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. 1995 Nov;4(6):397–405. doi: 10.1155/S0962935195000640

Nitric oxide as a mediator of gastrointestinal mucosal injury?—Say it ain't so

Paul Kubes 1, John L Wallace 1,✉
PMCID: PMC2365665  PMID: 18475671

Abstract

Nitric oxide has been suggested as a contributor to tissue injury in various experimental models of gastrointestinal inflammation. However, there is overwhelming evidence that nitric oxide is one of the most important mediators of mucosal defence, influencing such factors as mucus secretion, mucosal blood flow, ulcer repair and the activity of a variety of mucosal immunocytes. Nitric oxide has the capacity to down-regulate inflammatory responses in the gastrointestinal tract, to scavenge various free radical species and to protect the mucosa from injury induced by topical irritants. Moreover, questions can be raised regarding the evidence purported to support a role for nitric oxide in producing tissue injury. In this review, we provide an overview of the evidence supporting a role for nitric oxide in protecting the gastrointestinal tract from injury.

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Selected References

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  1. Albina J. E., Reichner J. S. Nitric oxide in inflammation and immunity. New Horiz. 1995 Feb;3(1):46–64. [PubMed] [Google Scholar]
  2. Alican I., Coşkun T., Corak A., Yeğen B. C., Oktay S., Kurtel H. Role of neutrophils in indomethacin-induced gastric mucosal lesions in rats. Inflamm Res. 1995 Apr;44(4):164–168. doi: 10.1007/BF01782814. [DOI] [PubMed] [Google Scholar]
  3. Andrews F. J., Malcontenti-Wilson C., O'Brien P. E. Protection against gastric ischemia-reperfusion injury by nitric oxide generators. Dig Dis Sci. 1994 Feb;39(2):366–373. doi: 10.1007/BF02090210. [DOI] [PubMed] [Google Scholar]
  4. Aoki N., Johnson G., 3rd, Lefer A. M. Beneficial effects of two forms of NO administration in feline splanchnic artery occlusion shock. Am J Physiol. 1990 Feb;258(2 Pt 1):G275–G281. doi: 10.1152/ajpgi.1990.258.2.G275. [DOI] [PubMed] [Google Scholar]
  5. Assreuy J., Cunha F. Q., Liew F. Y., Moncada S. Feedback inhibition of nitric oxide synthase activity by nitric oxide. Br J Pharmacol. 1993 Mar;108(3):833–837. doi: 10.1111/j.1476-5381.1993.tb12886.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. 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 U S A. 1990 Feb;87(4):1620–1624. doi: 10.1073/pnas.87.4.1620. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bissonnette E. Y., Hogaboam C. M., Wallace J. L., Befus A. D. Potentiation of tumor necrosis factor-alpha-mediated cytotoxicity of mast cells by their production of nitric oxide. J Immunol. 1991 Nov 1;147(9):3060–3065. [PubMed] [Google Scholar]
  8. Brown J. F., Keates A. C., Hanson P. J., Whittle B. J. Nitric oxide generators and cGMP stimulate mucus secretion by rat gastric mucosal cells. Am J Physiol. 1993 Sep;265(3 Pt 1):G418–G422. doi: 10.1152/ajpgi.1993.265.3.G418. [DOI] [PubMed] [Google Scholar]
  9. Brown J. F., Tepperman B. L., Hanson P. J., Whittle B. J., Moncada S. Differential distribution of nitric oxide synthase between cell fractions isolated from the rat gastric mucosa. Biochem Biophys Res Commun. 1992 Apr 30;184(2):680–685. doi: 10.1016/0006-291x(92)90643-y. [DOI] [PubMed] [Google Scholar]
  10. Clancy R. M., Leszczynska-Piziak J., Abramson S. B. Nitric oxide, an endothelial cell relaxation factor, inhibits neutrophil superoxide anion production via a direct action on the NADPH oxidase. J Clin Invest. 1992 Sep;90(3):1116–1121. doi: 10.1172/JCI115929. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Craig P. M., Territo M. C., Karnes W. E., Walsh J. H. Helicobacter pylori secretes a chemotactic factor for monocytes and neutrophils. Gut. 1992 Aug;33(8):1020–1023. doi: 10.1136/gut.33.8.1020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Elliott S. N., McKnight W., Cirino G., Wallace J. L. A nitric oxide-releasing nonsteroidal anti-inflammatory drug accelerates gastric ulcer healing in rats. Gastroenterology. 1995 Aug;109(2):524–530. doi: 10.1016/0016-5085(95)90341-0. [DOI] [PubMed] [Google Scholar]
  13. Evangelista S., Meli A. Influence of antioxidants and radical scavengers on ethanol-induced gastric ulcers in the rat. Gen Pharmacol. 1985;16(3):285–286. doi: 10.1016/0306-3623(85)90085-0. [DOI] [PubMed] [Google Scholar]
  14. Filep J. G., Földes-Filep E., Rousseau A., Sirois P., Fournier A. Vascular responses to endothelin-1 following inhibition of nitric oxide synthesis in the conscious rat. Br J Pharmacol. 1993 Nov;110(3):1213–1221. doi: 10.1111/j.1476-5381.1993.tb13944.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Furchgott R. F., Zawadzki J. V. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980 Nov 27;288(5789):373–376. doi: 10.1038/288373a0. [DOI] [PubMed] [Google Scholar]
  16. Gaboury J., Woodman R. C., Granger D. N., Reinhardt P., Kubes P. Nitric oxide prevents leukocyte adherence: role of superoxide. Am J Physiol. 1993 Sep;265(3 Pt 2):H862–H867. doi: 10.1152/ajpheart.1993.265.3.H862. [DOI] [PubMed] [Google Scholar]
  17. Granger D. N., Höllwarth M. E., Parks D. A. Ischemia-reperfusion injury: role of oxygen-derived free radicals. Acta Physiol Scand Suppl. 1986;548:47–63. [PubMed] [Google Scholar]
  18. Granger D. N. Role of xanthine oxidase and granulocytes in ischemia-reperfusion injury. Am J Physiol. 1988 Dec;255(6 Pt 2):H1269–H1275. doi: 10.1152/ajpheart.1988.255.6.H1269. [DOI] [PubMed] [Google Scholar]
  19. Grisham M. B., Von Ritter C., Smith B. F., Lamont J. T., Granger D. N. Interaction between oxygen radicals and gastric mucin. Am J Physiol. 1987 Jul;253(1 Pt 1):G93–G96. doi: 10.1152/ajpgi.1987.253.1.G93. [DOI] [PubMed] [Google Scholar]
  20. Hermanowicz A., Gibson P. R., Jewell D. P. The role of phagocytes in inflammatory bowel disease. Clin Sci (Lond) 1985 Sep;69(3):241–249. doi: 10.1042/cs0690241. [DOI] [PubMed] [Google Scholar]
  21. Hernandez L. A., Grisham M. B., Twohig B., Arfors K. E., Harlan J. M., Granger D. N. Role of neutrophils in ischemia-reperfusion-induced microvascular injury. Am J Physiol. 1987 Sep;253(3 Pt 2):H699–H703. doi: 10.1152/ajpheart.1987.253.3.H699. [DOI] [PubMed] [Google Scholar]
  22. Hogaboam C. M., Befus A. D., Wallace J. L. Modulation of rat mast cell reactivity by IL-1 beta. Divergent effects on nitric oxide and platelet-activating factor release. J Immunol. 1993 Oct 1;151(7):3767–3774. [PubMed] [Google Scholar]
  23. Holzer P., Livingston E. H., Saria A., Guth P. H. Sensory neurons mediate protective vasodilatation in rat gastric mucosa. Am J Physiol. 1991 Mar;260(3 Pt 1):G363–G370. doi: 10.1152/ajpgi.1991.260.3.G363. [DOI] [PubMed] [Google Scholar]
  24. Kanwar S., Wallace J. L., Befus D., Kubes P. Nitric oxide synthesis inhibition increases epithelial permeability via mast cells. Am J Physiol. 1994 Feb;266(2 Pt 1):G222–G229. doi: 10.1152/ajpgi.1994.266.2.G222. [DOI] [PubMed] [Google Scholar]
  25. Kazura J. W. Platelet-neutrophil interaction: modulation of the inflammatory response. J Lab Clin Med. 1989 Nov;114(5):469–470. [PubMed] [Google Scholar]
  26. Kitagawa H., Takeda F., Kohei H. Effect of endothelium-derived relaxing factor on the gastric lesion induced by HCl in rats. J Pharmacol Exp Ther. 1990 Jun;253(3):1133–1137. [PubMed] [Google Scholar]
  27. Konturek S. J., Brzozowski T., Majka J., Pytko-Polonczyk J., Stachura J. Inhibition of nitric oxide synthase delays healing of chronic gastric ulcers. Eur J Pharmacol. 1993 Aug 3;239(1-3):215–217. doi: 10.1016/0014-2999(93)90997-v. [DOI] [PubMed] [Google Scholar]
  28. Kubes P., Hunter J., Granger D. N. Ischemia/reperfusion-induced feline intestinal dysfunction: importance of granulocyte recruitment. Gastroenterology. 1992 Sep;103(3):807–812. doi: 10.1016/0016-5085(92)90010-v. [DOI] [PubMed] [Google Scholar]
  29. Kubes P. Ischemia-reperfusion in feline small intestine: a role for nitric oxide. Am J Physiol. 1993 Jan;264(1 Pt 1):G143–G149. doi: 10.1152/ajpgi.1993.264.1.G143. [DOI] [PubMed] [Google Scholar]
  30. Kubes P., Kanwar S., Niu X. F., Gaboury J. P. Nitric oxide synthesis inhibition induces leukocyte adhesion via superoxide and mast cells. FASEB J. 1993 Oct;7(13):1293–1299. doi: 10.1096/fasebj.7.13.8405815. [DOI] [PubMed] [Google Scholar]
  31. Kubes P. Nitric oxide modulates epithelial permeability in the feline small intestine. Am J Physiol. 1992 Jun;262(6 Pt 1):G1138–G1142. doi: 10.1152/ajpgi.1992.262.6.G1138. [DOI] [PubMed] [Google Scholar]
  32. Kubes P., Reinhardt P. H., Payne D., Woodman R. C. Excess nitric oxide does not cause cellular, vascular, or mucosal dysfunction in the cat small intestine. Am J Physiol. 1995 Jul;269(1 Pt 1):G34–G41. doi: 10.1152/ajpgi.1995.269.1.G34. [DOI] [PubMed] [Google Scholar]
  33. Kubes P., Suzuki M., Granger D. N. Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4651–4655. doi: 10.1073/pnas.88.11.4651. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Kubes P., Suzuki M., Granger D. N. Platelet-activating factor-induced microvascular dysfunction: role of adherent leukocytes. Am J Physiol. 1990 Jan;258(1 Pt 1):G158–G163. doi: 10.1152/ajpgi.1990.258.1.G158. [DOI] [PubMed] [Google Scholar]
  35. Kurose I., Anderson D. C., Miyasaka M., Tamatani T., Paulson J. C., Todd R. F., Rusche J. R., Granger D. N. Molecular determinants of reperfusion-induced leukocyte adhesion and vascular protein leakage. Circ Res. 1994 Feb;74(2):336–343. doi: 10.1161/01.res.74.2.336. [DOI] [PubMed] [Google Scholar]
  36. Kurose I., Kubes P., Wolf R., Anderson D. C., Paulson J., Miyasaka M., Granger D. N. Inhibition of nitric oxide production. Mechanisms of vascular albumin leakage. Circ Res. 1993 Jul;73(1):164–171. doi: 10.1161/01.res.73.1.164. [DOI] [PubMed] [Google Scholar]
  37. Kvietys P. R., Perry M. A., Gaginella T. S., Granger D. N. Ethanol enhances leukocyte-endothelial cell interactions in mesenteric venules. Am J Physiol. 1990 Oct;259(4 Pt 1):G578–G583. doi: 10.1152/ajpgi.1990.259.4.G578. [DOI] [PubMed] [Google Scholar]
  38. Kvietys P. R., Twohig B., Danzell J., Specian R. D. Ethanol-induced injury to the rat gastric mucosa. Role of neutrophils and xanthine oxidase-derived radicals. Gastroenterology. 1990 Apr;98(4):909–920. doi: 10.1016/0016-5085(90)90015-s. [DOI] [PubMed] [Google Scholar]
  39. Li D. S., Raybould H. E., Quintero E., Guth P. H. Role of calcitonin gene-related peptide in gastric hyperemic response to intragastric capsaicin. Am J Physiol. 1991 Oct;261(4 Pt 1):G657–G661. doi: 10.1152/ajpgi.1991.261.4.G657. [DOI] [PubMed] [Google Scholar]
  40. Lippe I. T., Holzer P. Participation of endothelium-derived nitric oxide but not prostacyclin in the gastric mucosal hyperaemia due to acid back-diffusion. Br J Pharmacol. 1992 Mar;105(3):708–714. doi: 10.1111/j.1476-5381.1992.tb09043.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Lopez-Belmonte J., Whittle B. J., Moncada S. The actions of nitric oxide donors in the prevention or induction of injury to the rat gastric mucosa. Br J Pharmacol. 1993 Jan;108(1):73–78. doi: 10.1111/j.1476-5381.1993.tb13442.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. MacKendrick W., Caplan M., Hsueh W. Endogenous nitric oxide protects against platelet-activating factor-induced bowel injury in the rat. Pediatr Res. 1993 Aug;34(2):222–228. doi: 10.1203/00006450-199308000-00025. [DOI] [PubMed] [Google Scholar]
  43. MacNaughton W. K., Cirino G., Wallace J. L. Endothelium-derived relaxing factor (nitric oxide) has protective actions in the stomach. Life Sci. 1989;45(20):1869–1876. doi: 10.1016/0024-3205(89)90540-7. [DOI] [PubMed] [Google Scholar]
  44. Masini E., Salvemini D., Pistelli A., Mannaioni P. F., Vane J. R. Rat mast cells synthesize a nitric oxide like-factor which modulates the release of histamine. Agents Actions. 1991 May;33(1-2):61–63. doi: 10.1007/BF01993127. [DOI] [PubMed] [Google Scholar]
  45. Masuda E., Kawano S., Nagano K., Tsuji S., Takei Y., Tsujii M., Oshita M., Michida T., Kobayashi I., Nakama A. Endogenous nitric oxide modulates ethanol-induced gastric mucosal injury in rats. Gastroenterology. 1995 Jan;108(1):58–64. doi: 10.1016/0016-5085(95)90008-x. [DOI] [PubMed] [Google Scholar]
  46. McCall T. B., Boughton-Smith N. K., Palmer R. M., Whittle B. J., Moncada S. Synthesis of nitric oxide from L-arginine by neutrophils. Release and interaction with superoxide anion. Biochem J. 1989 Jul 1;261(1):293–296. doi: 10.1042/bj2610293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Miller M. J., Sadowska-Krowicka H., Chotinaruemol S., Kakkis J. L., Clark D. A. Amelioration of chronic ileitis by nitric oxide synthase inhibition. J Pharmacol Exp Ther. 1993 Jan;264(1):11–16. [PubMed] [Google Scholar]
  48. Ogle C. W., Qiu B. S. Nitric oxide inhibition intensifies cold-restraint induced gastric ulcers in rats. Experientia. 1993 Apr 15;49(4):304–307. doi: 10.1007/BF01923407. [DOI] [PubMed] [Google Scholar]
  49. Payne D., Kubes P. Nitric oxide donors reduce the rise in reperfusion-induced intestinal mucosal permeability. Am J Physiol. 1993 Jul;265(1 Pt 1):G189–G195. doi: 10.1152/ajpgi.1993.265.1.G189. [DOI] [PubMed] [Google Scholar]
  50. Pihan G., Regillo C., Szabo S. Free radicals and lipid peroxidation in ethanol- or aspirin-induced gastric mucosal injury. Dig Dis Sci. 1987 Dec;32(12):1395–1401. doi: 10.1007/BF01296666. [DOI] [PubMed] [Google Scholar]
  51. Pique J. M., Whittle B. J., Esplugues J. V. The vasodilator role of endogenous nitric oxide in the rat gastric microcirculation. Eur J Pharmacol. 1989 Dec 19;174(2-3):293–296. doi: 10.1016/0014-2999(89)90324-5. [DOI] [PubMed] [Google Scholar]
  52. Price K. J., Hanson P. J., Whittle B. J. Stimulation by carbachol of mucus gel thickness in rat stomach involves nitric oxide. Eur J Pharmacol. 1994 Sep 22;263(1-2):199–202. doi: 10.1016/0014-2999(94)90542-8. [DOI] [PubMed] [Google Scholar]
  53. Rachmilewitz D., Stamler J. S., Karmeli F., Mullins M. E., Singel D. J., Loscalzo J., Xavier R. J., Podolsky D. K. Peroxynitrite-induced rat colitis--a new model of colonic inflammation. Gastroenterology. 1993 Dec;105(6):1681–1688. doi: 10.1016/0016-5085(93)91063-n. [DOI] [PubMed] [Google Scholar]
  54. Radi R., Beckman J. S., Bush K. M., Freeman B. A. Peroxynitrite oxidation of sulfhydryls. The cytotoxic potential of superoxide and nitric oxide. J Biol Chem. 1991 Mar 5;266(7):4244–4250. [PubMed] [Google Scholar]
  55. Radomski M. W., Vallance P., Whitley G., Foxwell N., Moncada S. Platelet adhesion to human vascular endothelium is modulated by constitutive and cytokine induced nitric oxide. Cardiovasc Res. 1993 Jul;27(7):1380–1382. doi: 10.1093/cvr/27.7.1380. [DOI] [PubMed] [Google Scholar]
  56. Rautelin H., Blomberg B., Fredlund H., Järnerot G., Danielsson D. Incidence of Helicobacter pylori strains activating neutrophils in patients with peptic ulcer disease. Gut. 1993 May;34(5):599–603. doi: 10.1136/gut.34.5.599. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Rubanyi G. M., Ho E. H., Cantor E. H., Lumma W. C., Botelho L. H. Cytoprotective function of nitric oxide: inactivation of superoxide radicals produced by human leukocytes. Biochem Biophys Res Commun. 1991 Dec 31;181(3):1392–1397. doi: 10.1016/0006-291x(91)92093-y. [DOI] [PubMed] [Google Scholar]
  58. Rubbo H., Radi R., Trujillo M., Telleri R., Kalyanaraman B., Barnes S., Kirk M., Freeman B. A. Nitric oxide regulation of superoxide and peroxynitrite-dependent lipid peroxidation. Formation of novel nitrogen-containing oxidized lipid derivatives. J Biol Chem. 1994 Oct 21;269(42):26066–26075. [PubMed] [Google Scholar]
  59. Salvemini D., Masini E., Anggard E., Mannaioni P. F., Vane J. Synthesis of a nitric oxide-like factor from L-arginine by rat serosal mast cells: stimulation of guanylate cyclase and inhibition of platelet aggregation. Biochem Biophys Res Commun. 1990 Jun 15;169(2):596–601. doi: 10.1016/0006-291x(90)90372-t. [DOI] [PubMed] [Google Scholar]
  60. Takeuchi K., Ohuchi T., Okabe S. Endogenous nitric oxide in gastric alkaline response in the rat stomach after damage. Gastroenterology. 1994 Feb;106(2):367–374. doi: 10.1016/0016-5085(94)90594-0. [DOI] [PubMed] [Google Scholar]
  61. Tepperman B. L., Soper B. D. Nitric oxide synthase induction and cytoprotection of rat gastric mucosa from injury by ethanol. Can J Physiol Pharmacol. 1994 Nov;72(11):1308–1312. doi: 10.1139/y94-188. [DOI] [PubMed] [Google Scholar]
  62. Unno N., Menconi M. J., Smith M., Fink M. P. Nitric oxide mediates interferon-gamma-induced hyperpermeability in cultured human intestinal epithelial monolayers. Crit Care Med. 1995 Jul;23(7):1170–1176. doi: 10.1097/00003246-199507000-00004. [DOI] [PubMed] [Google Scholar]
  63. Vaananen P. M., Meddings J. B., Wallace J. L. Role of oxygen-derived free radicals in indomethacin-induced gastric injury. Am J Physiol. 1991 Sep;261(3 Pt 1):G470–G475. doi: 10.1152/ajpgi.1991.261.3.G470. [DOI] [PubMed] [Google Scholar]
  64. Wallace J. L., Arfors K. E., McKnight G. W. A monoclonal antibody against the CD18 leukocyte adhesion molecule prevents indomethacin-induced gastric damage in the rabbit. Gastroenterology. 1991 Apr;100(4):878–883. doi: 10.1016/0016-5085(91)90259-n. [DOI] [PubMed] [Google Scholar]
  65. Wallace J. L. Gastric ulceration: critical events at the neutrophil--endothelium interface. Can J Physiol Pharmacol. 1993 Jan;71(1):98–102. doi: 10.1139/y93-014. [DOI] [PubMed] [Google Scholar]
  66. Wallace J. L., McKnight G. W. The mucoid cap over superficial gastric damage in the rat. A high-pH microenvironment dissipated by nonsteroidal antiinflammatory drugs and endothelin. Gastroenterology. 1990 Aug;99(2):295–304. doi: 10.1016/0016-5085(90)91009-u. [DOI] [PubMed] [Google Scholar]
  67. Wallace J. L., Reuter B., Cicala C., McKnight W., Grisham M. B., Cirino G. Novel nonsteroidal anti-inflammatory drug derivatives with markedly reduced ulcerogenic properties in the rat. Gastroenterology. 1994 Jul;107(1):173–179. doi: 10.1016/0016-5085(94)90074-4. [DOI] [PubMed] [Google Scholar]
  68. Wallace J. L., Reuter B., Cicala C., McKnight W., Grisham M., Cirino G. A diclofenac derivative without ulcerogenic properties. Eur J Pharmacol. 1994 May 23;257(3):249–255. doi: 10.1016/0014-2999(94)90136-8. [DOI] [PubMed] [Google Scholar]
  69. Whittle B. J., Lopez-Belmonte J., Moncada S. Regulation of gastric mucosal integrity by endogenous nitric oxide: interactions with prostanoids and sensory neuropeptides in the rat. Br J Pharmacol. 1990 Mar;99(3):607–611. doi: 10.1111/j.1476-5381.1990.tb12977.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Wink D. A., Hanbauer I., Krishna M. C., DeGraff W., Gamson J., Mitchell J. B. Nitric oxide protects against cellular damage and cytotoxicity from reactive oxygen species. Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):9813–9817. doi: 10.1073/pnas.90.21.9813. [DOI] [PMC free article] [PubMed] [Google Scholar]

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