Inflammation is a fundamental physiological process that is crucial for survival, but at the same time it is one of the major causes of human morbidity and mortality. The production of pro-inflammatory cytokines is beneficial and protects the organism against infections and injury. However, excessive production of these cytokines can be more dangerous than the original infection, resulting in lethal systemic inflammation. These cytokines are successful pharmacological targets for the treatment of a variety of clinical disorders.
Severe sepsis, the leading cause of death in intensive care units, is one of the most dramatic examples of the pathological potential of inflammation is sepsis. Severe sepsis is the third leading cause of death in developed societies, equals the number of fatalities from acute myocardial infarction, and accounts for 9.3% of overall deaths in the United States annually.
Vagus-nerve stimulation, acetylcholine and nicotine inhibit the production of pro-inflammatory cytokines from macrophages through a 'nicotinic anti-inflammatory pathway' that is dependent on the α7 nicotinic acetylcholine receptor (α7nAChR).
Similar to the development of α- and β-agonists for adrenergic receptors, the design of selective nicotinic agonists for the α(α7nAChR could represent a promising pharmacological strategy against infectious and inflammatory diseases.
The therapeutic potential of nicotinic agonists has been limited by the characterization of the specific receptors for drug development. The recent characterization of the α7nAChR in macrophages supports the design of selective nicotine agonists that can overcome the toxic effect of nicotine mediated by other receptors.
Physiological anti-inflammatory mechanisms are selected by evolution to effectively control the immune system and can be exploited for the treatment of inflammatory disorders. Recent studies indicate that the vagus nerve (which is the longest of the cranial nerves and innervates most of the peripheral organs) can modulate the immune response and control inflammation through a 'nicotinic anti-inflammatory pathway' dependent on the α7-nicotinic acetylcholine receptor (α7nAChR). Nicotine has been used in clinical trials for the treatment of ulcerative colitis, but its clinical applications are limited by its unspecific effects and subsequent toxicity. This article reviews recent advances supporting the therapeutic potential of selective nicotinic agonists in several diseases. Similar to the development of α- and β-agonists for adrenoceptors, selective agonists for α7nAChR could represent a promising pharmacological strategy against infectious and inflammatory diseases.
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Sands, K. E. et al. Epidemiology of sepsis syndrome in 8 academic medical centers. Academic Medical Center Consortium Sepsis Project Working Group. JAMA 278, 234–240 (1997).
Angus, D. C. et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit. Care Med. 29, 1303–1310 (2001).
Martin, G. S. et al. The epidemiology of sepsis in the United States from 1979 through 2000. N. Engl. J. Med. 348, 1546–1554 (2003).
Friedman, G., Silva, E. & Vincent, J. L. Has the mortality of septic shock changed with time. Crit. Care Med. 26, 2078–2086 (1998). References 1–4 are epidemiological studies of the clinical relevance for severe sepsis, one of the most dramatic examples of the pathological potential of pro-inflammatory cytokines.
Abraham, E. et al. Consensus conference definitions for sepsis, septic shock, acute lung injury, and acute respiratory distress syndrome: a reevaluation. Crit. Care Med. 28, 232–235 (2000).
Matot, I. & Sprung, C. L. Definition of sepsis. Intensive Care Med. 27, 3–9 (2001).
Ulloa, L. & Tracey, K. J. The 'cytokine profile': a code for sepsis. Trends Mol. Med. 11, 56–63 (2005).
Riedemann, N. C. et al. Novel strategies for the treatment of sepsis. Nature Med. 9, 517–524 (2003). References 7 and 8 are recent and comprehensive reviews on potential pharmacological targets to control systemic inflammation and the treatment of severe sepsis.
Hotkiss, R. S. & Karl, I. E. The pathophysiology and treatment of sepsis. N. Engl. J. Med. 348, 138–150 (2003).
Tracey, K. J. & Cerami, A. Tumor necrosis factor: a pleiotropic cytokine and therapeutic target. Annu. Rev. Med. 45, 491–503 (1994).
Tracey, K. J. & Cerami, A. Tumor necrosis factor, other cytokines and disease. Annu. Rev. Cell Biol. 9, 317–343 (1993).
Ulloa, L., Doody, J. & Massague, J. Inhibition of transforming growth factor-β/SMAD signalling by the interferon-γ/STAT pathway. Nature 397, 710–713 (1999).
Monteleone, G., Pallone, F. & MacDonald, T. T. Smad7 in TGF- β-mediated negative regulation of gut inflammation. Trends Immunol. 25, 513–517 (2004).
Van der Poll, T. & Lowry, S. F. Tumor necrosis factor in sepsis: mediator of multiple organ failure or essential part of host defense? Shock 3, 1–12 (1995).
Feldmann, M. Development of anti-TNF therapy for rheumatoid arthritis. Nature Rev. Immunol. 2, 364–371 (2002).
Van Assche, G. & Rutgeerts, P. Anti-TNF agents in Crohn's disease. Expert Opin. Investig. Drugs 9, 103–111 (2000).
Dinarello, C. A. The interleukin-1 family: 10 years of discovery. FASEB J. 8, 1314–1325 (1994). References 15–17 report succesful clinical trials targeting pro-inflammatory cytokines for the treatment of diverse inflammatory disorders.
Abraham, E. et al. Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock. Norasept ii study group. Lancet 351, 929–933 (1998).
Abraham, E. et al. Lenercept (p55 tumor necrosis factor receptor fusion protein) in severe sepsis and early septic shock: a randomized, double-blind, placebo-controlled, multicenter phase iii trial with 1, 342 patients. Crit. Care Med. 29, 503–510 (2001).
Fisher, C. J. et al. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1RA sepsis syndrome study group. JAMA 271, 1836–1843 (1994).
Van der, P. T., Coyle, S. M., Barbosa, K., Braxton, C. C. & Lowry, S. F. Epinephrine inhibits tumor necrosis factor-α and potentiates interleukin 10 production during human endotoxemia. J. Clin. Invest. 97, 713–719 (1996).
Scheinman, R. I., Cogswell, P. C., Lofquist, A. K. & Baldwin, A. S. Jr. Role of transcriptional activation of IκBκ in mediation of immunosuppression by glucocorticoids. Science 270, 283–286 (1995).
Madden, K. S., Sanders, V. M. & Felten, D. L. Catecholamine influences and sympathetic neural modulation of immune responsiveness. Annu. Rev. Pharmacol. Toxicol. 35, 417–448 (1995).
Borovikova, L. V. et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405, 458–462 (2000).
Wang, H. et al. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nature Med. 10, 1216–1221 (2004).
Matthay, M. A. & Ware, L. B. Can nicotine treat sepsis? Nature Med. 10, 1161–1162 (2004).
Wang, H. et al. Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation. Nature 421, 384–388 (2003). References 25 and 27 present a characterization of α7 nicotinic acetylcholine receptor in human macrophages and its contribution to control the production of pro-inflammatory cytokines.
Tracey, K. J. The inflammatory reflex. Nature 420, 853–859 (2002).
Bernik, T. R. et al. Pharmacological stimulation of the cholinergic antiinflammatory pathway. J. Exp. Med. 195, 781–788 (2002).
Borovikova, L. V. et al. Role of vagus nerve signaling in CNI-1493-mediated suppression of acute inflammation. Auton. Neurosci. 85, 141–147 (2000). References 29 and 30 present evidence of a previously unrecognized role of the vagus nerve in mediating the action of a pharmacological anti-inflammatory compound.
Sitaraman, S. V., Hoteit, M. & Gewirtz, A. T. Semapimod. Cytokine. Curr. Opin. Investig. Drugs 4, 1363–1368 (2003).
Ben Menachem, E. Vagus nerve stimulation, side effects, and long-term safety. J. Clin. Neurophysiol. 18, 415–418 (2001).
Wucherpfennig, K. W. Infectious triggers for inflammatory neurological diseases. Nature Med. 8, 455–457 (2002).
Aarli, J. A. Role of cytokines in neurological disorders. Curr. Med. Chem. 10, 1931–1937 (2003). References 33 and 34 are comprehensive reviews of the pathological contribution of pro-inflammatory cytokines to neurological disorders.
Guarini, S. et al. Adrenocorticotropin reverses hemorrhagic shock in anesthetized rats through the rapid activation of a vagal anti-inflammatory pathway. Cardiovasc. Res. 63, 357–365 (2004).
Larsson, E. et al. CNI-1493, an inhibitor of pro-inflammatory cytokines, retards cartilage destruction in rats with collagen induced arthritis. Ann. Rheum. Dis. 64, 494–496 (2005).
D'Haens, G. Anti-TNF therapy for Crohn's disease. Curr. Pharm. Des. 9, 289–294 (2003).
Ulloa, L., Batliwalla, F. M., Andersson, U., Gregersen, P. K. & Tracey, K. J. High mobility group box chromosomal protein 1 as a nuclear protein, cytokine, and potential therapeutic target in arthritis. Arthritis Rheum. 48, 876–881 (2003).
Gault, J. et al. Genomic organization and partial duplication of the human α7 neuronal nicotinic acetylcholine receptor gene (CHRNA7). Genomics 52, 173–185 (1998).
Villiger, Y. et al. Expression of an α7 duplicate nicotinic acetylcholine receptor–related protein in human leukocytes. J. Neuroimmunol. 126, 86–98 (2002).
Miyazawa, A., Fujiyoshi, Y. & Unwin, N. Structure and gating mechanism of the acetylcholine receptor pore. Nature 423, 949–955 (2003).
Marubio, L. M. & Changeux, J. -P. Nicotinic acetylcholine receptor knockout mice as animal models for studying receptor function. Eur. J. Pharmacol. 393, 113–121 (2000).
Hogg, R. C., Raggenbass, M. & Bertrand, D. Nicotinic acetylcholine receptors: from structure to brain function. Rev. Physiol. Biochem. Pharmacol. 147, 1–46 (2003).
Peng, X. et al. Human α7 acetylcholine receptor: cloning of the α7 subunit from the SH-SY5Y cell line and determination of pharmacological properties of native receptors and functional α7 homomers expressed in Xenopus oocytes. Mol. Pharmacol. 45, 546–554 (1994).
Drisdel, R. C. & Green, W. N. Neuronal α-bungarotoxin receptors are α7 subunit homomers. J. Neurosci. 20, 133–139 (2000). References 43–45 present the original characterization and structure of the α7 nicotinic acetylcholine receptor.
Andersson, U. et al. High mobility group 1 protein (HMG-1) stimulates pro-inflammatory cytokine synthesis in human monocytes. J. Exp. Med. 192, 565–570 (2000).
Orr-Urtreger, A. et al. Mice deficient in the α7 neuronal nicotinic acetylcholine receptor lack α-bungarotoxin binding sites and hippocampal fast nicotinic currents. J. Neurosci. 17, 9165–9171 (1997).
Franceschini, D. et al. Altered baroreflex responses in α7 deficient mice. Behav. Brain Res. 113, 3–10 (2000).
Wang, H. et al. Hmg-1 as a late mediator of endotoxin lethality in mice. Science 285, 248–251 (1999).
Ulloa, L. et al. Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation. Proc. Natl Acad. Sci. USA 99, 12351–12356 (2002).
Ulloa, L. et al. Ethyl pyruvate protects against lethal systemic inflammation by preventing HMGB1 release. Ann. NY Acad. Sci. 987, 319–321 (2003).
Yang, H. et al. Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc. Natl Acad. Sci. USA 101, 296–301 (2004).
Calogero, S. et al. The lack of chromosomal protein Hmg1 does not disrupt cell growth but causes lethal hypoglycaemia in newborn mice. Nature Genet. 22, 276–280 (1999).
Bustin, M. At the crossroads of necrosis and apoptosis, signaling to multiple cellular targets by HMGB1. Sci STKE 151 (2002).
Yang, H. et al. Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc. Natl Acad. Sci. USA 101, 296–301 (2004).
Bonaldi, T. et al. Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J. 22, 5551–5560 (2003).
Scaffidi, P., Misteli, T. & Bianchi, M. E. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418, 191–195 (2002).
Stemmer, C., Schwander, A., Bauw, G., Fojan, P. & Grasser, K. D. Protein kinase CK2 differentially phosphorylates maize chromosomal high mobility group B (HMGB) proteins modulating their stability and DNA interactions. J. Biol. Chem. 277, 1092–1098 (2002).
Lee, J. C. et al. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 372, 739–746 (1994).
Derijard, B. et al. Independent human Map kinase signal transduction pathways defined by mek and mkk isoforms. Science 267, 682–685 (1995).
Baeuerle, P. A. & Henkel, T. Function and activation of NF-κB in the immune system. Annu. Rev. Immunol. 12, 141–179 (1994).
Li, Q. & Verma, I. M. NF-κB regulation in the immune system. Nature Rev. Immunol. 2, 725–734 (2002).
Ando, Y. Transdermal nicotine for ulcerative colitis. Ann. Intern. Med. 127, 491–492 (1997).
Guarini, S. et al. Efferent vagal fibre stimulation blunts nuclear factor-κB activation and protects against hypovolemic hemorrhagic shock. Circulation 107, 1189–1194 (2003).
Motley, R. J., Rhodes, J., Kay, S. & Morris, T. J. Late presentation of ulcerative colitis in ex-smokers. Int. J. Colorectal Dis. 3, 171–175 (1988).
Roberts, C. J. & Diggle, R. Non-smoking: a feature of ulcerative colitis. BMJ 285, 440–440 (1982).
Harries, A. D., Baird, A. & Rhodes, J. Non-smoking: a feature of ulcerative colitis. BMJ 284, 706–706 (1982).
Logan, R. F. A., Edmond, M., Somerville, K. W., Langman, M. J. Smoking and ulcerative colitis. BMJ 288, 751–753 (1984).
Motley, R. J. et al. Time relationships between cessation of smoking and onset of ulcerative colitis. Digestion 37, 125–127 (1987).
de Castella, H. Non-smoking: a feature of ulcerative colitis. BMJ 284, 1706–1706 (1982). References 65–70 are epidemiological studies relating ulcerative colitis with non-smoking and suggesting nicotine as a potential therapeutic agent.
Srivastava, E. D. et al. Transdermal nicotine in active ulcerative colitis. Eur. J. Gastroenterol. 3, 815–818 (1991).
Pullan, R. D. et al. Transdermal nicotine for active ulcerative colitis. N. Engl. J. Med. 330, 811–815 (1994).
Benoni, C, Nilsson A. Smoking habits in patients with inflammatory bowel disease. Scand. J. 19, 824–830 (1984).
Tapper, A. R. et al. Nicotine activation of α4 receptors: sufficient for reward, tolerance, and sensitization. Science 306, 1029–1032 (2004).
Avila, J. & Diaz-Nido, J. Tangling with hypothermia. Nature Med. 10, 460–461 (2004).
Zijlstra, F. J. et al. Effect of nicotine on rectal mucus and mucosal eicosanoids. Gut 35, 247–251 (1994).
Thomas, G. A. et al. Transdermal nicotine as maintenance therapy for ulcerative colitis. N. Engl. J. Med. 332, 988–992 (1995). References 71, 72 and 77 describe clinical trials using nicotine for the treatment of ulcerative colitis.
Cope, G. F., Heatley, R. V., Kelleher, J. & Axon, A. T. R. In vitro mucus glycoprotein production by colonic tissue from patients with ulcerative colitis. Gut 29, 229–234 (1988).
Calandra, T. et al. Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nature Med. 6, 164–170 (2000).
Martin, T. R. Mif mediation of sepsis. Nature Med. 6, 140–142 (2000).
Mandavilli, A. Nicotine fix. Nature Med. 10, 660–661 (2004).
Libert, C. Inflammation: A nervous connection. Nature 421, 328–329 (2003).
Gotti, C. & Clementi, F. Neuronal nicotinic receptors: from structure to pathology. Prog. Neurobiol. 74, 363–396 (2004).
Kitagawa, H. et al. Safety, pharmacokinetics, and effects on cognitive function of multiple doses of GTS-21 in healthy, male volunteers. Neuropsychopharmacology 28, 542–551 (2003).
Nanri, M., Kasahara, N., Yamamoto, J., Miyake, H. & Watanabe, H. A comparative study on the effects of nicotine and GTS-21, a new nicotinic agonist, on the locomotor activity and brain monoamine level. Jpn J. Pharmacol. 78, 385–389 (1998).
Crespi, F. Nefiracetam. Daiichi Seiyaku. Curr. Opin. Investig. Drugs 3, 788–793 (2002).
Meyer, E. M., Kuryatov, A., Gerzanich, V., Lindstrom, J. & Papke, R. L. Analysis of 3-(4-hydroxy, 2-Methoxybenzylidene)anabaseine selectivity and activity at human and rat α-7 nicotinic receptors. J. Pharmacol. Exp. Ther. 287, 918–925 (1998).
Lang, P. M., Burgstahler, R., Haberberger, R. V., Sippel, W. & Grafe, P. A conus peptide blocks nicotinic receptors of unmyelinated axons in human nerves. Neuroreport 16, 479–483 (2005).
Dussor, G. O. et al. Potentiation of evoked calcitonin gene-related peptide release from oral mucosa: a potential basis for the pro-inflammatory effects of nicotine. Eur. J. Neurosci. 18, 2515–2526 (2003).
Vincler, M. & Eisenach, J. C. Plasticity of spinal nicotinic acetylcholine receptors following spinal nerve ligation. Neurosci. Res. 48, 139–145 (2004).
Vincler, M. A. & Eisenach, J. C. Knock down of the α5 nicotinic acetylcholine receptor in spinal nerve-ligated rats alleviates mechanical allodynia. Pharmacol. Biochem. Behav. 80, 135–143 (2005).
Sixma, T. K. & Smit, A. B. Acetylcholine binding protein (AChBP): a secreted glial protein that provides a high-resolution model for the extracellular domain of pentameric ligand-gated ion channels. Annu. Rev. Biophys. Biomol. Struct. 32, 311–334 (2003).
Brejc, K. et al. Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors. Nature 411, 269–276 (2001).
Smit, A. B. et al. A glia-derived acetylcholine-binding protein that modulates synaptic transmission. Nature 411, 261–268 (2001).
Karlin, A. Emerging structure of the nicotinic acetylcholine receptors. Nature Rev. Neurosci. 3, 102–114 (2002).
Celie, P. H. et al. Nicotine and carbamylcholine binding to nicotinic acetylcholine receptors as studied in AChBP crystal structures. Neuron 41, 907–914 (2004).
Parpura, V. et al. Glutamate-mediated astrocyte-neuron signalling. Nature 369, 744–747 (1994).
Pasti, L., Volterra, A., Pozzan, T. & Carmignoto, G. Intracellular calcium oscillations in astrocytes: a highly plastic, bidirectional form of communication between neurons and astrocytes in situ. J. Neurosci. 17, 7817–7830 (1997).
Akk, G. & Steinbach, J. H. Galantamine activates muscle-type nicotinic acetylcholine receptors without binding to the acetylcholine-binding site. J. Neurosci. 25, 1992–2001 (2005).
Pereira, E. F. et al. Unconventional ligands and modulators of nicotinic receptors. J. Neurobiol. 53, 479–500 (2002).
Cooper, J. C., Gutbrod, O., Witzemann, V. & Methfessel, C. Pharmacology of the nicotinic acetylcholine receptor from fetal rat muscle expressed in Xenopus oocytes. Eur. J. Pharmacol. 309, 287–298 (1996).
Fayuk, D. & Yakel, J. L. Regulation of nicotinic acetylcholine receptor channel function by acetylcholinesterase inhibitors in rat hippocampal CA1 interneurons. Mol. Pharmacol. 66, 658–666 (2004).
Ueno, S., Bracamontes, J., Zorumski, C., Weiss, D. S. & Steinbach, J. H. Bicuculline and gabazine are allosteric inhibitors of channel opening of the GABAA receptor. J. Neurosci. 17, 625–634 (1997).
Sugano, N., Shimada, K., Ito, K. & Murai, S. Nicotine inhibits the production of inflammatory mediators in U937 cells through modulation of nuclear factor-κB activation. Biochem. Biophys. Res. Commun. 252, 25–28 (1998).
Saeed, R. W. et al. Cholinergic stimulation blocks endothelial cell activation and leukocyte recruitment during inflammation. J. Exp. Med. 201, 1113–1123 (2005).
Westerloo, D. J. et al. The Cholinergic Anti-Inflammatory Pathway Regulates the Host Response during Septic Peritonitis. J. Infect. Dis. 191, 2138–2148 (2005).
Han, Y., Englert, J. A., Yang, R., Delude, R. L. & Fink, M. P. Ethyl pyruvate inhibits nuclear factor-κB-dependent signaling by directly targeting p65. J. Pharmacol. Exp. Ther. 312, 1097–1105 (2005).
Critical Therapeutics, Inc. Critical Therapeutics initiates Phase II clinical study of CT1-01 [online], <http://phx.corporate-ir.net/phoenix.zhtml?c=177530&p=irol-newsArticle&ID=675157&highlight=> (15 Feb 2005).
The author is supported by the Faculty Award Program of the North Shore Health System and the North Shore-LIJ GCRC. The author is grateful for the critical reading and thoughtful suggestions from K. J. Tracey, E.Tuomanen. E. J. Miller, P. Morcillo, and P. Wang.
The author declares no competing financial interests.
The clinical signs of a systemic inflammatory response to infection; 'severe sepsis' refers to organ dysfunction observed during systemic inflammation even in the absence of confirmed infection.
Bodily collapse or near collapse caused by inadequate oxygen delivery to the cells; characterized by reduced cardiac output, rapid heartbeat, circulatory insufficiency and pallor. Loss of blood is an important cause of shock.
A decrease in the blood supply to a bodily organ, tissue or body part caused by constriction or obstruction of the blood vessels.
A crystalline derivative of choline that is released at the ends of nerve fibres in the somatic and parasympathetic nervous systems and is involved in the transmission of nerve impulses in the body.
- NICOTINIC ACETYLECHOLINE RECEPTORS
One of the two classes of cholinergic receptors. Nicotinic receptors are defined by their preference for binding nicotine over muscarine.
- NICOTINIC AGONISTS
Chemical analogues of nicotine that can bind to a specific subset of nicotine acetylcholine receptors.
A toxin produced by Gram-negative bacteria and released from the bacterial cell.
Surgical sectioning of fibres of the vagus nerve, previously used to diminish acid secretion of the stomach and control a duodenal ulcer.
- MUSCARINIC RECEPTORS
One of the two major classes of cholinergic receptors. Muscarinic receptors were originally defined by their preference for muscarine over nicotine.
A highly toxic alkaloid related to the cholines, derived from the red form of the mushroom Amanita muscaria and found in decaying animal tissue.
Pain originating from a non-injurious stimulus to the skin.
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Ulloa, L. The vagus nerve and the nicotinic anti-inflammatory pathway. Nat Rev Drug Discov 4, 673–684 (2005). https://doi.org/10.1038/nrd1797
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