Nitric oxide in mucosal defense: a little goes a long way.

Nitric oxide (NO) is now recognized as an important modulator of an enormous number of physiological processes, ranging from blood pressure regulation to neuronal transmission to penile erectile function. In the gastrointestinal tract, NO also participates in many physiological and pathophysiological processes. In this review, we summarize the contribution made by NO to the ability of the gastrointestinal mucosa to resist injury induced by luminal toxins and to defend against microbial invasion. We also review some of the main features of NO chemistry and the potential of NO as a target for new drugs to treat gastrointestinal disorders.

[1]  J. Wallace,et al.  Underlying mechanisms of portal hypertensive gastropathy. , 1997, Journal of clinical gastroenterology.

[2]  M. Currie,et al.  The effect of inhibitors of inducible nitric oxide synthase on chronic colitis in the rhesus monkey. , 1997, The Journal of pharmacology and experimental therapeutics.

[3]  K. Takeuchi,et al.  Effect of indomethacin on gastric mucosal blood flow around acetic acid-induced gastric ulcers in rats. , 1991, Gastroenterology.

[4]  J. Stachura,et al.  Inhibition of nitric oxide synthase delays healing of chronic gastric ulcers. , 1993, European journal of pharmacology.

[5]  J. Wallace,et al.  Potent ulcerogenic actions of platelet-activating factor on the stomach , 1986, Nature.

[6]  J. Wallace,et al.  Endothelin has potent ulcerogenic and vasoconstrictor actions in the stomach. , 1989, The American journal of physiology.

[7]  R. Groszmann,et al.  NO overproduction by eNOS precedes hyperdynamic splanchnic circulation in portal hypertensive rats. , 1999, American journal of physiology. Gastrointestinal and liver physiology.

[8]  J. Scholefield,et al.  Glyceryl trinitrate is an effective treatment for anal fissure , 1997, Diseases of the colon and rectum.

[9]  J. Lancaster,et al.  Simulation of the diffusion and reaction of endogenously produced nitric oxide. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[10]  J. Schölmerich,et al.  Interleukin‐1 production by mouse macrophages is regulated in a feedback fashion by nitric oxide , 1999, Journal of leukocyte biology.

[11]  L. Fändriks,et al.  Acid-induced duodenal mucosal nitric oxide output parallels bicarbonate secretion in the anaesthetized pig. , 1998, Acta physiologica Scandinavica.

[12]  A. M. Lefer,et al.  Inhibition of endothelial-derived nitric oxide promotes P-selectin expression and actions in the rat microcirculation. , 1994, Gastroenterology.

[13]  W. MacNaughton Nitric oxide-donating compounds stimulate electrolyte transport in the guinea pig intestine in vitro. , 1993, Life sciences.

[14]  T. Billiar,et al.  IV. Determinants of nitric oxide protection and toxicity in liver. , 1999, American journal of physiology. Gastrointestinal and liver physiology.

[15]  J. F. Brown,et al.  Nitric oxide generators and cGMP stimulate mucus secretion by rat gastric mucosal cells. , 1993, The American journal of physiology.

[16]  P. Kubes,et al.  Nitric oxide: an endogenous modulator of leukocyte adhesion. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[17]  L. Ignarro,et al.  Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[18]  T. Gaginella,et al.  Direct evidence for nitric oxide stimulation of electrolyte secretion in the rat colon. , 1993, Free radical research communications.

[19]  M. Miller,et al.  Localization of inducible nitric oxide synthase mRNA in inflamed gastrointestinal mucosa by in situ reverse transcriptase-polymerase chain reaction. , 1998, Nitric oxide : biology and chemistry.

[20]  J. Wallace,et al.  Enhanced anti-inflammatory effects of a nitric oxide-releasing derivative of mesalamine in rats. , 1999, Gastroenterology.

[21]  A. Ramachandran,et al.  Nitric oxide prevents anoxia-induced apoptosis in colonic HT29 cells. , 1999, Archives of biochemistry and biophysics.

[22]  C. Hawkey,et al.  Nitric oxide synthase activity in ulcerative colitis and Crohn's disease , 1993, The Lancet.

[23]  M. Grisham,et al.  Effects of nitric oxide synthase inhibition on the pathophysiology observed in a model of chronic granulomatous colitis. , 1994, The Journal of pharmacology and experimental therapeutics.

[24]  S. Thom,et al.  Nitric oxide inhibits neutrophil β2 integrin function by inhibiting membrane‐associated cyclic GMP synthesis , 1997, Journal of cellular physiology.

[25]  P. Efron,et al.  Nitric oxide, an autocrine regulator of wound fibroblast synthetic function. , 1997, Journal of immunology.

[26]  M. Shichiri,et al.  NO Inhibits Cytokine-Induced iNOS Expression and NF-κB Activation by Interfering With Phosphorylation and Degradation of IκB-α , 1998 .

[27]  J. Wallace,et al.  A nitric oxide-releasing nonsteroidal anti-inflammatory drug accelerates gastric ulcer healing in rats. , 1995, Gastroenterology.

[28]  J. Wallace,et al.  Impaired vasodilatory responses in the gastric microcirculation of anesthetized rats with secondary biliary cirrhosis. , 1995, Gastroenterology.

[29]  P. Holzer,et al.  Nitric oxide‐dependent and ‐independent hyperaemia due to calcitonin gene‐related peptide in the rat stomach , 1993, British journal of pharmacology.

[30]  P. Holzer,et al.  Gastric mucosal protection against ulcerogenic factors in the rat mediated by capsaicin-sensitive afferent neurons. , 1986, Gastroenterology.

[31]  J. Esplugues,et al.  The vasodilator role of endogenous nitric oxide in the rat gastric microcirculation. , 1989, European journal of pharmacology.

[32]  R. Macdermott Granulocytes: The culprit in ischemic damage to the intestine , 1988 .

[33]  M. Miller,et al.  Role of inducible nitric oxide synthase expression and peroxynitrite formation in guinea pig ileitis. , 1995, Gastroenterology.

[34]  P. Lala,et al.  Animal Model Nitric Oxide Synthase Inhibition by N G -Nitro- L Arginine Methyl Ester Inhibits Tumor-Induced Angiogenesis in Mammary Tumors , 1999 .

[35]  Y. Vodovotz,et al.  Superoxide Modulates the Oxidation and Nitrosation of Thiols by Nitric Oxide-derived Reactive Intermediates , 1997, The Journal of Biological Chemistry.

[36]  W. MacNaughton,et al.  Role of nitric oxide in inflammation-induced suppression of secretion in a mouse model of acute colitis. , 1998, The American journal of physiology.

[37]  H. Mashimo,et al.  Lessons from genetically engineered animal models. IV. Nitric oxide synthase gene knockout mice. , 1999, The American journal of physiology.

[38]  E. Livingston,et al.  Afferent nerve-mediated protection against deep mucosal damage in the rat stomach. , 1990, Gastroenterology.

[39]  J. Wallace,et al.  Modulation of rat mast cell reactivity by IL-1 beta. Divergent effects on nitric oxide and platelet-activating factor release. , 1993, Journal of immunology.

[40]  S. Moncada,et al.  The induction of nitric oxide synthase and intestinal vascular permeability by endotoxin in the rat , 1993, British journal of pharmacology.

[41]  J. Wallace,et al.  V. Therapeutic potential of nitric oxide donors and inhibitors. , 1999, American journal of physiology. Gastrointestinal and liver physiology.

[42]  G. Feng,et al.  Nitric oxide regulates Th1 cell development through the inhibition of IL‐12 synthesis by macrophages , 1998, European journal of immunology.

[43]  S. Moncada,et al.  Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor , 1987, Nature.

[44]  F. Leung,et al.  Tobacco cigarette smoke aggravates gastric ulcer in rats by attenuation of ulcer margin hyperemia. , 1995, The American journal of physiology.

[45]  S. Moncada,et al.  Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor , 1986, Nature.

[46]  M. Fink,et al.  Cytokine-induced intestinal epithelial hyperpermeability: role of nitric oxide. , 1999, Critical care medicine.

[47]  J. Wallace,et al.  The cellular and molecular basis of gastric mucosal defense , 1996, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[48]  J. Wallace,et al.  Nitric oxide synthesis inhibition increases epithelial permeability via mast cells. , 1994, The American journal of physiology.

[49]  E. Deitch,et al.  Bacterial translocation is inhibited in inducible nitric oxide synthase knockout mice after endotoxin challenge but not in a model of bacterial overgrowth. , 1997, Archives of surgery.

[50]  G. Rubanyi,et al.  Cytoprotective function of nitric oxide: inactivation of superoxide radicals produced by human leukocytes. , 1991, Biochemical and biophysical research communications.

[51]  J. Wallace,et al.  A monoclonal antibody against the CD18 leukocyte adhesion molecule prevents indomethacin-induced gastric damage in the rabbit. , 1991, Gastroenterology.

[52]  P. Holzer Neural emergency system in the stomach. , 1998, Gastroenterology.

[53]  T. Billiar,et al.  Nitric Oxide IV . Determinants of nitric oxide protection and toxicity in liver , 1999 .

[54]  P. Moore,et al.  The role of nitric oxide as an endogenous regulator of platelet and neutrophil activation within the pulmonary circulation of the rabbit , 1991, British journal of pharmacology.

[55]  P. Holzer,et al.  Participation of endothelium‐derived nitric oxide but not prostacyclin in the gastric mucosal hyperaemia due to acid back‐diffusion , 1992, British journal of pharmacology.

[56]  A. Morelli,et al.  Pentoxifylline prevents indomethacin induced acute gastric mucosal damage in rats: role of tumour necrosis factor alpha. , 1994, Gut.

[57]  J. Beckman,et al.  The comparative toxicity of nitric oxide and peroxynitrite to Escherichia coli. , 1995, Archives of biochemistry and biophysics.

[58]  P. Kubes,et al.  Nitric oxide syni hesis inhibition induces leukocyte adhesion via superoxid and mast cells , 2004 .

[59]  J. Wallace,et al.  Potentiation of tumor necrosis factor-alpha-mediated cytotoxicity of mast cells by their production of nitric oxide. , 1991, Journal of immunology.

[60]  J. Wallace,et al.  Mast cell activation augments gastric mucosal injury through a leukotriene-dependent mechanism. , 1994, The American journal of physiology.

[61]  J. Wallace The 1994 Merck Frosst Award. Mechanisms of nonsteroidal anti-inflammatory drug (NSAID) induced gastrointestinal damage--potential for development of gastrointestinal tract safe NSAIDs. , 1994, Canadian journal of physiology and pharmacology.

[62]  D. McKay,et al.  Integrative immunophysiology in the intestinal mucosa. , 1994, The American journal of physiology.

[63]  R. Furchgott,et al.  The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine , 1980, Nature.

[64]  M. Miller,et al.  Peroxynitrite-induced apoptosis in epithelial (T84) and macrophage (RAW 264.7) cell lines: effect of legume-derived polyphenols (phytolens). , 1997, Nitric oxide : biology and chemistry.

[65]  F. Murad,et al.  Stimulation of guanylate cyclase by sodium nitroprusside, nitroglycerin and nitric oxide in various tissue preparations and comparison to the effects of sodium azide and hydroxylamine. , 1977, Journal of cyclic nucleotide research.

[66]  E. Fontham,et al.  Inducible nitric oxide synthase, nitrotyrosine, and apoptosis in Helicobacter pylori gastritis: effect of antibiotics and antioxidants. , 1996, Cancer research.

[67]  M. Miller,et al.  Nitric Oxide. III. A molecular prelude to intestinal inflammation. , 1999, The American journal of physiology.

[68]  M. Fink,et al.  Nitric oxide donor-induced hyperpermeability of cultured intestinal epithelial monolayers: role of superoxide radical, hydroxyl radical, and peroxynitrite. , 1998, Biochimica et biophysica acta.

[69]  M. Miller,et al.  Peroxynitrite-induced apoptosis in human intestinal epithelial cells is attenuated by mesalamine. , 1997, Gastroenterology.

[70]  J. Turvill,et al.  Proabsorptive and prosecretory roles for nitric oxide in cholera toxin induced secretion , 1999, Gut.

[71]  R. Mannucci,et al.  Gastrointestinal safety of nitric oxide-derived aspirin is related to inhibition of ICE-like cysteine proteases in rats. , 1999, Gastroenterology.

[72]  J. Wallace,et al.  Prolonged colonic epithelial hyporesponsiveness after colitis: role of inducible nitric oxide synthase. , 1999, American journal of physiology. Gastrointestinal and liver physiology.

[73]  E. Masini,et al.  Synthesis of a nitric oxide-like factor from L-arginine by rat serosal mast cells: stimulation of guanylate cyclase and inhibition of platelet aggregation. , 1990, Biochemical and biophysical research communications.

[74]  U. Tantry,et al.  Nitric oxide regulates wound healing. , 1996, The Journal of surgical research.

[75]  Simon C Watkins,et al.  Inhibition of nitric oxide with aminoguanidine reduces bacterial translocation after endotoxin challenge in vivo. , 1996, Archives of surgery.

[76]  J. Wallace,et al.  V. Therapeutic potential of nitric oxide donors and inhibitors. , 1999, American journal of physiology. Gastrointestinal and liver physiology.

[77]  J. Wallace,et al.  Gastrointestinal‐sparing anti‐inflammatory drugs: The development of nitric oxide‐releasing NSAIDs , 1997 .

[78]  M. Marletta,et al.  Mammalian nitrate biosynthesis: mouse macrophages produce nitrite and nitrate in response to Escherichia coli lipopolysaccharide. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[79]  L. Moldawer,et al.  Enhanced collagen accumulation following direct transfection of the inducible nitric oxide synthase gene in cutaneous wounds. , 1998, Biochemical and biophysical research communications.

[80]  S. Moncada Nitric Oxide in the Vasculature: Physiology and Pathophysiology , 1997, Annals of the New York Academy of Sciences.

[81]  M. Fink,et al.  Inhibition of inducible nitric oxide synthase ameliorates endotoxin-induced gut mucosal barrier dysfunction in rats. , 1997, Gastroenterology.

[82]  Renzo,et al.  Nitric oxide‐releasing NSAIDs inhibit interleukin‐1β converting enzyme‐like cysteine proteases and protect endothelial cells from apoptosis induced by TNFα , 1999, Alimentary pharmacology & therapeutics.

[83]  B. Whittle,et al.  Stimulation by carbachol of mucus gel thickness in rat stomach involves nitric oxide. , 1994, European journal of pharmacology.