Cholinergic antiinflammatory pathway inhibition of tumor necrosis factor during ischemia reperfusion
Open accessAbstract
Objective Ischemia-reperfusion injury is a pathologic event characterized by tissue damage. It is mediated by tumor necrosis factor (TNF) and other cytokines that activate complement and proteases and stimulate fibrinolysis, degranulation of white blood cells, and free radical production. We recently reported that vagus nerve stimulation (VNS) suppresses endotoxin-induced cytokine synthesis through alpha bungarotoxin-sensitive cholinergic receptors. VNS protects against endotoxin-induced shock by inhibiting hepatic and cardiac synthesis of TNF. Here, the effects of VNS on suppression of ischemia-reperfusion injury and cytokine release were studied in a rat model of aortic occlusion.Methods Adult male Lewis rats were subjected to laparotomy and suprarenal aortic clamping for 15 minutes followed by reperfusion. Blood pressure, heart rate, and respiratory rate were recorded every 3 minutes for 90 minutes. Exposed cervical vagus nerves in the experimental group were stimulated for 5 minutes before and after aortic occlusion, with constant voltage (1 V, 2 ms, 5 Hz); sham-operated animals received no stimulation. TNF levels in serum and organs were measured with enzyme-linked immunosorbent assay ELISA (BioSource International, Camarillo, Calif). Data analysis was performed with the Student t test.Results Control animals had shock develop (mean, 59% decrease in blood pressure) whereas blood pressure in the stimulated animals did not decrease (control versus stimulated animals, P <.05). VNS significantly inhibited TNF levels in serum (7 +/- 1 ng/mL versus 45 +/- 6 ng/mL; P =.0008), heart (21 +/- 11 ng/g protein versus 85 +/- 15 ng/g protein; P =.01), and liver (16 +/- 2 ng/g protein versus 42 +/- 12 ng/g protein; P =.02).Conclusion VNS significantly attenuates TNF synthesis and shock during reperfusion injury in a standard model of aortic occlusion. Clinical evaluation of VNS for this condition may be warranted.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
Intracerebral administration of CNI-1493 increases vagus nerve activity and confers protection against ischemia/reperfusion-mediated damage.
“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).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [44]
Vagus nerve stimulation significantly attenuates cytokine responses in a rat model of aortic ischemia/reperfusion injury.
“Vagus nerve stimulation significantly attenuated cytokine responses in a rat model of aortic ischemia/reperfusion injury (44).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [44]
The protective effects of intracerebral CNI-1493 require vagus nerve signals.
“The protective effects of intracerebral CNI-1493 required vagus nerve signals because vagotomy ablated the protective effects of administering the drug.”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [44]
Reperfusion of ischemic tissues stimulates cytokine overproduction, including TNF, IL-1, and HMGB1, which contributes to the pathogenesis of resulting tissue damage.
“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).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [44]
Cites
Vagus 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 · see citing works
Self-citationVagus nerve stimulation: a new tool for brain research and therapy
George, M. S., Sackeim, H. A., Rush, A. J., Marangell, L. B., Nahas, Z., Husain, M. M., Lisanby, S., Burt, T., Goldman, J., & Ballenger, J. C. (2000) · Biological Psychiatry · doi:10.1016/s0006-3223(99)00308-x · Cited by 461 · see citing works
Role of vagus nerve signaling in CNI-1493-mediated suppression of acute inflammation
Borovikova, L. V., Ivanova, S., Nardi, D., Zhang, M., Yang, H., Ombrellino, M., & Tracey, K. J. (2000) · Autonomic Neuroscience · doi:10.1016/s1566-0702(00)00233-2 · Cited by 322 · see citing works
Self-citationElevated Circulating Levels of Inflammatory Cytokines in Patients With Abdominal Aortic Aneurysm
Juvonen, J., Surcel, H., Satta, J., Teppo, A., Bloigu, A. H., Syrjälä, H., Airaksinen, J. K. E., Leinonen, M., Saikku, P., & Juvonen, T. S. (1997) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.17.11.2843 · Cited by 302 · see citing works
George, M. S., Sackeïm, H. A., Marangell, L. B., Husain, M. M., Nahas, Z. H., Lisanby, S. H., Ballenger, J. C., & Rush, A. J. (2000) · Psychiatric Clinics of North America · doi:10.1016/s0193-953x(05)70196-9 · Cited by 87 · see citing works
Swartbol, P., Norgren, L., Albrechtsson, U., Cwikiel, W. B., Jahr, J., Jonung, T., Pärsson, H., Ribbe, E. B., Thörne, J., Truedsson, L., et al. (1996) · European Journal of Vascular and Endovascular Surgery · doi:10.1016/s1078-5884(96)80270-x · Cited by 83 · see citing works
Groeneveld, A. B. J., Raijmakers, P. G. H. M., Rauwerda, H., & Hack, C. E. (1997) · European Journal of Vascular and Endovascular Surgery · doi:10.1016/s1078-5884(97)80284-5 · Cited by 79 · see citing works
Froon, A. H. M., Greve, J. W. M., van der Linden, J., et al. (1996) · PubMed · Cited by 55 · see citing works
PRO-AND ANTI-INFLAMMATORY CYTOKINE-RESPONSE IN ABDOMINAL AORTIC ANEURYSM REPAIR
Holzheimer, R. G., Gross, J., & Schein, M. (1999) · Shock · doi:10.1097/00024382-199905000-00001 · Cited by 50 · see citing works
Ziegenfuß, T., Wanner, G. A., Grass, C., Bauer, I., Schüder, G., Kleinschmidt, S., Menger, M. D., & Bauer, M. W. (1999) · Intensive Care Medicine · doi:10.1007/s001340050836 · Cited by 41 · see citing works
Role of TNF-α in myocardial dysfunction after hemorrhagic shock and lower-torso ischemia
Shahani, R., Marshall, J. G., Rubin, B. B., Li, R., Walker, P. M., & Lindsay, T. F. (2000) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.2000.278.3.h942 · Cited by 34 · see citing works
Kumins, N. H., Hunt, J., Gamelli, R. L., & Filkins, J. P. (1996) · Shock · doi:10.1097/00024382-199605000-00012 · Cited by 32 · see citing works
Inflammatory response to aorto-bifemoral graft surgery.
Pärsson, H., Nässberger, L., & Norgren, L. (1997) · PubMed · Cited by 14 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Physiology and immunology of the cholinergic antiinflammatory pathway
Tracey, K. J. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30555 · Cited by 1,563 · see citing works
Self-citationHuston, J. M., Ochani, M., Rosas-Ballina, M., Liao, H., Ochani, K., Pavlov, V. A., Gallowitsch-Puerta, M., Ashok, M., Czura, C. J., Foxwell, B., et al. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20052362 · Cited by 683 · see citing works
Self-citationBonaz, B., Sinniger, V., & Pellissier, S. (2016) · The Journal of Physiology · doi:10.1113/jp271539 · Cited by 561 · see citing works
Reflex principles of immunological homeostasis
Andersson, U., & Tracey, K. J. (2012) · Annual Review of Immunology · doi:10.1146/annurev-immunol-020711-075015 · Cited by 414 · see citing works
Self-citationBonaz, B., Sinniger, V., & Pellissier, S. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01452 · Cited by 405 · see citing works
Rethinking inflammation: neural circuits in the regulation of immunity
Olofsson, P. S., Rosas‐Ballina, M., Levine, Y. A., & Tracey, K. J. (2012) · Immunological Reviews · doi:10.1111/j.1600-065x.2012.01138.x · Cited by 393 · see citing works
Self-citationThe Vagus Nerve and Nicotinic Receptors Modulate Experimental Pancreatitis Severity in Mice
van Westerloo, D. J., Giebelen, I. A., Florquin, S., Bruno, M. J., LaRosa, G. J., Ulloa, L., Tracey, K. J., & van der Poll, T. (2006) · Gastroenterology · doi:10.1053/j.gastro.2006.02.022 · Cited by 377 · see citing works
Self-citationThe Cholinergic Anti‐Inflammatory Pathway Regulates the Host Response during Septic Peritonitis
van Westerloo, D. J., Giebelen, I. A. J., Florquin, S., Daalhuisen, J., Bruno, M. J., de Vos, A. F., Tracey, K. J., & van der Poll, T. (2005) · The Journal of Infectious Diseases · doi:10.1086/430323 · Cited by 316 · see citing works
Self-citationAnti-inflammatory effect of vagus nerve stimulation in a rat model of inflammatory bowel disease
Meregnani, J., Clarençon, D., Vivier, M., Peinnequin, A., Mouret, C., Sinniger, V., Picq, C., Job, A., Canini, F., Jacquier-Sarlin, M., et al. (2011) · Autonomic Neuroscience · doi:10.1016/j.autneu.2010.10.007 · Cited by 310 · see citing works
Taylor, A. G., Goehler, L. E., Galper, D. I., Innes, K. E., & Bourguignon, C. (2010) · EXPLORE · doi:10.1016/j.explore.2009.10.004 · Cited by 287 · see citing works
Autonomic neural regulation of immunity
CZURA, C. J., & TRACEY, K. J. (2005) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2004.01442.x · Cited by 255 · see citing works
Self-citationVagus nerve stimulation: a new promising therapeutic tool in inflammatory bowel disease
Bonaz, B., Sinniger, V., & Pellissier, S. (2017) · Journal of Internal Medicine · doi:10.1111/joim.12611 · Cited by 213 · see citing works
Identification of a brainstem locus that inhibits tumor necrosis factor
Kressel, A. M., Tsaava, T., Levine, Y. A., Chang, E. H., Addorisio, M. E., Chang, Q., Burbach, B. J., Carnevale, D., Lembo, G., Zador, A. M., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2008213117 · Cited by 133 · see citing works
Self-citationBruchfeld, A., Goldstein, R. S., Chavan, S., Patel, N. B., Rosas‐Ballina, M., Kohn, N., Qureshi, A. R., & Tracey, K. J. (2010) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2010.02226.x · Cited by 99 · see citing works
Self-citationVAN WESTERLOO, D. J., GIEBELEN, I. A. J., MEIJERS, J. C. M., DAALHUISEN, J., DE VOS, A. F., LEVI, M., & VAN DER POLL, T. (2006) · Journal of Thrombosis and Haemostasis · doi:10.1111/j.1538-7836.2006.02112.x · Cited by 84 · see citing works
Reichert, V., Xue, X., Bartscherer, D., Jacobsen, D., Fardellone, C., Folan, P., Kohn, N., Talwar, A., & Metz, C. N. (2009) · Chest · doi:10.1378/chest.08-2288 · Cited by 55 · see citing works
- Authors
- Bernik, T. R., Friedman, S. G., Ochani, M., DiRaimo, R., Susarla, S., Czura, C. J., & Tracey, K. J.
- Affiliations
- North Shore University Hospital (US)
- Venue
- Journal of Vascular Surgery
- Publisher
- Elsevier BV
- Published
- 2002-12
- Volume
- 36
- Issue
- 6
- Pages
- 1231-1236
- ISSN
- 0741-5214 (ISSN-L)
- OpenAlex
- W1967372050
- Cited by
- 228
- References
- 13
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 7 · 2023: 3 · 2022: 7 · 2021: 11 · 2020: 7 · 2019: 12 · 2018: 14 · 2017: 12 · 2016: 8 · 2015: 14 · 2014: 15 · 2013: 13 · 2012: 13
- FWCI
- 2.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Vascular Surgery (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (R01 GM 57226-02, R01GM057226)
- Topics
- Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Health Sciences › Medicine › Psychiatry and Mental health › Cancer, Stress, Anesthesia, and Immune Response
- Keywords
- vagus nerve stimulation, TNF-α, ischemia-reperfusion injury, cholinergic anti-inflammatory pathway, aortic occlusion, shock, cytokine inhibition, endotoxic shock, heart, liver
- MeSH terms
- Animals, Blood Pressure, Cholinergic Fibers, Disease Models, Animal, Electric Stimulation, Heart Rate, Inflammation, Male, Neural Pathways, Rats, Inbred Lew, Time Factors, Tumor Necrosis Factor-alpha, Vagus Nerve, Reperfusion Injury, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
