Abstract
Inducible nitric oxide synthase (iNOS) is a transcriptionally regulated enzyme that synthesizes nitric oxide from L–arginine1 that has a key role in the pathophysiology of systemic inflammation and sepsis. Transgenic animals with a null mutation for the iNOS gene are resistant to hypotension and death caused by Escherichia coli lipopolysaccharide (IPS)2,3. The regulation of peripheral iNOS has been well studied in sepsis, but little is known about iNOS regulation in the brain during systemic inflammation or sepsis. We show that at baseline there is no detectable iNOS gene expression in the brain, but a detailed neuroanatomical study reveals that early in the course of systemic inflammation there is a profound induction of iNOS messenger RNA in vascular, glial and neuronal structures of the rat brain, accompanied by the production of nitric oxide (NO) metabolites in brain parenchyma and cerebrospinal fluid (CSF). We propose that the spillover of nitrite into the CSF has the potential to be a diagnostic marker for systemic inflammation and sepsis. Pharmacological interventions aimed at regulating iNOS function in the brain might represent a new treatment strategy in sepsis. Brain iNOS may be relevant to the pathophysiology, diagnosis and treatment of systemic inflammation and sepsis.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Xie, Q.-W. et al. Cloning and characterization of inducible nitric oxide synthase from mouse macrophages. Science 256, 225–228 (1992).
Wei, X.-Q. et al. Altered immune responses in mice lacking inducible nitric oxide synthase. Nature 375, 408–411 (1995).
MacMicking, J.D. et al. Altered response to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell 81, 641–650 (1995).
Moncada, S. & Higgs, A. The L-arginine-nitric oxide pathway. N. Engl. J. Med. 329, 2002–2012 (1993).
Nathan, C. & Xie, Q.-W. Nitric oxide synthases: Roles, tolls, and controls. Cell 78, 915–918 (1994).
Bredt, D.S. & Snyder, S.H. Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proc. Natl. Acad. Sci. USA 87, 682–685 (1990).
Dawson, T.M. & Snyder, S.H. Gases as biological messengers: Nitric oxide and carbon monoxide in the brain. J. Neurvsci. 14, 5147–59 (1994).
Kuo, P.C. & Schroeder, R.A. The emerging multifaceted roles of nitric oxide. Ann. Surg. 221, 220–235 (1995).
Iyengar, R., Stuehr, D.J. & Marietta, M.A. Macrophage synthesis of nitrite, nitrate, and N-nitrosamines: Precursors and role of the respiratory burst. Proc. Natl. Acad. Sci. USA 84, 6369–6373 (1987).
Ialenti, A., lanaro, A., Moncada, S. & DiRosa, M. Modulation of acute inflammation by endogenous nitric oxide. Eur. J. Pharmacol. 211, 177–182 (1992).
Bredt, D.S. & Snyder, S.H. Nitric oxide mediates glutamate-1 inked enhancement of cGMP levels in the cerebellum. Proc. Natl. Acad. Sci. USA 86, 9030–3 (1989).
Dawson, V.L., Dawson, T.M., London, E.D., Bredt, D.S. & Snyder, S.H. Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc. Natl. Acad. Sci. USA 88, 6368–6371 (1991).
Beckman, J.S., Beckman, T.W., Chen, J., Marshall, P.A. & Freeman, B.A. Apparent hydroxyl radical production by peroxynitrite: Implications for endothelial injury from nitric oxide and superoxide. Proc. Natl. Acad. Sci. USA 87, 1620–1624 (1990).
Middleton, S.J., Shorthouse, M. & Hunter, J.O. Increased nitric oxide synthesis in ulcerative colitis. Lancet 341, 465–466 (1993).
Boughton, S.N. et al. Nitric oxide synthase activity in ulcerative colitis and Crohn's disease. Lancet 342, 338–340 (1993).
Lundberg, J.O., Hellstrom, P.M., Lundberg, J.M. & Alving, K. Greatly increased luminal nitric oxide in ulcerative colitis. Lancet 344, 1673–1674 (1994).
Li, P. et al. Mice deficient in IL-1β converting enzyme are defective in prGuuition of mature IL-1β and resistant to endotoxic shock. Cell 80, 401–411 (1995).
Dennhardt, R., Gramm, H.J., Meinhold, K. & Voigt, K. Patterns of endocrine secretion during sepsis. Prog. Clin. Biol. Res. 308, 751–756 (1989).
Bone, R.C. Toward an epidemiology and natural history of SIRS (systemic inflammatory response syndrome). JAMA 268, 3452–3455 (1992).
Dinarello, C.A., Gelfand, J.A. & Wolff, S.M. Anticytokine strategies in the treatment of the systemic inflammatory response syndrome. JAMA 269, 1829–1835 (1993).
Young, G.B., Bolton, C.F., Archibald, Y.M., Austin, T.W. & Wells, G.A. The electroencephalogram in sepsis-associated encephalopathy. J. Clin. Neurophysiol. 9, 145–152 (1992).
Young, G.B., Bolton, C.F., Austin, T.W., Archibald, Y.M., Gonder, J. & Wells, G.A. The encephalopathy associated with septic illness. Clin. Invest. Med. 13, 297–304 (1990).
Rossor, M.N. Alzheimer's disease. in Oxford Textbook of Medicine, vol. 3 (eds. Weatherall, D.J., Ledingham, J.G.C. & Warell, D.A.) 3971–3974 (Oxford Univ. Press, Oxford, 1996).
Dawson, V.L., Dawson, T.M., Bartley, D.A., Uhl, G.R. & Snyder, S.H. Mechanisms of nitric oxide-mediated neurotoxicity in primary brain cultures. J. Neurosci. 13, 2651–2661 (1993).
Costa, A., Trainer, P., Besser, M. & Grossman, A. Nitric oxide modulates the release of corticotropin-releasing hormone from the rat hypothalamus in vitro. Brain Res. 605, 187–192 (1993).
Rivier, C. & Shen, G.H. In the rat, endogenous nitric oxide modulates the re-N sponse of the hypothalamic-pituitary-adrenal axis to interleukin-1 beta, vasopressin, and oxytocln. J. Neurosci. 14, 1985–1993 (1994).
Sandi, C. & Guaza, C. Evidence for a role of nitric oxide in the corticotropin-releasing factor release induced by interleukin-1 beta. Eur. J. Pharmacol. 274, 17–23 (1995).
Sternberg, E.M. et al. A central nervous system defect in biosynthesis of corticotropin-releasing hormone is associated with susceptibility to streptococcal cell wall-induced arthritis in Lewis rats. Proc. Natl. Acad. Sri. USA 86, 4771–4775 (1989).
Barriere, S.L. & Lowry, S.F. An overview of mortality risk prediction in sepsis. Crit. Care Med. 23, 376–393 (1995).
Galea, E., Reis, D.J. & Feinstein, D.L. Cloning and expression of inducible nitric oxide synthase from rat astrocytes. J. Neurosci. Res. 37, 406–414 (1994).
Wong, M.-L. Gold, P.W. & Licinio, J. In situ hybridization techniques for the localization of interleukin-1 and interleukin-1 receptor antagonist mRNA in brain. Methods Neurosci. 16, 81–99 (1993).
Licinio, J., Bongiorno, P., Gold, P.W. & Wong, M.-L. The gene encoding for the novel transacting factor propiomelanocortin corticotropin-releasing hormone responsive element binding protein 1 (PCRH-REB-1) is constitutively expressed in rat pituitary and in discrete brain regions containing CRH or CRH receptors: Pathophysiological implications. Endocrinology 136, 4709–4712 (1995).
Canteros, G. et al. Nitric oxide synthase (NOS) content of hypothalamic explants: Increased by norepinephrine and inactivated by NO and cyclic GMP. Proc. Natl. Acad. Sci. USA (in the press).
Green, L.C. et al. Analysis of nitrate, nitrite, and 15N nitrate in biological fluids. Anal. Biochem. 126, 131–138 (1982).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Wong, ML., Rettori, V., AL-Shekhlee, A. et al. Inducible nitric oxide synthase gene expression in the brain during systemic inflammation. Nat Med 2, 581–584 (1996). https://doi.org/10.1038/nm0596-581
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/nm0596-581
This article is cited by
-
Old Friends, immunoregulation, and stress resilience
Pflügers Archiv - European Journal of Physiology (2019)
-
Neuroimmunomodulation in Major Depressive Disorder: Focus on Caspase 1, Inducible Nitric Oxide Synthase, and Interferon-Gamma
Molecular Neurobiology (2019)
-
Vasopressin Impairment During Sepsis Is Associated with Hypothalamic Intrinsic Apoptotic Pathway and Microglial Activation
Molecular Neurobiology (2017)
-
Critical illness-related corticosteroid insufficiency (CIRCI): a narrative review from a Multispecialty Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM)
Intensive Care Medicine (2017)
-
Interleukin-1 Receptor Antagonist Decreases Hypothalamic Oxidative Stress During Experimental Sepsis
Molecular Neurobiology (2016)