Physiology in medicine
Nitric oxide and intestinal inflammation

https://doi.org/10.1016/S0002-9343(00)00480-0Get rights and content

Abstract

Inflammation of the intestinal tract remains a very serious concern in the clinical setting. Unfortunately, to date, the mechanisms underlying many inflammatory conditions such as sepsis or inflammatory bowel diseases are poorly understood and our therapeutic interventions are less than ideal. Over the past decade, an abundance of research has been directed toward the role of nitric oxide (NO) in intestinal inflammation. It has become apparent that NO might have a dichotomous role as both a beneficial and detrimental molecule. Nitric oxide is a weak radical produced from L-arginine via the enzyme nitric oxide synthase (NOS). NOS exists in three distinct isoforms; constitutively (cNOS) expressed neuronal NOS (NOS1 or nNOS) and endothelial NOS (NOS3 or eNOS) or an inducible isoform (NOS2 or iNOS) capable of high production output of NO during inflammation. Constitutively expressed NOS has been shown to be critical to normal physiology and inhibition of these enzymes (nNOS or eNOS) caused damage. It has been proposed that the high output production of NO from iNOS causes injury, perhaps through the generation of potent radicals such as peroxynitrite and hence may explain the apparent dichotomous role of NO. However, recent studies have challenged this simple paradigm providing evidence that iNOS may have some protective role in some inflammatory models. Moreover, the importance of peroxynitrite has been questioned. In this review we discuss the role of cNOS and iNOS in intestinal inflammation and provide an overview of peroxynitrite in intestinal inflammation, highlighting some of the controversy that exists.

Section snippets

Homeostatic function of nitric oxide

Nitric oxide is synthesized from a guanidino group of L-arginine and can be produced by virtually all mammalian cells, including endothelium lining the vasculature, neurons of the central and enteric nervous system, and cells of the immune system 2, 3. Nitric oxide is constitutively produced by two distinct enzymes: an enzyme normally present primarily in endothelium lining the vasculature (eNOS), and a neurally–associated NO synthase found in neurons of the brain and enteric nervous system

Nitric oxide and acute inflammation: role as antioxidant

Many studies have documented that in acute inflammatory models, inhibition of endogenous NO exacerbates injury 15, 16, 17, 18, 19, 20, 21, 22 and exogenous NO protects the gastrointestinal mucosa against noxious stimuli 15, 23, 24, 25, 26, 27. The mechanisms are poorly understood, however. Certainly the improvement in blood flow associated with increased NO delivery would be an important factor in countering the compromised blood flow due to damaging effects of lumen-based insults such as HCl

Nitric oxide in subacute and chronic inflammation

iNOS is an enzyme whose expression in endothelium, epithelium, and inflammatory cells requires protein synthesis, is induced by cytokines and LPS, and produces large amounts of NO for extended periods of time (3). Based on the essential role of NO under normal conditions and the beneficial effect of NO under acute inflammatory conditions, it is conceivable that more NO would be beneficial regardless of its source. Indeed, iNOS may be an endogenous mechanism to increase local NO levels, minimize

References (102)

  • E. Nava et al.

    Inhibition of nitric oxide synthesis in septic shockhow much is beneficial?

    Lancet

    (1991)
  • J.D. MacMicking et al.

    Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase

    Cell

    (1995)
  • S. Aiko et al.

    Spontaneous intestinal inflammation and nitric oxide metabolism in HLA-B27 transgenic rats

    Gastroenterology

    (1995)
  • K.A. Ribbons et al.

    Potential role of nitric oxide in a chronic model of colitis in rhesus macaques

    Gastroenterology

    (1995)
  • C. Szabo et al.

    Mercaptoethylguanidine and guanidine inhibitors of nitric-oxide synthase react with peroxynitrite and protect against peroxynitrite-induced oxidative damage

    J Biol Chem

    (1997)
  • D.-M. McCafferty et al.

    Inducible nitric oxide synthase plays a critical role in resolving intestinal inflammation

    Gastroenterology

    (1997)
  • R. Radi et al.

    Peroxynitric oxidation of sulfhydryls. The cytotoxic potential of superoxide and nitric oxide

    J Biol Chem

    (1991)
  • R. Radi et al.

    Peroxynitrite-induced membrane lipid peroxidationthe cytotoxic potential of superoxide and nitric oxide

    Arch Biochem Biophys

    (1991)
  • H. Rubbo et al.

    Nitric oxide regulation of superoxide and peroxynitrite-dependent lipid peroxidation. Formation of novel nitrogen-containing oxidized lipid derivatives

    J Biol Chem

    (1994)
  • M. Kennedy et al.

    Poly(ADP-ribose) synthetase activation mediates increased permeability induced by peroxynitrite in Caco-2BBe cells

    Gastroenterology

    (1998)
  • H. Ischiropoulos et al.

    Peroxynitrite-mediated tyrosine nitration catalyzed by superoxide dismutase

    Arch Biochem Biophys

    (1992)
  • J.B. Sampson et al.

    Myeloperoxidase and horseradish peroxidase catalyze tyrosine nitration in proteins from nitrite and hydrogen peroxide

    Arch Biochem Biophys

    (1998)
  • S. Pfeiffer et al.

    Lack of tyrosine nitration by peroxynitrite generated at physiological pH

    J Biol Chem

    (1998)
  • D.A. Wink et al.

    Chemical biology of nitric oxideinsights into regulatory, cytotoxic, and cytoprotective mechanisms of nitric oxide

    Free Rad Biol Med

    (1998)
  • D. Rachmilewitz et al.

    Peroxynitrite-induced rat colitis—a new model of colonic inflammation

    Gastroenterology

    (1993)
  • Andres PG, Friedman LS. Epidemiology and the natural course of inflammatory bowel disease. Gastroenterol Clin North Am....
  • S. Moncada

    The L-arginine:nitric oxide pathway

    Acta Physiol Scand

    (1992)
  • P. Kubes et al.

    Nitric oxide modulates microvascular permeability

    Am J Physiol

    (1992)
  • P. Kubes et al.

    Nitric oxidean endogenous modulator of leukocyte adhesion

    Proc Natl Acad Sci USA

    (1991)
  • P. Kubes

    Nitric oxide modulates epithelial permeability in the feline small intestine

    Am J Physiol

    (1992)
  • McCafferty DM, Miampamba M, Sihota E, et al. Role of inducible nitric oxide synthase in trinitrobenzene sulphonic...
  • P. Kubes et al.

    Nitric oxide synthesis inhibition induces leukocyte adhesion via superoxide and mast cells

    FASEB J

    (1993)
  • M. Suematsu et al.

    Microvascular oxidative stress preceding leukocyte activation elicited by in vivo nitric oxide suppression

    Am J Physiol

    (1994)
  • M.J. Miller et al.

    Inhibition of calcium-dependent nitric oxide synthase causes ileitis and leukocytosis in guinea pigs

    Dig Dis Sci

    (1994)
  • M.J. Miller et al.

    Nitric oxidethe Jekyll and Hyde of gut inflammation

    Agents Actions

    (1993)
  • S. Kanwar et al.

    Nitric oxide synthesis inhibition increases epithelial permeability via mast cells

    Am J Physiol

    (1994)
  • H. Kitagawa et al.

    Effect of endothelium-derived relaxing factor on the gastric lesion induced by HCl in rats

    J Pharm Exp Ther

    (1990)
  • B.J.R. Whittle et al.

    Regulation of gastric mucosal integrity by endogenous nitric oxideinteractions with prostanoids and sensory neuropeptides in the rat

    Br J Pharmacol

    (1990)
  • W. MacKendrick et al.

    Endogenous nitric oxide protects against platelet-activating factor-induced bowel injury in the rat

    Pediatr Res

    (1993)
  • J.G. Filep et al.

    Vascular responses to endothelin-1 following inhibition of nitric oxide synthesis in the conscious rat

    Br J Pharmacol

    (1993)
  • P. Kubes

    Ischemia/reperfusion in the feline small intestinea role for nitric oxide

    Am J Physiol

    (1993)
  • C.W. Ogle et al.

    Nitric oxide inhibition intensifies cold-restraint induced gastric ulcers in rats

    Experientia

    (1993)
  • I.R. Hutcheson et al.

    Role of nitric oxide in maintaining vascular integrity in endotoxin-induced acute intestinal damage in the rat

    Br J Pharmacol

    (1990)
  • J.L. Wallace et al.

    Nitric oxide-releasing non-steroidal anti-inflammatory drugsa novel approach for reducing gastrointestinal toxicity

    J Gastroenterol Hepatol

    (1994)
  • D. Payne et al.

    Nitric oxide donors reduce the rise in reperfusion-induced intestinal mucosal permeability

    Am J Physiol

    (1993)
  • P. Kubes et al.

    Excess nitric oxide does not cause cellular, vascular or mucosal dysfunction in the cat small intestine

    Am J Physiol

    (1995)
  • J. Lopez-Belmonte et al.

    The actions of nitric oxide donors in the prevention or induction of injury to the rat gastric mucosa

    Pharmacology

    (1993)
  • F.J. Andrews et al.

    Protection against gastric ischemia-reperfusion injury by nitric oxide generators

    Dig Dis Sci

    (1994)
  • J. Gaboury et al.

    Nitric oxide prevents leukocyte adherencerole of superoxide

    Am J Physiol

    (1993)
  • D.A. Wink et al.

    Nitric oxide protects against cellular damage and cytotoxicity from reactive oxygen species

    Proc Natl Acad Sci USA

    (1993)
  • Cited by (297)

    View all citing articles on Scopus
    View full text