The DOI matches its Crossref record; 105 of the 107 references it cites were found in a registry or an index; 2 of the 138 sources its claims cite were checked for support.
Physiology and immunology of the cholinergic antiinflammatory pathway
Open accessAbstract
Cytokine production by the immune system contributes importantly to both health and disease.The nervous system, via an inflammatory reflex of the vagus nerve, can inhibit cytokine release and thereby prevent tissue injury and death.The efferent neural signaling pathway is termed the cholinergic antiinflammatory pathway.Cholinergic agonists inhibit cytokine synthesis and protect against cytokine-mediated diseases.Stimulation of the vagus nerve prevents the damaging effects of cytokine release in experimental sepsis, endotoxemia, ischemia/reperfusion injury, hemorrhagic shock, arthritis, and other inflammatory syndromes.Herein is a review of this physiological, functional anatomical mechanism for neurological regulation of cytokine-dependent disease that begins to define an immunological homunculus.The germ is nothing; the terrain is everything. -Louis Pasteur (on his deathbed)Historical perspective of the cytokine theory of disease For more than 1,500 years, the predominant medical doctrine of disease causation was the humoral theory of disease.As posited by Galen (Claudius Galenus of Pergamum, 129-200 AD), this theory held that disease was caused by an imbalance in bodily humors.Produced by internal organs, the humors mediated healthful effects when their levels were properly regulated and balanced.This theory was not displaced until advances in microscopy and microbiology enabled Rudolf Virchow to formulate the theory of cellular pathology and Louis Pasteur the germ theory of disease.Research into the causes of illness turned outward as a growing body of investigation focused on exogenous rather than endogenous factors in disease causation.Pasteur's deathbed remark, however, belied the notion that germs could tell the whole story.It was a tacit acknowledgment to Claude Bernard, who advocated that health was due to equilibrium in the "milieu interieur" and maintained by "a continuous and delicate compensation, established as by the most sensitive of balances" (Lessons on the phenomena of life common to animals and vegetables).Common wisdom in the 1970s dictated that the immune response to pathogens or injury was uniformly for the good.Every facet of the immune response was believed to have a role (albeit some unknown) in eradicating invaders and neutralizing the potential for damage.Certainly, or so the reasoning went, the body would not use its own cells to make potentially toxic molecules in quantities large enough to injure tissues or even kill.The development of shock, tissue injury, circulatory collapse, hemorrhagic necrosis, multiple organ failure, and other physiological calamities associated with bacterial infection were attributed to the direct action of pathogenic toxins, not the host response.A few dared to challenge this view, notably Lewis Thomas, who wrote in his classic 1975 book The lives of a cell, "When we sense lipopolysaccharide, we are likely to turn on every defense at our disposal; we will bomb, defoliate, blockade, seal off, and destroy all the tissues in the area.All of this seems unnecessary, panicdriven . . .The self-disintegration of the whole animal that follows a systemic injection can be interpreted as a well-intentioned but lethal error.The mechanism is itself quite a good one, when used with precision and restraint (1)."Scientific advances would soon prove his statement to be unerringly prescient.Early investigators exploring physiological mechanisms of fever, weight loss, and acute phase responses to acute and chronic infection led the way in changing beliefs about disease pathogenesis.They gave evidence that proteins produced by macrophages and other immune cells, not pathogens, caused tissue damage and disease syndromes in experimental animals.Studies in the 1980s of these proteins, newly named cytokines (including, for example, IL-1, IL-6, and TNF), revealed that they possessed pleiotropic biological activities that were either beneficial or injurious.From this emerged the cytokine theory of disease, the concept that cytokines produced by the immune system can cause the signs, symptoms, and damaging aftereffects of disease (Figure 1) (reviewed in ref. 2).Consider as one example the case of TNF, a cytokine implicated as a necessary and sufficient mediator of lethal septic shock caused by infection with Gram-negative bacteria.TNF is produced during Gram-negative bacteria-induced acute septic shock (3).Administration of TNF to healthy mammals (including humans) reproduces the hemodynamic, metabolic, immunological, and pathological manifestations of the disease (4), and gene knockout or pharmacological blockade of TNF activity prevents the development of lethal septic shock (5).Other pathophysiological activities ascribed to TNF were the capacity to cause fever and localized inflammation (4, 6).Clinical successes in the 1990s using drugs that specifically inhibit TNF for patients with inflammatory bowel disease or rheumatoid arthritis directly implicated a pathogenic role of
Overview
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TL;DR
This review synthesizes evidence that the vagus nerve, via its principal neurotransmitter acetylcholine acting on the α7 subunit of the nicotinic acetylcholine receptor (α7 nAChR), suppresses proinflammatory cytokine production through an "inflammatory reflex" termed the cholinergic antiinflammatory pathway. The author argues this neural circuit restrains cytokine-mediated tissue damage across experimental sepsis, endotoxemia, ischemia/reperfusion, hemorrhagic shock, arthritis, ileus, and pancreatitis, and proposes an "immunological homunculus" framework for CNS regulation of immunity.
Key findings
- Vagus nerve stimulation significantly inhibits TNF release in animals receiving lethal endotoxin, and inhibits IL-1, IL-6, IL-8, and HMGB1 as well; the effect is absent in α7 nAChR–knockout animals and in vagotomized animals, indicating α7 nAChR–dependent signaling.
- The spleen is identified as the principal source of systemic TNF during endotoxemia: splenectomy significantly reduces TNF levels in liver and blood, and vagus nerve stimulation then fails to reduce them further; common celiac branch vagotomy abrogates the TNF-suppressing effects of stimulation in spleen and serum.
- In cecal perforation sepsis, nicotine given 24 hours after onset of lethal peritonitis significantly reduced serum HMGB1, indicating the pathway can act after disease is established; in E. coli peritonitis, vagotomy increased inflammatory cell recruitment, cytokine levels, and liver damage, while nicotine restored balance.
- In hemorrhagic shock, vagus nerve stimulation conferred protection against hypotension, prolonged survival, and decreased TNF; protective effects were reversed by the nicotinic antagonist chlorisondamine, and bilateral vagotomy ablated ACTH1-24's protective effects.
- Signaling is proposed to proceed via decreased nuclear translocation of NF-κB and JAK2-mediated phosphorylation/activation of STAT3 recruited to α7 nAChR.
Methods
- Narrative review article (Journal of Clinical Investigation), not primary research; it synthesizes the author's own laboratory work and the broader literature on the cholinergic antiinflammatory pathway.
- Evidence base is predominantly preclinical animal models (rodent endotoxemia, cecal ligation/perforation sepsis, live E. coli peritonitis, hemorrhagic shock, aortic and splanchnic ischemia/reperfusion, myocardial ischemia/reperfusion, carrageenan paw edema and air pouch inflammation, experimental pancreatitis, surgery-induced ileus) plus cited clinical observations.
- No new data, systematic search strategy, or meta-analysis is reported; the paper presents a mechanistic wiring diagram and a conceptual framework.
Limitations
- Stated: the paper notes that clinical studies show decreased vagus nerve activity is associated with increased disease severity but "have not established a causal relationship," and that it remains possible severe disease itself suppresses vagus nerve activity; the final answer "shall await clinical studies of vagus nerve modulation in humans."
- Stated: whether α7 nAChR downstream signaling in immunologically competent cells requires cofactors, ion channel activity, or other substrates is uncertain, and ongoing studies are needed.
- Stated: whether compensation, sensitization, desensitization, or tolerance occurs in the pathway is unknown (e.g., after truncal vagotomy), and the role of α7 AChR on lymphocytes and microglia in autoimmune disease is described as "an unexplored possibility."
- Evident from the text: the review is single-authored by a researcher whose laboratory generated much of the cited work, and the "immunological homunculus" is explicitly speculative ("I suspect," "it is plausible," "artistic rendition"), with no direct evidence presented for somatotopic CNS control of specific immune responses.
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Claims the paper makes
78 Not checked yet · 6 No basis given · 4 Own interpretation · 2 Partly supported · accuracy not yet measured
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In the paper
“Vagus nerve stimulation of mice in a model of subcutaneous inflammation caused by injecting carrageenan into an air pouch significantly inhibited the recruitment of polymorphonuclear leukocytes to the inflammatory zone (25).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Experimental arthritis.
What the sources say
- Partly supportedcites [25] Saeed, 2005, J. Exp. Med. sourceExperimental — accuracy not yet measured
The Methods describe vagus nerve stimulation in mice with subcutaneous carrageenan air pouches, and the Results report 60% less leukocyte recruitment than in sham-operated mice. The reported outcome is recruitment of leukocytes overall, not a separately measured reduction in polymorphonuclear leukocytes. (LLM, conf=0.85)
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- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Reperfusion of ischemic tissues stimulates cytokine overproduction (e.g., TNF, IL-1, HMGB1), which contributes to the pathogenesis of resulting tissue damage (42)(43)(44).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Ischemia/reperfusion.
What the sources say
- Not checked yetcites [42] Izuishi, 2006, J. Immunol. source
- Partly supportedcites [43] Colletti, 1990, J. Clin. Invest. sourceExperimental — accuracy not yet measured
The Results report TNF release after hepatic ischemia/reperfusion in rats, and the Discussion links TNF to subsequent lung and liver injury. The Discussion mentions IL-1 as a possible contributor but does not establish its overproduction after reperfusion; our copy does not mention HMGB1. The study also concerns hepatic ischemia in rats, rather than ischemic tissues generally. (LLM, conf=0.88)
- Not checked yetcites [44] Bernik, 2002, J. Vasc. Surg. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“From this emerged the cytokine theory of disease, the concept that cytokines produced by the immune system can cause the signs, symptoms, and damaging aftereffects of disease (Figure 1) (reviewed in ref. 2).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Abstract
What the sources say
- Not checked yetcites [2] Tracey, K.J. 2005.Fatal sequence: the killer within. Dana Press. Washington, DC, USA. 238 pp.
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“gene knockout or pharmacological blockade of TNF activity prevents the development of lethal septic shock (5).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Abstract
What the sources say
- Not checked yetcites [5] Pfeffer, 1993, Cell. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Administration of TNF to healthy mammals (including humans) reproduces the hemodynamic, metabolic, immunological, and pathological manifestations of the disease (4)”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Abstract
What the sources say
- Not checked yetcites [4] Tracey, 1986, Science. source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“TNF is produced during Gram-negative bacteria-induced acute septic shock (3).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Abstract
What the sources say
- Not checked yetcites [3] Tracey, 1987, Nature. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Nonetheless, together the present results indicate that α7 nAChR-dependent signals, which can be activated via vagus nerve stimulation, regulate cytokine production and the capacity for damage.”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Figure 1
What the sources say
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Stimulation of vagus nerve signals was shown to significantly inhibit TNF release in animals receiving lethal amounts of endotoxin (18).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > The cholinergic antiinflammatory pathway
What the sources say
- Not checked yetcites [18] Borovikova, 2000, Nature. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Recent results showing that intracerebroventricular administration of muscarine receptor agonists significantly decreases serum TNF levels during endotoxemia indicate that muscarinic brain networks also regulate the cytokine-controlling function of the vagus nerve.(34).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Figure 2
What the sources say
- Not checked yetcites [34] Pavlov, 2006, Proc. Natl. Acad. Sci. U. S. A. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Treatment of these mice with nicotine, a potent α7 nAChR agonist, significantly reduced serum levels of HMGB1, a cytokine mediator of lethality in this model (27).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Sepsis.
What the sources say
- Not checked yetcites [27] Wang, 2004, Nat. Med. source
plaindirect- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 31
- Probably not a substantial claim. 1
None of the sources cited for this claim have been checked yet.
In the paper
“Other pathophysiological activities ascribed to TNF were the capacity to cause fever and localized inflammation (4, 6).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Abstract
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Consider as one example the case of TNF, a cytokine implicated as a necessary and sufficient mediator of lethal septic shock caused by infection with Gram-negative bacteria.”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Abstract
What the sources say
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Vagus nerve stimulation in WT mice inhibits TNF synthesis in spleen, liver, and blood but not in α7 nAChR subunit-knockout animals (28).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Figure 2
What the sources say
- Not checked yetcites [28] Huston, 2006, J. Exp. Med. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“an accidental discovery revealed that intracerebral administration of a molecule that inhibited TNF production also increased efferent vagus nerve activity and inhibited inflammation outside the CNS (17).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > The cholinergic antiinflammatory pathway
What the sources say
- Not checked yetcites [17] Bernik, 2002, J. Exp. Med. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“vagus nerve stimulation in α7 nAChR-knockout animals fails to suppress cytokine synthesis whereas it significantly inhibits cytokine release in wild-type littermates (26).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Figure 1
What the sources say
- Not checked yetcites [26] Wang, 2003, Nature. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“When sufficient concentrations are achieved, proinflammatory cytokine levels are inhibited, the magnitude of the inflammatory response is dampened, and damage is prevented.”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Antiinflammatory humoral mechanisms restrain cytokine production
What the sources say
- Not checked yetcites [10] Nathan, 2002, Nature. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The spleen is the major source of both hepatic and systemic TNF during endotoxemia; it releases newly synthesized TNF into the splenic vein, which drains into the liver, and from there, TNF crosses into the systemic circulation (28).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Figure 2
What the sources say
- Not checked yetcites [28] Huston, 2006, J. Exp. Med. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Subsequent work established that vagus nerve signaling inhibits cytokine activities and improves disease endpoints in experimental models of sepsis, ischemia/reperfusion, hemorrhagic shock, myocardial ischemia, ileus, experimental arthritis, and pancreatitis (17)(18)(19)(20)(21)(22)(23)(24)(25).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > The cholinergic antiinflammatory pathway
What the sources say
boosteddirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“this cranial nerve, which meanders through the thorax and abdomen and has been termed the single most important nerve in the body, is a primitive extension of the CNS to the visceral organs, including organs of the reticuloendothelial system, such as the spleen and liver, that are major sources of damaging cytokines.”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > The cholinergic antiinflammatory pathway
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Splenectomy significantly reduces TNF levels in liver and blood, and vagus nerve stimulation fails to reduce levels further (28).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Figure 2
What the sources say
- Not checked yetcites [28] Huston, 2006, J. Exp. Med. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Ligand-receptor interaction on cytokine-expressing cells culminates in decreased nuclear translocation of NF-κB as well as activation of the transcription factor STAT3 via phosphorylation by JAK2, which is recruited to the α7 nAChR (Figure 3) (22,27).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Figure 1
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Clinical successes in the 1990s using drugs that specifically inhibit TNF for patients with inflammatory bowel disease or rheumatoid arthritis directly implicated a pathogenic role of this cytokine in other diseases (7-9) and validated in humans the fundamental premise of the cytokine theory of disease.”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Abstract
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“IL-10-deficient mice have increased susceptibility to both inflammatory bowel disease and adjuvant arthritis”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Antiinflammatory humoral mechanisms restrain cytokine production
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In a model of bacterial peritonitis based upon intraperitoneal injection of live Escherichia coli, vagotomy caused a significant increase in the number of inflammatory cells recruited to the peritoneum, higher cytokine levels, and more extensive tissue damage in the liver (35).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Sepsis.
What the sources say
- Not checked yetcites [35] van Westerloo, 2005, J. Infect. Dis. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Stimulation of the vagus nerve in mice with surgery-induced ileus significantly attenuated hypomotility and reduced cytokine production (22).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Experimental arthritis.
What the sources say
- Not checked yetcites [22] de Jonge, 2005, Nat. Immunol. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In another model, vagus nerve stimulation conferred significant protection against the development of shock after splanchnic artery reperfusion injury and inhibited the production of TNF and other cytokines (20).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Ischemia/reperfusion.
What the sources say
- Not checked yetcites [20] Altavilla, 2006, Shock. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Stimulation of the vagus nerve in animals subjected to carrageenan-induced paw swelling significantly attenuated the development of edema formation and inhibited the local production of cytokines in the zone of inflammation (23).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Experimental arthritis.
What the sources say
- Not checked yetcites [23] Borovikova, 2000, Auton. Neurosci. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Other studies indicate that cholinergic stimulation controls endothelial activation, leukocyte recruitment, coagulation, and fibrinolysis, which modulates the development of damage during sepsis (25,36).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Sepsis.
What the sources say
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Administration of GTS-21, an α7 nAChR receptor agonist, significantly decreased pancreati-tis severity and attenuated pulmonary inflammation (24).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Pancreatitis.
What the sources say
- Not checked yetcites [24] van Westerloo, 2006, Gastroenterology. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Stimulation of the vagus nerve during myocardial ischemia/reperfusion in rats significantly reduced the accumulation of free radicals and reduced the incidence of severe arrhythmias and lethality (19).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Ischemia/reperfusion.
What the sources say
- Not checked yetcites [19] Mioni, 2005, Crit. Care Med. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“A high-fat diet also activates increased efferent vagus nerve activity, which decreases TNF levels and confers significant protection against hemorrhagic shock (41).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Hemorrhagic shock.
What the sources say
- Not checked yetcites [41] Luyer, 2005, J. Exp. Med. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Vagus nerve stimulation conferred protection against leukocyte accumulation in the ileum and lung and reduced the severity of tissue damage; the protective effects were reversed by administration of nicotinic receptor antagonists (20).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Ischemia/reperfusion.
What the sources say
- Not checked yetcites [20] Altavilla, 2006, Shock. source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Sudden death, increased morbidity and mortality following cardiac surgery in hostile or depressed patients, and increased death rates in patients with sepsis or organ failure are linked clinically to decreased vagus nerve activity (50)(51)(52)(53)(54).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Figure 4
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Intracerebral administration of CNI-1493, a tetravalent guanylhydrazone that stimulates muscarinic brain networks, increased vagus nerve activity and conferred significant protection against ischemia/ reperfusion-mediated damage (17,44).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Ischemia/reperfusion.
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The wiring diagram for the cholinergic antiinflammatory pathway (Figure 2) maps the concept that the brain can anatomically and functionally coordinate cytokine responses through neural networks that are analogous to other complex and essential physiological systems.”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > A wiring diagram as a template for the immunological homunculus
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Probably not a substantial claim.
In the paper
“Similar beneficial effects were achieved by administration of nicotine, which activated phosphorylation of STAT3 and its binding to and transactivation of its corresponding DNA-response elements.”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Experimental arthritis.
What the sources say
- Not checked yetcites [22] de Jonge, 2005, Nat. Immunol. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Vagus nerve stimulation of rats during lethal hemorrhagic shock conferred significant protection against the development of hypotension, prolonged survival, and decreased TNF production (21).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Hemorrhagic shock.
What the sources say
- Not checked yetcites [21] Guarini, 2003, Circulation. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Administration of nicotine to these animals restored the cytokine balance, reduced influx of inflammatory cells, and attenuated tissue damage in the liver (35).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Sepsis.
What the sources say
- Not checked yetcites [35] van Westerloo, 2005, J. Infect. Dis. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“As the vagus nerve does not signal directly to either the paw or the subcutaneous tissues, it is likely that the reduction in inflammation observed following vagus nerve stimulation in these models is attributable to the downregulation of cytokine production by the reticuloendothelial system and redirection of leukocyte trafficking away from the periphery (28).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Experimental arthritis.
What the sources say
- Not checked yetcites [28] Huston, 2006, J. Exp. Med. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Exercise reduces levels of TNF and other cytokines, confers protection against cardiovascular disease and type 2 diabetes, increases vagus nerve activity, and confers protection against the development of atherosclerosis (84)(85)(86)(87)(88)(89)(90).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Shedding light on ancient concepts and modern clinical problems
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Since weight loss and exercise are each associated with increasing vagus nerve activity, one can consider whether enhanced activity in the cholinergic antiinflammatory pathway might decrease cytokine production and reduce the damage and metabolic derangements mediated by chronic, low-grade systemic inflammation that is characteristic of the metabolic syndrome.”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Shedding light on ancient concepts and modern clinical problems
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Behavioral modification, meditation, hypnosis, biofeedback, and cognitive and relaxation therapies, which have been advocated for treatment of inflammation, can stimulate vagus nerve activity (69)(70)(71)(72)(73)(74)(75).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Shedding light on ancient concepts and modern clinical problems
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
Complex behavior originating in higher brain centers can directly influence outflow through the vagus nerve.
“Abundant evidence points to the concept that complex behavior originating in higher brain centers can directly influence outflow through the vagus nerve.”
The paper relies on this without support.
Deficiencies in the cholinergic antiinflammatory pathway lead to exaggerated cytokine responses and worsened morbidity.
“The available evidence today may favor the former interpretation because deficiencies in the cholinergic antiinflammatory pathway lead to exaggerated cytokine responses and worsened morbidity.”
The paper relies on this without support.
Nicotine inhibits cytokine production via an α7 nAChR-dependent mechanism.
“current understanding that nicotine inhibits cytokine production via an α7 nAChR-dependent mechanism makes it plausible to consider whether this pathway is activated in the subset of patients that derive benefit from nicotine.”
The paper relies on this without support.
Alzheimer disease and other brain degenerative disorders are characterized by cholinergic deficiency and decreased vagus nerve activity.
“Alzheimer disease and other brain degenerative disorders are characterized by cholinergic deficiency and decreased vagus nerve activity.”
The paper relies on this without support.
The CNS is organized somatotopically, such that specific neural networks regulate or coordinate particular actions in the periphery.
“The CNS is organized somatotopically, such that specific neural networks regulate or coordinate particular actions in the periphery.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“The vagus nerve was reported to have important anti-inflammatory activities in acute inflammation due to inhibition of TNF [107].”
From Interaction of the endocrine system with inflammation: a function of energy and volume regulation (2014) · cites this paper as [107]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Shedding light on ancient concepts and modern clinical problems
“The NIH fact sheet on acupuncture notes that "preclinical studies have documented acupuncture's effects, but they have not been able to fully explain how acupuncture works within the framework of the Western system of medicine" (64).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > References
“64. Biswas, A.K., Scott, W.A., Sommerauer, J.F., and Luckett, P.M. 2000. Heart rate variability after acute traumatic brain injury in children. Crit. Care Med. 28:3907-3912.”
Citations
Cites
2 retracted
Mioni, C., Bazzani, C., Giuliani, D., Altavilla, D., Leone, S., Ferrari, A., Minutoli, L., Bitto, A., Marini, H., Zaffe, D., et al. (2005) · Critical Care Medicine · doi:10.1097/01.ccm.0000186762.05301.13 · Cited by 148
RetractedWu, X., Gao, J., Yan, J., Owyang, C., & Li, Y. (2004) · Journal of Neurophysiology · doi:10.1152/jn.00791.2003 · Cited by 53
RetractedVagus nerve stimulation attenuates the systemic inflammatory response to endotoxin
Borovikova, L. V., Ivanova, S., Zhang, M., Yang, H., Botchkina, G. I., Watkins, L. R., Wang, H., Abumrad, N., Eaton, J. W., & Tracey, K. J. (2000) · Nature · doi:10.1038/35013070 · Cited by 4,211
Self-citationTracey, K. J. (2002) · Nature · doi:10.1038/nature01321 · Cited by 3,728
Self-citationNicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation
Wang, H., Yu, M., Ochani, M., Amella, C. A., Tanovic, M., Susarla, S., Li, J. H., Wang, H., Yang, H., Ulloa, L., et al. (2003) · Nature · doi:10.1038/nature01339 · Cited by 3,228
Self-citationTargan, S. R., Hanauer, S. B., van Deventer, S. J. H., Mayer, L., Present, D. H., Braakman, T., DeWoody, K. L., Schaible, T. F., & Rutgeerts, P. J. (1997) · New England Journal of Medicine · doi:10.1056/nejm199710093371502 · Cited by 3,135
The anti-inflammatory effect of exercise
Petersen, A. M. W., & Pedersen, B. K. (2005) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00164.2004 · Cited by 3,100 · cited 1×
“Exercise reduces levels of TNF and other cytokines, confers protection against cardiovascular disease and type 2 diabetes, increases vagus nerve activity, and confers protection against the development of atherosclerosis (84–90).”
Gralton, B. (2008) · Art monthly Australia · Cited by 3,001
Points of control in inflammation
Nathan, C. (2002) · Nature · doi:10.1038/nature01320 · Cited by 2,738
Shock and Tissue Injury Induced by Recombinant Human Cachectin
Tracey, K. J., Beutler, B., Lowry, S. F., Merryweather, J., Wolpe, S., Milsark, I. W., Hariri, R. J., Fahey, T. J., Zentella, A., Albert, J. D., et al. (1986) · Science · doi:10.1126/science.3764421 · Cited by 2,549
Self-citation
Research works printed but not linked: 6
- Zingarelli, 1994, Am. J. Physiol., 266, H1512
- Balanescu, 2004, Med. Sci. Monit., 10, CR307
- Laversuch, 1997, J. Rheumatol., 24, 1540
- Shi, 1995, Zhongguo Zhong. Xi. Yi. Jie. He. Za Zhi., 15, 536
- Papadopoulos, 2005, Clin. Exp. Rheumatol., 23, 861
- Holguin, 2005, Chest., 127, 1102
Cited by
Sorted by citations
Items 201–300 of 996
Paroxysmal Sympathetic Hyperactivity After Acute Brain Injury
Choi, H. A., Jeon, S., Samuel, S., Allison, T. A., & Lee, K. (2013) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-013-0370-3 · Cited by 95
Remote Limb Perconditioning and Postconditioning
Hess, D. C., Hoda, M. N., & Bhatia, K. (2013) · Stroke · doi:10.1161/strokeaha.112.678482 · Cited by 95
Huang, L. Z., Parameswaran, N., Bordia, T., McIntosh, J. M., & Quik, M. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06011.x · Cited by 94
Wu, R., Dong, W., Ji, Y., Zhou, M., Marini, C. P., Ravikumar, T. S., & Wang, P. (2008) · PLoS ONE · doi:10.1371/journal.pone.0002026 · Cited by 92
“An underlying defect in the activity of the cholinergic antiinflammatory pathway may trigger an overwhelming and selfdestructive immune response to an otherwise innocuous immunological stimulus and thus contribute to disease pathogenesis [3,33].”
BackgroundTear film and ocular surface changes in diabetes mellitus
Alves, M., Carvalheira, J. B. C., Módulo, C. M., & Rocha, E. M. (2008) · Arquivos Brasileiros de Oftalmologia · doi:10.1590/s0004-27492008000700018 · Cited by 94
“The progressive peripheral neural damage is an example of afferent and efferent neural signaling pathway, that once damaged, as in neurotrophic keratitis interrupts the anti-inflammatory neural feedback((74-76)).”
BackgroundSato, T., Abe, T., Chida, D., Nakamoto, N., Hori, N., Kokabu, S., Sakata, Y., Tomaru, Y., Iwata, T., Usui, M., et al. (2010) · FEBS Letters · doi:10.1016/j.febslet.2010.01.001 · Cited by 93
“In rodent models of endotoxemia and hemorrhagic shock, stimulation of the efferent vagus nerve dampens macrophage activation [5].”
BackgroundBağdaş, D., Gurun, M. S., Flood, P. D., Papke, R. L., & Damaj, M. I. (2018) · Current Neuropharmacology · doi:10.2174/1570159x15666170818102108 · Cited by 93
“The identification of cholinergic anti-inflammatory activity mediated by α7 nAChR in cells of the immune system [16-18] has drawn attention to the likelihood that ligandinduced conformational changes of α7 receptors are global and apparently encompass changes in signaling associated with the receptor's interactome [19…”
BackgroundGhezzi, P., Floridi, L., Boraschi, D., Cuadrado, A., Manda, G., Levic, S., D’Acquisto, F., Hamilton, A., Athersuch, T. J., & Selley, L. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7147 · Cited by 95
“The identification of cytokines as mediators of inflammation in the mid 1980s led to what Tracey called the ‘‘cytokine theory of disease’’ (176).”
Weber, K. T., Jacobsen, T. D., Maidhof, R., Virojanapa, J. N., Overby, C., Bloom, O., Quraishi, S., Levine, M. E., & Chahine, N. O. (2015) · Current Reviews in Musculoskeletal Medicine · doi:10.1007/s12178-014-9253-8 · Cited by 97
The brain–joint axis in osteoarthritis: nerves, circadian clocks and beyond
Berenbaum, F., & Meng, Q. (2016) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2016.93 · Cited by 91
Egleton, R. D., Brown, K. C., & Dasgupta, P. (2008) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2008.10.007 · Cited by 91
Ren, C., Tong, Y., Li, J., Lu, Z., & Yao, Y.-M. (2016) · International Journal of Biological Sciences · doi:10.7150/ijbs.16404 · Cited by 93
“Activated by peripheral or central stimuli, the brain cholinergic neurons deliver the information to efferent vagus nerves which innervate peripheral organs and release acetylcholine that can inhibit the production of pro-inflammatory cytokines by interacting with α7nAchR on inflammatory cells [1, 8, 9].”
BackgroundAutonomic nervous system dysregulation in irritable bowel syndrome
Salvioli, B., Pellegatta, G., Malacarne, M., Pace, F., Malesci, A., Pagani, M., & Lucini, D. (2015) · Neurogastroenterology & Motility · doi:10.1111/nmo.12512 · Cited by 88
Akamizu, T., & Kangawa, K. (2010) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1007/s13539-010-0011-5 · Cited by 88
“Although the molecular mechanisms and cellular targets mediating ghrelin inhibition of NF-κB activation remain to be determined, the vagus nerve may play an important role in the ghrelinmediated inhibition of proinflammatory cytokine release [44, 48].”
BackgroundAkbar, M., Shabbir, A., Rehman, K., Akash, M. S. H., & Shah, M. A. (2021) · Journal of Food Biochemistry · doi:10.1111/jfbc.13936 · Cited by 97
The, F., Cailotto, C., van der Vliet, J., de Jonge, W. J., Bennink, R. J., Buijs, R. M., & Boeckxstaens, G. E. (2011) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2011.01296.x · Cited by 89
“Inflammation is sensed by the brain via afferent nerve fibres or through cytokine signalling in the general circulation, and both routes are integrated in the nucleus of the tractus solitarius (NTS) (Tracey, 2007).”
BackgroundMethodIntestinal resident macrophages: Multitaskers of the gut
Viola, M. F., & Boeckxstaens, G. E. (2020) · Neurogastroenterology & Motility · doi:10.1111/nmo.13843 · Cited by 93
Hartmann, P., Szabó, A., Erős, G., Gurabi, D., Horváth, G., Németh, I. B., Ghyczy, M., & Boros, M. (2009) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2009.09.012 · Cited by 87
Consolim‐Colombo, F. M., Sangaleti, C. T., Costa, F. O., de Morais, T. L., Lopes, H. F., Motta, J. M. E., Irigoyen, M. C., Bortolotto, L. A., Rochitte, C. E., Harris, Y., et al. (2017) · JCI Insight · doi:10.1172/jci.insight.93340 · Cited by 89
Self-citationImmunologic impact of the intestine in metabolic disease
Winer, D. A., Winer, S., Dranse, H. J., & Lam, T. K. T. (2017) · Journal of Clinical Investigation · doi:10.1172/jci88879 · Cited by 95
“Direct stimulation of vagus nerves triggers a gut/brain/spleen axis that inhibits cytokine release from the splenic macrophages via a T cell–dependent cholinergic signaling axis (94, 95).”
BackgroundSanders, R. D., Hussell, T., & Maze, M. (2009) · Critical Care Clinics · doi:10.1016/j.ccc.2009.05.001 · Cited by 86
CNS-peripheral immune interactions in hemorrhagic stroke
Li, X., & Chen, G. (2022) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x221145089 · Cited by 86
“More severe splenic constriction, more risk of infection, and poorer prognosis are reported in patients with a larger area of cerebral hemorrhage.(104,105) With splenic constriction, the cytokine levels, such as IFN-c, IL-6, IL-10, IL-12, and IL-13, are all elevated after stroke patients.”
BackgroundDexmedetomidine attenuates lipopolysaccharide-induced proinflammatory response in primary microglia
Peng, M., Wang, Y., Wang, C., & Chen, C. (2012) · Journal of Surgical Research · doi:10.1016/j.jss.2012.05.047 · Cited by 86
Straub, R., Bijlsma, J., Masi, A., & Cutolo, M. (2013) · Seminars in Arthritis & Rheumatism · doi:10.1016/j.semarthrit.2013.04.008 · Cited by 83
“This decrease might be unfavorable because it could impede anti-inflammatory activity of the vagus nerve (see below) [85].”
BackgroundElectromagnetic hypersensitivity: Fact or fiction?
Genuis, S. J., & Lipp, C. T. (2011) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2011.11.008 · Cited by 85
“…patientswith TILT, subsequent triggering of the hypersensitive immune system by chemical or electromagnetic incitants precipitates a clinical reaction resulting from a dysregulated biochemical response from various components of the immune system (Genuis, 2010a; Duramad et al., 2007; Tracey, 2007).”
BackgroundHuston, J. M. (2012) · Surgical Infections · doi:10.1089/sur.2012.126 · Cited by 87
“From a teleologic perspective, it would appear advantageous for the immune system to emulate the nervous system, which responds to environmental changes with unparalleled speed and accuracy [8].”
Bansal, V., Ryu, S. Y., Lopez, N., Allexan, S. S., Krzyżaniak, M., Eliceiri, B. P., Baird, A., & Coimbra, R. S. M. (2011) · Inflammation · doi:10.1007/s10753-011-9307-7 · Cited by 87
“It is now well-established that increasing parasympathetic tone, through vagal nerve stimulation, decreases inflammation in various models of physiologic insult including cecal ligation and puncture, LPS injection, severe burn injury and TBI [5, 15, 16].”
BackgroundPapaioannou, V. E., Pneumatikos, I. A., & Maglaveras, N. (2013) · Frontiers in Physiology · doi:10.3389/fphys.2013.00174 · Cited by 87
“This region increases firing of the noradrenergic preganglionic neurons in the spinal cord (Tracey, 2007).”
BackgroundNeuro‐glial crosstalk in inflammatory bowel disease
Neunlist, M., Landeghem, L. V., Bourreille, A., & Savidge, T. (2008) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2008.01963.x · Cited by 82
Multilevel interactions between the sympathetic and parasympathetic nervous systems: a minireview
Ondičová, K., & Mravec, B. (2010) · Endocrine Regulations · doi:10.4149/endo_2010_02_69 · Cited by 85
Liu, F., Li, Y., Jiang, R., Nie, C., Zeng, Z., Zhao, N., Huang, C., Shao, Q., Ding, C., Qing, C., et al. (2015) · Experimental Lung Research · doi:10.3109/01902148.2015.1004206 · Cited by 73
Sympathetic Hyperactivity After Traumatic Brain Injury and the Role of Beta-Blocker Therapy
Heffernan, D. S., Inaba, K., Arbabi, S., & Cotton, B. A. (2010) · The Journal of Trauma: Injury, Infection, and Critical Care · doi:10.1097/ta.0b013e3181f2d3e8 · Cited by 82
Vagus nerve stimulation reduces infarct size in rat focal cerebral ischemia
Ay, İ., Lu, J., Ay, H., & Sorensen, A. G. (2009) · Neuroscience Letters · doi:10.1016/j.neulet.2009.05.018 · Cited by 84
Julio-Pieper, M., Bravo, J. A., Aliaga, E., & Gotteland, M. (2014) · Alimentary Pharmacology & Therapeutics · doi:10.1111/apt.12950 · Cited by 84
High-Resolution Multi-Scale Computational Model for Non-Invasive Cervical Vagus Nerve Stimulation
Mourdoukoutas, A. P., Truong, D. Q., Adair, D., Simon, B. J., & Bikson, M. (2017) · Neuromodulation Technology at the Neural Interface · doi:10.1111/ner.12706 · Cited by 86
Fontana, L. (2009) · Experimental Gerontology · doi:10.1016/j.exger.2008.04.005 · Cited by 81
“…parasympathetic tone The two principal branches of the autonomic nervous system (parasympathetic and sympathetic pathways) control heart rate, blood pressure, and respiratory rate, gastrointestinal motility, and other essential life functions such as the innate immune system (Tracey 2007).”
BackgroundEnteric Glia Cells Attenuate Cytomix-Induced Intestinal Epithelial Barrier Breakdown
Cheadle, G. A., Costantini, T. W., Lopez, N., Bansal, V., Eliceiri, B. P., & Coimbra, R. S. M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0069042 · Cited by 88
“effects of VNS [30–33].”
Targeting neural reflex circuits in immunity to treat kidney disease
Okusa, M. D., Rosin, D. L., & Tracey, K. J. (2017) · Nature Reviews Nephrology · doi:10.1038/nrneph.2017.132 · Cited by 85
Self-citationFactor Structure Underlying Components of Allostatic Load
McCaffery, J. M., Marsland, A. L., Strohacker, K. A., Muldoon, M. F., & Manuck, S. B. (2012) · PLoS ONE · doi:10.1371/journal.pone.0047246 · Cited by 89
“Further, the inverse association between vagal tone and markers of systemic inflammation observed in this study could be consistent with the ‘‘cholinergic anti-inflammatory pathway’’ [45,46], which describes bi-directional communication between vagus nerve fibers and inflammatory mediators observed in animal models [4…”
ResultCostantini, T. W., Bansal, V., Peterson, C. Y., Loomis, W. H., Putnam, J. G., Rankin, F., Wolf, P. L., Eliceiri, B. P., Baird, A., & Coimbra, R. S. M. (2010) · The Journal of Trauma: Injury, Infection, and Critical Care · doi:10.1097/ta.0b013e3181dccea0 · Cited by 81
Radek, K. A., Elias, P. M., Taupenot, L., Mahata, S. K., O’Connor, D. T., & Gallo, R. L. (2010) · Cell Host & Microbe · doi:10.1016/j.chom.2010.03.009 · Cited by 84
“However, activation of a cholinergic anti-inflammatory pathway has been previously shown to be mediated by vagal nerve stimulation and a7 cholinergic receptors and can decrease inflammatory responses (Tracey, 2007).”
BackgroundPathophysiology of perinatal asphyxia: can we predict and improve individual outcomes?
Morales, P., Bustamante, D., Espina-Marchant, P., Neira-Peña, T., Gutierrez-Hernandez, M., Allende-Castro, C., & Rojas-Mancilla, E. (2011) · The EPMA Journal · doi:10.1007/s13167-011-0100-3 · Cited by 79
“or excessive inflammation has been associated with neurotoxicity and numerous neuropathologies [174–177].”
BackgroundHe, X., Zhao, M. F., Bi, X., Sun, L., Yu, X., Zhao, M., & Zang, W. (2014) · British Journal of Pharmacology · doi:10.1111/bph.13010 · Cited by 81
“Role of anti-inflammatory pathways activated by the vagal nerve It is well known that the activation of efferent vagal nerve fibres can modulate local and systemic inflammatory responses, now known as the ‘cholinergic anti-inflammatory pathway’ (Tracey, 2007; Johnston and Webster, 2009; Huston and Tracey, 2011) and th…”
BackgroundHarms, H., Reimnitz, P., Böhner, G., Werich, T., Klingebiel, R., Meisel, C., & Meisel, A. (2011) · Cerebrovascular Diseases · doi:10.1159/000331922 · Cited by 81
Kim, T., Kim, S., & Lee, S. (2013) · The Journal of Infectious Diseases · doi:10.1093/infdis/jit669 · Cited by 80
“Cholinergic and anticholinergic drugs are widely used in intensive care units, where patients with sepsis and organ failure often have increased cytokine levels and depressed vagus nerve activity [14].”
BackgroundAy, İ., Sorensen, A. G., & Ay, H. (2011) · Brain Research · doi:10.1016/j.brainres.2011.03.060 · Cited by 80
“Nevertheless the medullary vagal complex, particularly the solitary nucleus where the primary activation following VNS occurs, has connections with other brain regions that are known to potentially alter the vascular tone upon stimulation (Agassandian et al., 2003; Walters et al., 1986).”
BackgroundDepression and heart disease: What do we know, and where are we headed?
Pozuelo, L., Zhang, J., Franco, K. S. N., Tesar, G., Penn, M. S., & Jiang, W. (2009) · Cleveland Clinic Journal of Medicine · doi:10.3949/ccjm.75a.08011 · Cited by 84
KANG, S. ‐., Kim, Y. S., Hong, T. H., Chae, M. S., Cho, M., Her, Y., & Lee, J. (2012) · Acta Anaesthesiologica Scandinavica · doi:10.1111/aas.12039 · Cited by 80
“Alternatively, the anti-inflammatory effects of dexmedetomidine may be related to its central sympatholytic effects and relative stimulation of the cholinergic anti-inflammatory pathway.(15,25,26) Both HR and MAP at the end of surgery were lower in group D than in group S, and this was thought to have been caused by c…”
BackgroundThe Effect of miR-132, miR-146a, and miR-155 on MRP8/TLR4-Induced Astrocyte-Related Inflammation
Kong, H., Yin, F., He, F., Omran, A., Li, L., Wu, T., Wang, Y., & Peng, J. (2015) · Journal of Molecular Neuroscience · doi:10.1007/s12031-015-0574-x · Cited by 81
“This enzyme limits the level of acetylcholine (ACh), an important inhibitor of peripheral inflammation and one of the characterized mediators of Bcholinergic antiinflammatory pathway^ (Tracey 2007).”
BackgroundImpact of Gut Dysbiosis on Neurohormonal Pathways in Chronic Kidney Disease
Jazani, N. H., Savoj, J., Lustgarten, M. S., Lau, W. L., & Vaziri, N. D. (2019) · Diseases · doi:10.3390/diseases7010021 · Cited by 84
“On the other hand, a cholinergic anti-inflammatory pathway through vagus nerve activation may actually reduce peripheral inflammation, inhibit the release of pro-inflammatory cytokines such as TNF-α, and improve intestinal barrier integrity [150,152].”
BackgroundTerrando, N., Yang, T., Ryu, J. K., Newton, P. T., Monaco, C. G., Feldmann, M., Ma, D., Akassoglou, K., & Maze, M. (2014) · Molecular Medicine · doi:10.2119/molmed.2014.00143 · Cited by 80
“Social Ties, Health and Wellbeing: A Literature Review and Model”,
Kemp, A. H., Arias, J. A., & Fisher, Z. (2017) · Neuroscience and Social Science · doi:10.1007/978-3-319-68421-5_17 · Cited by 79
Wazea, S. A., Wadie, W., Bahgat, A. K., & El-Abhar, H. S. (2018) · Scientific Reports · doi:10.1038/s41598-018-23359-6 · Cited by 79
Rosas‐Ballina, M., Valdés‐Ferrer, S. I., Dancho, M. E., Ochani, M., Katz, D., Cheng, K. F., Olofsson, P. S., Chavan, S. S., Al‐Abed, Y., Tracey, K. J., et al. (2014) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2014.07.010 · Cited by 79
“Andersson U and Tracey K J (2012) Neural Reflexes in Inflammation and Immunity.”
BackgroundInfluentialSelf-citationVagal nerve stimulation decreases blood-brain barrier disruption after traumatic brain injury
Lopez, N. E., Krzyżaniak, M., Costantini, T., Putnam, J. G., Hageny, A.-M., Eliceiri, B., Coimbra, R., & Bansal, V. (2012) · Journal of Trauma and Acute Care Surgery · doi:10.1097/ta.0b013e3182569875 · Cited by 70
“Although the cholinergic anti-inflammatory pathway has not, to our knowledge, been described to have a specific role in the maintenance of the BBB, it has been extensively studied as a physiologic mechanism inhibiting cytokine production and minimizing tissue injury during inflammation.(2) Therefore, it is possible th…”
BackgroundSakamoto (2011) · Vascular Health and Risk Management · doi:10.2147/vhrm.s10783 · Cited by 77
Duan, M., Xu, Y., Li, Y., Feng, H., & Chen, Y. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03101-y · Cited by 85
“…have shown that cerebral hemorrhage leads to a significant reduction in splenic-derived leukocytes and lymphocytes in the peripheral blood [80], and the greater the hemorrhage is, the more severe the splenic constriction, the greater the risk of late infection, and the worse the prognosis [81, 82].”
BackgroundLehrer, P. M., Karavidas, M. K., Lu, S., Coyle, S. M., Oikawa, L. O., Macor, M., Calvano, S. E., & Lowry, S. F. (2010) · Applied Psychophysiology and Biofeedback · doi:10.1007/s10484-010-9139-5 · Cited by 97
“…S. E. Calvano S. F. Lowry Division of Surgical Sciences, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ, USA inflammatory mediator activity (Alvarez et al. 2007; Tracey 2007) as well as systemic regulation during experimentally induced inflammation and infection (Westerloo et al. 2005).”
BackgroundInfluentialGholami, M., Mazaheri, P., Mohamadi, A., Dehpour, T., Safari, F., Hajizadeh, S., Moore, K. P., & Mani, A. R. (2012) · Shock · doi:10.1097/shk.0b013e318240b4be · Cited by 77
“Acetylcholine, the principal vagal neurotransmitter, significantly attenuated the release of proinflammatory cytokines through activation of !7-nicotinic receptors on macrophage and other cells (29, 30).”
BackgroundRegulation of muscle growth by pathogen-associated molecules1,2
Frost, R. A., & Lang, C. H. (2008) · Journal of Animal Science · doi:10.2527/jas.2007-0483 · Cited by 80
“Yet, all proposed endogenous TLR ligands should be rigorously tested to eliminate the potential confounding effects of contamination by known PAMPS (Tsan and Baochong, 2007).”
BackgroundThe Multiple Organ Dysfunction Syndrome
Mizock, B. A. (2009) · Disease-a-Month · doi:10.1016/j.disamonth.2009.04.002 · Cited by 83
Intrinsic Gastrointestinal Macrophages: Their Phenotype and Role in Gastrointestinal Motility
Cipriani, G., Gibbons, S. J., Kashyap, P., & Farrugia, G. (2016) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2016.01.003 · Cited by 77
Purkayastha, S., Stokes, M. A., & Bell, K. R. (2019) · Brain Injury · doi:10.1080/02699052.2019.1631488 · Cited by 86
“However, in TBI, an imbalance between these negative feedback mechanisms leads to dysfunction of the immune system and higher susceptibility to infection (46,49).”
BackgroundDexmedetomidine Attenuates the Microcirculatory Derangements Evoked by Experimental Sepsis
de Miranda, M. L., Balarini, M. M., & Bouskela, E. (2014) · Anesthesiology · doi:10.1097/aln.0000000000000491 · Cited by 76
Chatterjee, P. K., Yeboah, M. M., Dowling, O., Xue, X., Powell, S. R., Al‐Abed, Y., & Metz, C. N. (2012) · PLoS ONE · doi:10.1371/journal.pone.0035361 · Cited by 78
“cholinergic anti-inflammatory pathway [17].”
Fanelli, V., Morita, Y., Cappello, P., Ghazarian, M., Sugumar, B., Delsedime, L., Batt, J. A. E., Ranieri, V. M., Zhang, H., & Slutsky, A. S. (2015) · Anesthesiology · doi:10.1097/aln.0000000000000907 · Cited by 80
Inflammation and depression but where does the inflammation come from?
Halaris, A. E. (2019) · Current Opinion in Psychiatry · doi:10.1097/yco.0000000000000531 · Cited by 76
“Tracey KJ. Physiology and immunology of the cholinergic antiinflammatory pathway.”
MethodInfluentialYu, T., Liu, D., Gao, M., Yang, P., Zhang, M., Song, F., Zhang, X., & Liu, Y. (2019) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2019.109231 · Cited by 72
Boettger, M. K., Weber, K., Grossmann, D., Gajda, M. R., Bauer, R., Bär, K., Schulz, S., Voss, A., Geis, C., Bräuer, R., et al. (2010) · Arthritis & Rheumatism · doi:10.1002/art.27380 · Cited by 75
Zhu, Y., Peng, K., Meng, X., & Ji, F. (2016) · Brain Research · doi:10.1016/j.brainres.2016.04.074 · Cited by 77
Integrative neurobiology of metabolic diseases, neuroinflammation, and neurodegeneration
van Dijk, G., van Heijningen, S., Reijne, A. C., Nyakas, C., van der Zee, E. A., & Eisel, U. L. M. (2015) · Frontiers in Neuroscience · doi:10.3389/fnins.2015.00173 · Cited by 75
“As already mention, Tracey exposed the effects of stimulating the vagus nerve and administrating nicotine which inhibits TNFα release and various other pro-inflammatory cytokines (Borovikova et al., 2000; Wang et al., 2003; Tracey, 2007; Pavlov and Tracey, 2012).”
BackgroundXue, Y., He, J., Xiao, C., Guo, Y., Fu, T., Liu, J., Lin, C., Wu, M., Yang, Y., Dong, D., et al. (2018) · Mucosal Immunology · doi:10.1038/s41385-018-0031-6 · Cited by 75
Staats, P. S., Giannakopoulos, G., Blake, J., Liebler, E. J., & Levy, R. M. (2020) · Neuromodulation Technology at the Neural Interface · doi:10.1111/ner.13172 · Cited by 76
Novel Therapeutic Targets for Sepsis: Regulation of Exaggerated Inflammatory Responses
Matsuda, A., Jacob, A., Wu, R., Aziz, M., Yang, W.-L., Matsutani, T., Suzuki, H., Furukawa, K., Uchida, E., & Wang, P. (2012) · Journal of Nippon Medical School · doi:10.1272/jnms.79.4 · Cited by 74
Fadul, N. A., Strasser, F., Palmer, J. L., Yusuf, S. W., Guo, Y., Li, Z., Allo, J. A., & Bruera, E. D. (2010) · Journal of Pain and Symptom Management · doi:10.1016/j.jpainsymman.2009.06.014 · Cited by 72
Calorie restriction and cardiometabolic health
Fontana, L. (2008) · European Journal of Cardiovascular Prevention & Rehabilitation · doi:10.1097/hjr.0b013e3282f17bd4 · Cited by 72
The Evolution of Neuromodulation in the Treatment of Chronic Pain: Forward-Looking Perspectives
Fishman, M. A., Antony, A. B., Esposito, M. F., Deer, T. R., & Levy, R. M. (2019) · Pain Medicine · doi:10.1093/pm/pnz074 · Cited by 76
“Stimulation of the vagus nerve prevents the damaging effects of cytokine release in animal models of sepsis, endotoxemia, ischemia/ reperfusion injury, hemorrhagic shock, arthritis, and other inflammatory syndromes [117].”
Backgroundvan der Kleij, H. P. M., O’Mahony, C., Shanahan, F., O’Mahony, L., & Bienenstock, J. (2008) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.90434.2008 · Cited by 69
“The described cholinergic anti-inflammatory pathway is a physiological mechanism that modulates host inflammatory responses via cholinergic mediators or electrical stimulation of the vagus nerve (33, 34).”
BackgroundInvited review: Deterioration of the immune system after trauma: signals and cellular mechanisms
Flohé, S. B., Flohé, S., & Schade, F. U. (2008) · Innate Immunity · doi:10.1177/1753425908100016 · Cited by 72
Physiology in Medicine: Peripheral arterial disease
Muller, M. D., Reed, A. B., Leuenberger, U. A., & Sinoway, L. I. (2013) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00885.2013 · Cited by 69
“Vagal activity can exert important anti-inflammatory effects, thus potentially inhibiting vascular inflammation that underlies systemic atherosclerosis (81).”
BackgroundSaku, K., Kishi, T., Sakamoto, K., Hosokawa, K., Sakamoto, T., Murayama, Y., Kakino, T., Ikeda, M., Ide, T., & Sunagawa, K. (2014) · Physiological Reports · doi:10.14814/phy2.12136 · Cited by 68
“…been proposed, such as lowering of heart rate and oxygen consumption (Shimizu et al. 2009), reduction in inflammation through nicotinic receptors (Tracey 2007), attenuation of norepinephrine spillover into the left ventricle (Levy and Blattberg 1976), and suppression of free radical generation…”
BackgroundZhang, H., Ma, S., Han, T., Qu, G., Cheng, C., Uy, J. P., Shaikh, M. B., Zhou, Q., Song, E. J., & Sun, C. (2021) · European Journal of Integrative Medicine · doi:10.1016/j.eujim.2021.101313 · Cited by 76
Vital signs as physiomarkers of neonatal sepsis
Sullivan, B. A., & Fairchild, K. D. (2021) · Pediatric Research · doi:10.1038/s41390-021-01709-x · Cited by 70
Papaioannou, V. E., Dragoumanis, C., Theodorou, V., Gargaretas, C., & Pneumatikos, I. A. (2009) · Journal of Critical Care · doi:10.1016/j.jcrc.2008.11.010 · Cited by 72
“The first mechanism relies upon activation of vagus nerve afferent fibers from different cytokines that signal the brain that inflammation is occurring [2,3].”
BackgroundRespiratory mechanics in brain injury: A review
Koutsoukou, A. (2016) · World Journal of Critical Care Medicine · doi:10.5492/wjccm.v5.i1.65 · Cited by 67
Speed of Heart Rate Recovery in Response to Orthostatic Challenge
McCrory, C., Berkman, L. F., Nolan, H., O’Leary, N., Foley, M. M., & Kenny, R. A. (2016) · Circulation Research · doi:10.1161/circresaha.116.308577 · Cited by 70
Henje, E., Lekander, M., Ingvar, M., Åsberg, M., Mobarrez, F., & Serlachius, E. (2011) · Journal of Affective Disorders · doi:10.1016/j.jad.2011.10.002 · Cited by 71
“However, it is known that the nervous system can inhibit cytokine release via an anti-inflammatory cholinergic pathway of the vagus nerve and that stimulation of the vagus nerve prevents the damaging effects of cytokine release in several inflammatory conditions (Tracey, 2007).”
Gao, B.-X., Hierl, M., Clarkin, K., Juan, T., Nguyen, H. Q., van der Valk, M., Deng, H. X., Guo, W., Lehto, S. G., Matson, D. J., et al. (2010) · Pain · doi:10.1016/j.pain.2010.01.007 · Cited by 67
“the discrepancy between our studies in the formalin model and other studies with pain models is that a7* exerts its effects not on pain itself, but on the inflammation associated with or producing pain [114].”
ResultZhou, H. F., Liang, H., Li, Z., Xiang, H., Liu, W., & Li, J.-G. (2013) · Shock · doi:10.1097/shk.0b013e318299e9c0 · Cited by 67
Tan, F., Chen, Y., Yuan, D., GONG, C., Li, X., & Zhou, S. (2015) · Biomedical Reports · doi:10.3892/br.2015.427 · Cited by 68
Cholinergic anti-inflammatory pathway in intracerebral hemorrhage
Lee, S., Chu, K., Jung, K., Kang, K.-M., Kim, J. H., Bahn, J.-J., Jeon, D., Kim, M., Lee, S. K., & Roh, J. (2009) · Brain Research · doi:10.1016/j.brainres.2009.10.076 · Cited by 68
From CNI-1493 to the immunological homunculus: physiology of the inflammatory reflex
Oke, S. L., & Tracey, K. J. (2007) · Journal of Leukocyte Biology · doi:10.1189/jlb.0607363 · Cited by 67
Self-citationLiu, A., Zhao, F., Wang, J., Lu, Y., Tian, J., Zhao, Y., Gao, Y., Hu, X., Liu, X., Tan, J., et al. (2016) · Journal of Translational Medicine · doi:10.1186/s12967-016-0858-0 · Cited by 67
Prolonged Prothrombotic Effects of Antecedent Hypoglycemia in Individuals With Type 2 Diabetes
Chow, E., Iqbal, A., Walkinshaw, E., Phoenix, F. A., Macdonald, I. A., Storey, R. F., Ajjan, R., & Heller, S. R. (2018) · Diabetes Care · doi:10.2337/dc18-0050 · Cited by 67
“Suppression of cholinergic antiinflammatory pathways (13) may lead to prothrombotic and proinflammatory responses after hypoglycemia.”
BackgroundBioelectronic medicine for the autonomic nervous system: clinical applications and perspectives
Cracchiolo, M., Ottaviani, M. M., Panarese, A., Strauss, I., Vallone, F., Mazzoni, A., & Micera, S. (2021) · Journal of Neural Engineering · doi:10.1088/1741-2552/abe6b9 · Cited by 66
“effects on chronic diseases and pathological conditions that were previously treated with pharmacological approaches [14, 15].”
BackgroundMatarese, G., Isola, G., Anastasi, G., Favaloro, A., Milardi, D., Vermiglio, G., Vita, G., Cordasco, G., & Cutroneo, G. (2012) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2012.1024 · Cited by 66
Neuroscientific therapies for atrial fibrillation
Hanna, P., Buch, E. F., Stavrakis, S., Meyer, C. G., Tompkins, J. D., Ardell, J. L., & Shivkumar, K. (2021) · Cardiovascular Research · doi:10.1093/cvr/cvab172 · Cited by 68
THE PROTECTIVE EFFECT OF THE CHOLINERGIC ANTI-INFLAMMATORY PATHWAY AGAINST SEPTIC SHOCK IN RATS
Song, X., Li, J.-G., Wang, Y., Hu, Z., Zhou, Q., Du, Z., & Jia, B. (2008) · Shock · doi:10.1097/shk.0b013e31816d5e49 · Cited by 66
“The cholinergic anti-inflammatory pathway might have potential positive effects on sepsis, trauma, I/R injury, pancreatitis, experimental arthritis, ileus, and septic/hemorrhagic shock (10), but the precise mechanisms underlying the inhibitory effects are still unknown.”
BackgroundOttani, A., Giuliani, D., Mioni, C., Galantucci, M., Minutoli, L., Bitto, A., Altavilla, D., Zaffe, D., Botticelli, A. R., Squadrito, F., et al. (2008) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2008.140 · Cited by 65
“In this organ, in fact, there is an upregulation of inflammatory cell recruitment, with overproduction of several inflammatory mediators that contribute to multiple organ damage and dysfunction (Guarini et al, 2003, 2004; Altavilla et al, 2006; Tracey, 2007).”
BackgroundInfluentialRetractedDu, M. (2013) · World Journal of Gastroenterology · doi:10.3748/wjg.v19.i36.5988 · Cited by 66
Metadata
- Authors
- Tracey, K. J.
- Affiliations
- Feinstein Institute for Medical Research (US)
- Corresponding author
- Tracey, Kevin J.
- ORCID
- Tracey, Kevin J.
- Venue
- Journal of Clinical Investigation
- Published
- 2007-02-01
- Volume
- 117
- Issue
- 2
- Pages
- 289-296
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1783813
- OpenAlex
- W2002797282
- Semantic Scholar
- 76a50e9232b81d22a72d6631b636a0d756df76b8
- Cited by
- 1,563
- References
- 107
- Citations by year
- 2026: 73 · 2025: 58 · 2024: 76 · 2023: 58 · 2022: 72 · 2021: 89 · 2020: 92 · 2019: 76 · 2018: 79 · 2017: 87 · 2016: 78 · 2015: 78 · 2014: 88 · 2013: 87 · 2012: 89
- FWCI
- 8.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Defense Advanced Research Projects Agency
- Advanced Research Projects Agency
- National Institute of General Medical Sciences
- Topics
- Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- cholinergic anti-inflammatory pathway, vagus nerve, cytokine production, neuroimmune regulation, sepsis, endotoxemia, ischemia-reperfusion injury, hemorrhagic shock, arthritis, humoral theory, terrain theory, cholinergic agonists, neuroprotection, tissue damage, multiple organ failure
- MeSH terms
- Animals, Brain, Cholinergic Fibers, Humans, Inflammation, Models, Biological, Cytokines, History, 20th Century, History, 21st Century, History, Ancient
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