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      The Role of the Vagus Nerve: Modulation of the Inflammatory Reaction in Murine Polymicrobial Sepsis

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          Abstract

          The particular importance of the vagus nerve for the pathophysiology of peritonitis becomes more and more apparent. In this work we provide evidence for the vagal modulation of inflammation in the murine model of colon ascendens stent peritonitis (CASP). Vagotomy significantly increases mortality in polymicrobial sepsis. This effect is not accounted for by the dilatation of gastric volume following vagotomy. As the stimulation of cholinergic receptors by nicotine has no therapeutic effect, the lack of nicotine is also not the reason for the reduced survival rate. In fact, increased septic mortality is a consequence of the absent modulating influence of the vagus nerve on the immune system: we detected significantly elevated serum corticosterone levels in vagotomised mice 24 h following CASP and a decreased ex vivo TNF-alpha secretion of Kupffer cells upon stimulation with LPS. In conclusion, the vagus nerve has a modulating influence in polymicrobial sepsis by attenuating the immune dysregulation.

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          Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation.

          Hong. Wang, Man Yu, Mahendar Ochani … (2003)
          Excessive inflammation and tumour-necrosis factor (TNF) synthesis cause morbidity and mortality in diverse human diseases including endotoxaemia, sepsis, rheumatoid arthritis and inflammatory bowel disease. Highly conserved, endogenous mechanisms normally regulate the magnitude of innate immune responses and prevent excessive inflammation. The nervous system, through the vagus nerve, can inhibit significantly and rapidly the release of macrophage TNF, and attenuate systemic inflammatory responses. This physiological mechanism, termed the 'cholinergic anti-inflammatory pathway' has major implications in immunology and in therapeutics; however, the identity of the essential macrophage acetylcholine-mediated (cholinergic) receptor that responds to vagus nerve signals was previously unknown. Here we report that the nicotinic acetylcholine receptor alpha7 subunit is required for acetylcholine inhibition of macrophage TNF release. Electrical stimulation of the vagus nerve inhibits TNF synthesis in wild-type mice, but fails to inhibit TNF synthesis in alpha7-deficient mice. Thus, the nicotinic acetylcholine receptor alpha7 subunit is essential for inhibiting cytokine synthesis by the cholinergic anti-inflammatory pathway.
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            Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis.

            Hong. Wang, Hong Liao, Mahendar Ochani … (2004)
            Physiological anti-inflammatory mechanisms can potentially be exploited for the treatment of inflammatory disorders. Here we report that the neurotransmitter acetylcholine inhibits HMGB1 release from human macrophages by signaling through a nicotinic acetylcholine receptor. Nicotine, a selective cholinergic agonist, is more efficient than acetylcholine and inhibits HMGB1 release induced by either endotoxin or tumor necrosis factor-alpha (TNF-alpha). Nicotinic stimulation prevents activation of the NF-kappaB pathway and inhibits HMGB1 secretion through a specific 'nicotinic anti-inflammatory pathway' that requires the alpha7 nicotinic acetylcholine receptor (alpha7nAChR). In vivo, treatment with nicotine attenuates serum HMGB1 levels and improves survival in experimental models of sepsis, even when treatment is started after the onset of the disease. These results reveal acetylcholine as the first known physiological inhibitor of HMGB1 release from human macrophages and suggest that selective nicotinic agonists for the alpha7nAChR might have therapeutic potential for the treatment of sepsis.
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              Animal models of sepsis: setting the stage.

              Jon A Buras, Bernhard Holzmann, Michail Sitkovsky (2005)
              Sepsis is a state of disrupted inflammatory homeostasis that is often initiated by infection. The development and progression of sepsis is multi-factorial, and affects the cardiovascular, immunological and endocrine systems of the body. The complexity of sepsis makes the clinical study of sepsis and sepsis therapeutics difficult. Animal models have been developed in an effort to create reproducible systems for studying sepsis pathogenesis and preliminary testing of potential therapeutic agents. However, demonstrated benefit from a therapeutic agent in animal models has rarely been translated into success in human clinical trials. This review summarizes the common animal sepsis models and highlights how results of recent human clinical trials might affect their use.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Mediators Inflamm
                Journal ID (iso-abbrev): Mediators Inflamm
                Journal ID (publisher-id): MI
                Title: Mediators of Inflammation
                Publisher: Hindawi Publishing Corporation
                ISSN (Print): 0962-9351
                ISSN (Electronic): 1466-1861
                Publication date (Print): 2012
                Publication date (Electronic): 21 March 2012
                Volume: 2012
                Electronic Location Identifier: 467620
                Affiliations
                1Klinik und Poliklinik für Allgemeine Chirurgie, Viszeral, Thorax und Gefäßchirurgie der Ernst Moritz Arndt Universität Greifswald, Friedrich Loeffler Straße 23b, 17475 Greifswald, Germany
                2Mund, Kiefer und Gesichtschirurgische Klinik der Universität Erlangen, Glückstraße 11, 91054 Erlangen, Germany
                3Institut für diagnostische Radiologie und Neuroradiologie der Ernst Moritz Arndt Universität Greifswald, Ferdinand-Sauerbruch-Straße, 17475 Greifswald, Germany
                Author notes

                Academic Editor: Markus Wornle

                Article
                DOI: 10.1155/2012/467620
                PMC ID: 3321608
                PubMed ID: 22547905
                SO-VID: 130fa116-088f-4e98-bb3a-8aa3bff435e5
                Copyright © Copyright © 2012 Wolfram Kessler et al.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original paper is properly cited.

                History
                Date received : 15 September 2011
                Date accepted : 27 December 2011
                Categories
                Subject: Research Article

                ScienceOpen disciplines: Immunology
                Data availability:
                ScienceOpen disciplines: Immunology

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