
,
Höcht
C
,
Del Mauro
JS
,
Rodríguez
M
,
Gelpi
RJ
:
Changes in the loading conditions induced by vagal stimulation modify the myocardial infarct size through sympathetic-parasympathetic interactions.
Pflugers Arch
2015
;
467
:
1509
22
119.
Shinlapawittayatorn
K
,
Chinda
K
,
Palee
S
,
Surinkaew
S
,
Thunsiri
K
,
Weerateerangkul
P
,
Chattipakorn
S
,
KenKnight
BH
,
Chattipakorn
N
:
Low-amplitude, left vagus nerve stimulation significantly attenuates ventricular dysfunction and infarct size through prevention of mitochondrial dysfunction during acute ischemia-reperfusion injury.
Heart Rhythm
2013
;
10
:
1700
7
120.
Wang
Z
,
Yu
L
,
Wang
S
,
Huang
B
,
Liao
K
,
Saren
G
,
Tan
T
,
Jiang
H
:
Chronic intermittent low-level transcutaneous electrical stimulation of auricular branch of vagus nerve improves left ventricular remodeling in conscious dogs with healed myocardial infarction.
Circ Heart Fail
2014
;
7
:
1014
21
121.
Tong
H
,
Imahashi
K
,
Steenbergen
C
,
Murphy
E
:
Phosphorylation of glycogen synthase kinase-3beta during preconditioning through a phosphatidylinositol-3-kinase–dependent pathway is cardioprotective.
Circ Res
2002
;
90
:
377
9
122.
Terashima
Y
,
Sato
T
,
Yano
T
,
Maas
O
,
Itoh
T
,
Miki
T
,
Tanno
M
,
Kuno
A
,
Shimamoto
K
,
Miura
T
:
Roles of phospho-GSK-3β in myocardial protection afforded by activation of the mitochondrial K ATP channel.
J Mol Cell Cardiol
2010
;
49
:
762
70
123.
Kawada
T
,
Yamazaki
T
,
Akiyama
T
,
Kitagawa
H
,
Shimizu
S
,
Mizuno
M
,
Li
M
,
Sugimachi
M
:
Vagal stimulation suppresses ischemia-induced myocardial interstitial myoglobin release.
Life Sci
2008
;
83
:
490
5
124.
Kawada
T
,
Yamazaki
T
,
Akiyama
T
,
Li
M
,
Ariumi
H
,
Mori
H
,
Sunagawa
K
,
Sugimachi
M
:
Vagal stimulation suppresses ischemia-induced myocardial interstitial norepinephrine release.
Life Sci
2006
;
78
:
882
7
125.
Uemura
K
,
Li
M
,
Tsutsumi
T
,
Yamazaki
T
,
Kawada
T
,
Kamiya
A
,
Inagaki
M
,
Sunagawa
K
,
Sugimachi
M
:
Efferent vagal nerve stimulation induces tissue inhibitor of metalloproteinase-1 in myocardial ischemia-reperfusion injury in rabbit.
Am J Physiol Heart Circ Physiol
2007
;
293
:
H2254
61
126.
Kauvar
DS
,
Lefering
R
,
Wade
CE
:
Impact of hemorrhage on trauma outcome: An overview of epidemiology, clinical presentations, and therapeutic considerations.
J Trauma
2006
;
60
(
6 suppl
):
S3
11
127.
Fritz
JR
,
Huston
JM
:
The neural tourniquet.
Bioelectron Med
2014
;
2014
:
25
9
128.
Rosas-Ballina
M
,
Goldstein
RS
,
Gallowitsch-Puerta
M
,
Yang
L
,
Valdés-Ferrer
SI
,
Patel
NB
,
Chavan
S
,
Al-Abed
Y
,
Yang
H
,
Tracey
KJ
:
The selective alpha7 agonist GTS-21 attenuates cytokine production in human whole blood and human monocytes activated by ligands for TLR2, TLR3, TLR4, TLR9, and RAGE.
Mol Med
2009
;
15
:
195
202
129.
Cai
B
,
Chen
F
,
Ji
Y
,
Kiss
L
,
de Jonge
WJ
,
Conejero-Goldberg
C
,
Szabo
C
,
Deitch
EA
,
Ulloa
L
:
Alpha7 cholinergic-agonist prevents systemic inflammation and improves survival during resuscitation.
J Cell Mol Med
2009
;
13
:
3774
85
130.
Kox
M
,
Pompe
JC
,
Gordinou de Gouberville
MC
,
van der Hoeven
JG
,
Hoedemaekers
CW
,
Pickkers
P
:
Effects of the α7 nicotinic acetylcholine receptor agonist GTS-21 on the innate immune response in humans.
Shock
2011
;
36
:
5
11
131.
Stokes
C
,
Papke
JK
,
Horenstein
NA
,
Kem
WR
,
McCormack
TJ
,
Papke
RL
:
The structural basis for GTS-21 selectivity between human and rat nicotinic alpha7 receptors.
Mol Pharmacol
2004
;
66
:
14
24
132.
Pavlov
VA
,
Parrish
WR
,
Rosas-Ballina
M
,
Ochani
M
,
Puerta
M
,
Ochani
K
,
Chavan
S
,
Al-Abed
Y
,
Tracey
KJ
:
Brain acetylcholinesterase activity controls systemic cytokine levels through the cholinergic anti-inflammatory pathway.
Brain Behav Immun
2009
;
23
:
41
5
133.
Ji
H
,
Rabbi
MF
,
Labis
B
,
Pavlov
VA
,
Tracey
KJ
,
Ghia
JE
:
Central cholinergic activation of a vagus nerve-to-spleen circuit alleviates experimental colitis.
Mucosal Immunol
2014
;
7
:
335
47
134.
Satapathy
SK
,
Ochani
M
,
Dancho
M
,
Hudson
LK
,
Rosas-Ballina
M
,
Valdes-Ferrer
SI
,
Olofsson
PS
,
Harris
YT
,
Roth
J
,
Chavan
S
,
Tracey
KJ
,
Pavlov
VA
:
Galantamine alleviates inflammation and other obesity-associated complications in high-fat diet-fed mice.
Mol Med
2011
;
17
:
599
606
135.
Birmingham
K
,
Gradinaru
V
,
Anikeeva
P
,
Grill
WM
,
Pikov
V
,
McLaughlin
B
,
Pasricha
P
,
Weber
D
,
Ludwig
K
,
Famm
K
:
Bioelectronic medicines: A research roadmap.
Nat Rev Drug Discov
2014
;
13
:
399
400
136.
Famm
K
,
Litt
B
,
Tracey
KJ
,
Boyden
ES
,
Slaoui
M
:
Drug discovery: A jump-start for electroceuticals.
Nature
2013
;
496
:
159
61
137.
Penry
JK
,
Dean
JC
:
Prevention of intractable partial seizures by intermittent vagal stimulation in humans: Preliminary results.
Epilepsia
1990
;
31
(
suppl 2
):
S40
3
138.
Handforth
A
,
DeGiorgio
CM
,
Schachter
SC
,
Uthman
BM
,
Naritoku
DK
,
Tecoma
ES
,
Henry
TR
,
Collins
SD
,
Vaughn
BV
,
Gilmartin
RC
,
Labar
DR
,
Morris
GL
III
,
Salinsky
MC
,
Osorio
I
,
Ristanovic
RK
,
Labiner
DM
,
Jones
JC
,
Murphy
JV
,
Ney
GC
,
Wheless
JW
:
Vagus nerve stimulation therapy for partial-onset seizures: A randomized active-control trial.
Neurology
1998
;
51
:
48
55
139.
Tatum
WO
,
Johnson
KD
,
Goff
S
,
Ferreira
JA
,
Vale
FL
:
Vagus nerve stimulation and drug reduction.
Neurology
2001
;
56
:
561
3
140.
Helmers
SL
,
Wheless
JW
,
Frost
M
,
Gates
J
,
Levisohn
P
,
Tardo
C
,
Conry
JA
,
Yalnizoglu
D
,
Madsen
JR
:
Vagus nerve stimulation therapy in pediatric patients with refractory epilepsy: Retrospective study.
J Child Neurol
2001
;
16
:
843
8
141.
Kennedy
SH
,
Giacobbe
P
,
Rizvi
SJ
,
Placenza
FM
,
Nishikawa
Y
,
Mayberg
HS
,
Lozano
AM
:
Deep brain stimulation for treatment-resistant depression: Follow-up after 3 to 6 years.
Am J Psychiatry
2011
;
168
:
502
10
142.
Berry
SM
,
Broglio
K
,
Bunker
M
,
Jayewardene
A
,
Olin
B
,
Rush
AJ
:
A patient-level meta-analysis of studies evaluating vagus nerve stimulation therapy for treatment-resistant depression.
Med Devices (Auckl)
2013
;
6
:
17
35
143.
Cristancho
P
,
Cristancho
MA
,
Baltuch
GH
,
Thase
ME
,
O’Reardon
JP
:
Effectiveness and safety of vagus nerve stimulation for severe treatment-resistant major depression in clinical practice after FDA approval: Outcomes at 1 year.
J Clin Psychiatry
2011
;
72
:
1376
82
144.
Christmas
D
,
Steele
JD
,
Tolomeo
S
,
Eljamel
MS
,
Matthews
K
:
Vagus nerve stimulation for chronic major depressive disorder: 12-month outcomes in highly treatment-refractory patients.
J Affect Disord
2013
;
150
:
1221
5
145.
McClelland
J
,
Bozhilova
N
,
Campbell
I
,
Schmidt
U
:
A systematic review of the effects of neuromodulation on eating and body weight: Evidence from human and animal studies.
Eur Eat Disord Rev
2013
;
21
:
436
55
146.
Martelletti
P
,
Jensen
RH
,
Antal
A
,
Arcioni
R
,
Brighina
F
,
de Tommaso
M
,
Franzini
A
,
Fontaine
D
,
Heiland
M
,
Jürgens
TP
,
Leone
M
,
Magis
D
,
Paemeleire
K
,
Palmisani
S
,
Paulus
W
,
May
A
;
European Headache Federation
European Headache Federation
:
Neuromodulation of chronic headaches: Position statement from the European Headache Federation.
J Headache Pain
2013
;
14
:
86
147.
Zitnik
RJ
:
Treatment of chronic inflammatory diseases with implantable medical devices.
Cleve Clin J Med
2011
;
78
(
suppl 1
):
S30
4
148.
Ben-Menachem
E
:
Vagus nerve stimulation, side effects, and long-term safety.
J Clin Neurophysiol
2001
;
18
:
415
8
149.
Morris
GL
III
,
Mueller
WM
:
Long-term treatment with vagus nerve stimulation in patients with refractory epilepsy. The Vagus Nerve Stimulation Study Group E01-E05.
Neurology
1999
;
53
:
1731
5
150.
Ramsay
RE
,
Uthman
BM
,
Augustinsson
LE
,
Upton
AR
,
Naritoku
D
,
Willis
J
,
Treig
T
,
Barolat
G
,
Wernicke
JF
:
Vagus nerve stimulation for treatment of partial seizures: 2. Safety, side effects, and tolerability. First International Vagus Nerve Stimulation Study Group.
Epilepsia
1994
;
35
:
627
36
151.
Olofsson
PS
,
Levine
YA
,
Caravaca
A
,
Chavan
SS
,
Pavlov
VA
,
Faltys
M
,
Tracey
KJ
:
Single-pulse and unidirectional electrical activation of the cervical vagus nerve reduces TNF in endotoxemia.
Bioelectron Med
2015
;
2015
:
37
42
152.
Aalbers
MW
,
Klinkenberg
S
,
Rijkers
K
,
Verschuure
P
,
Kessels
A
,
Aldenkamp
A
,
Vles
J
,
Majoie
M
:
The effects of vagus nerve stimulation on pro- and anti-inflammatory cytokines in children with refractory epilepsy: An exploratory study.
Neuroimmunomodulation
2012
;
19
:
352
8
153.
Barone
L
,
Colicchio
G
,
Policicchio
D
,
Di Clemente
F
,
Di Monaco
A
,
Meglio
M
,
Lanza
GA
,
Crea
F
:
Effect of vagal nerve stimulation on systemic inflammation and cardiac autonomic function in patients with refractory epilepsy.
Neuroimmunomodulation
2007
;
14
:
331
6
154.
Majoie
HJ
,
Rijkers
K
,
Berfelo
MW
,
Hulsman
JA
,
Myint
A
,
Schwarz
M
,
Vles
JS
:
Vagus nerve stimulation in refractory epilepsy: Effects on pro- and anti-inflammatory cytokines in peripheral blood.
Neuroimmunomodulation
2011
;
18
:
52
6
155.
De Herdt
V
,
Bogaert
S
,
Bracke
KR
,
Raedt
R
,
De Vos
M
,
Vonck
K
,
Boon
P
:
Effects of vagus nerve stimulation on pro- and anti-inflammatory cytokine induction in patients with refractory epilepsy.
J Neuroimmunol
2009
;
214
:
104
8
156.
Corcoran
C
,
Connor
TJ
,
O’Keane
V
,
Garland
MR
:
The effects of vagus nerve stimulation on pro- and anti-inflammatory cytokines in humans: A preliminary report.
Neuroimmunomodulation
2005
;
12
:
307
9
157.
Sundman
E
,
Olofsson
PS
:
Neural control of the immune system.
Adv Physiol Educ
2014
;
38
:
135
9
158.
McMahon
SB
,
La Russa
F
,
Bennett
DL
:
Crosstalk between the nociceptive and immune systems in host defence and disease.
Nat Rev Neurosci
2015
;
16
:
389
402
159.
Undem
BJ
,
Carr
MJ
:
The role of nerves in asthma.
Curr Allergy Asthma Rep
2002
;
2
:
159
65
160.
Wu
Y
,
You
H
,
Ma
P
,
Li
L
,
Yuan
Y
,
Li
J
,
Ye
X
,
Liu
X
,
Yao
H
,
Chen
R
,
Lai
K
,
Yang
X
:
Role of transient receptor potential ion channels and evoked levels of neuropeptides in a formaldehyde-induced model of asthma in BALB/c mice.
PLoS One
2013
;
8
:
e62827
161.
Hox
V
,
Vanoirbeek
JA
,
Alpizar
YA
,
Voedisch
S
,
Callebaut
I
,
Bobic
S
,
Sharify
A
,
De Vooght
V
,
Van Gerven
L
,
Devos
F
,
Liston
A
,
Voets
T
,
Vennekens
R
,
Bullens
DM
,
De Vries
A
,
Hoet
P
,
Braun
A
,
Ceuppens
JL
,
Talavera
K
,
Nemery
B
,
Hellings
PW
:
Crucial role of transient receptor potential ankyrin 1 and mast cells in induction of nonallergic airway hyperreactivity in mice.
Am J Respir Crit Care Med
2013
;
187
:
486
93
162.
Tränkner
D
,
Hahne
N
,
Sugino
K
,
Hoon
MA
,
Zuker
C
:
Population of sensory neurons essential for asthmatic hyperreactivity of inflamed airways.
Proc Natl Acad Sci USA
2014
;
111
:
11515
20
163.
Talbot
S
,
Abdulnour
RE
,
Burkett
PR
,
Lee
S
,
Cronin
SJ
,
Pascal
MA
,
Laedermann
C
,
Foster
SL
,
Tran
JV
,
Lai
N
,
Chiu
IM
,
Ghasemlou
N
,
DiBiase
M
,
Roberson
D
,
Von Hehn
C
,
Agac
B
,
Haworth
O
,
Seki
H
,
Penninger
JM
,
Kuchroo
VK
,
Bean
BP
,
Levy
BD
,
Woolf
CJ
:
Silencing nociceptor neurons reduces allergic airway inflammation.
Neuron
2015
;
87
:
341
54
164.
Rogerio
AP
,
Andrade
EL
,
Calixto
JB
:
C-fibers, but not the transient potential receptor vanilloid 1 (TRPV1), play a role in experimental allergic airway inflammation.
Eur J Pharmacol
2011
;
662
:
55
62
165.
Alessandri
AL
,
Pinho
V
,
Souza
DG
,
Castro
MS
,
Klein
A
,
Teixeira
MM
:
Mechanisms underlying the inhibitory effects of tachykinin receptor antagonists on eosinophil recruitment in an allergic pleurisy model in mice.
Br J Pharmacol
2003
;
140
:
847
54
166.
Bowden
JJ
,
Baluk
P
,
Lefevre
PM
,
Schoeb
TR
,
Lindsey
JR
,
McDonald
DM
:
Sensory denervation by neonatal capsaicin treatment exacerbates Mycoplasma pulmonis infection in rat airways.
Am J Physiol
1996
;
270
(
3 pt 1
):
L393
403
167.
Fernandes
ES
,
Liang
L
,
Smillie
SJ
,
Kaiser
F
,
Purcell
R
,
Rivett
DW
,
Alam
S
,
Howat
S
,
Collins
H
,
Thompson
SJ
,
Keeble
JE
,
Riffo-Vasquez
Y
,
Bruce
KD
,
Brain
SD
:
TRPV1 deletion enhances local inflammation and accelerates the onset of systemic inflammatory response syndrome.
J Immunol
2012
;
188
:
5741
51
168.
Meseguer
V
,
Alpizar
YA
,
Luis
E
,
Tajada
S
,
Denlinger
B
,
Fajardo
O
,
Manenschijn
JA
,
Fernández-Peña
C
,
Talavera
A
,
Kichko
T
,
Navia
B
,
Sánchez
A
,
Señarís
R
,
Reeh
P
,
Pérez-García
MT
,
López-López
JR
,
Voets
T
,
Belmonte
C
,
Talavera
K
,
Viana
F
:
TRPA1 channels mediate acute neurogenic inflammation and pain produced by bacterial endotoxins.
Nat Commun
2014
;
5
:
3125
169.
Brogden
KA
,
Guthmiller
JM
,
Salzet
M
,
Zasloff
M
:
The nervous system and innate immunity: The neuropeptide connection.
Nat Immunol
2005
;
6
:
558
64
170.
Gomes
RN
,
Castro-Faria-Neto
HC
,
Bozza
PT
,
Soares
MB
,
Shoemaker
CB
,
David
JR
,
Bozza
MT
:
Calcitonin gene-related peptide inhibits local acute inflammation and protects mice against lethal endotoxemia.
Shock
2005
;
24
:
590
4
171.
Torres-Rosas
R
,
Yehia
G
,
Peña
G
,
Mishra
P
,
del Rocio Thompson-Bonilla
M
,
Moreno-Eutimio
MA
,
Arriaga-Pizano
LA
,
Isibasi
A
,
Ulloa
L
:
Dopamine mediates vagal modulation of the immune system by electroacupuncture.
Nat Med
2014
;
20
:
291
5
172.
Wong
CH
,
Jenne
CN
,
Lee
WY
,
Léger
C
,
Kubes
P
:
Functional innervation of hepatic iNKT cells is immunosuppressive following stroke.
Science
2011
;
334
:
101
5
173.
Arima
Y
,
Harada
M
,
Kamimura
D
,
Park
JH
,
Kawano
F
,
Yull
FE
,
Kawamoto
T
,
Iwakura
Y
,
Betz
UA
,
Márquez
G
,
Blackwell
TS
,
Ohira
Y
,
Hirano
T
,
Murakami
M
:
Regional neural activation defines a gateway for autoreactive T cells to cross the blood-brain barrier.
Cell
2012
;
148
:
447
57
174.
Riol-Blanco
L
,
Ordovas-Montanes
J
,
Perro
M
,
Naval
E
,
Thiriot
A
,
Alvarez
D
,
Paust
S
,
Wood
JN
,
von Andrian
UH
:
Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation.
Nature
2014
;
510
:
157
61