Skip to main content
Environmental Health Perspectives logoLink to Environmental Health Perspectives
. 1998 Oct;106(Suppl 5):1145–1149. doi: 10.1289/ehp.98106s51145

Nitric oxide and peroxynitrite production in ocular inflammation.

J B Allen 1, T Keng 1, C Privalle 1
PMCID: PMC1533362  PMID: 9788889

Abstract

Recent studies have implicated nitric oxide and peroxynitrite in the pathogenesis of many diseases, such as septic shock, arthritis, lung disease, and atherosclerosis. Nitric oxide (.NO) exerts many diverse effects on vascular tone, affecting neurotransmission and cellular cytotoxicity/communication. Our laboratory and others have documented a proinflammatory role for .NO in ocular inflammation. Uveitis, which is an inflammation of the highly vascular uveal tract in the eye, is a debilitating condition that can lead to visual impairment and blindness. It is characterized by acute, recurrent, or persistent inflammation with disruption of the blood-aqueous barrier and is accompanied by protein leakage and leukocyte infiltration into the aqueous humor and anterior chamber. Systemic injection of endotoxin into mice and rats, or intraocular injection of endotoxin into mice, rats, and rabbits induces acute uveitis, which clinically and histologically resembles acute anterior uveitis in humans. These models facilitate the study of pathogenic mechanisms that contribute to ocular inflammation. In addition to .NO, superoxide anion radicals (O2.-), and peroxynitrite (ONOO-), the products of the reaction between .NO and O2.-, are also implicated in uveitis. The role of peroxynitrite in ocular inflammation is still largely unknown. Characterization of the roles of these important uveitic mediators in the ocular inflammatory response will provide information critical to the understanding of the pathogenesis of intraocular inflammation so that more effective therapeutic intervention(s) can be developed.

Full text

PDF
1149

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allen J. B., McGahan M. C., Ferrell J. B., Adler K. B., Fleisher L. N. Nitric oxide synthase inhibitors exert differential time-dependent effects on LPS-induced uveitis. Exp Eye Res. 1996 Jan;62(1):21–28. doi: 10.1006/exer.1996.0003. [DOI] [PubMed] [Google Scholar]
  2. Allen J. B., McGahan M. C., Ogawa Y., Sellon D. C., Clark B. D., Fleisher L. N. Intravitreal transforming growth factor-beta 2 decreases cellular infiltration in endotoxin-induced ocular inflammation in rabbits. Curr Eye Res. 1996 Jan;15(1):95–103. doi: 10.3109/02713689609017616. [DOI] [PubMed] [Google Scholar]
  3. Beasley D., Schwartz J. H., Brenner B. M. Interleukin 1 induces prolonged L-arginine-dependent cyclic guanosine monophosphate and nitrite production in rat vascular smooth muscle cells. J Clin Invest. 1991 Feb;87(2):602–608. doi: 10.1172/JCI115036. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. 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]
  5. Beckman J. S., Chen J., Ischiropoulos H., Crow J. P. Oxidative chemistry of peroxynitrite. Methods Enzymol. 1994;233:229–240. doi: 10.1016/s0076-6879(94)33026-3. [DOI] [PubMed] [Google Scholar]
  6. Becquet F., Courtois Y., Goureau O. Nitric oxide in the eye: multifaceted roles and diverse outcomes. Surv Ophthalmol. 1997 Jul-Aug;42(1):71–82. doi: 10.1016/s0039-6257(97)84043-x. [DOI] [PubMed] [Google Scholar]
  7. Behar-Cohen F. F., Goureau O., D'Hermies F., Courtois Y. Decreased intraocular pressure induced by nitric oxide donors is correlated to nitrite production in the rabbit eye. Invest Ophthalmol Vis Sci. 1996 Jul;37(8):1711–1715. [PubMed] [Google Scholar]
  8. Bellot J. L., Palmero M., García-Cabanes C., Espí R., Hariton C., Orts A. Additive effect of nitric oxide and prostaglandin-E2 synthesis inhibitors in endotoxin-induced uveitis in the rabbit. Inflamm Res. 1996 Apr;45(4):203–208. doi: 10.1007/BF02285162. [DOI] [PubMed] [Google Scholar]
  9. Billiar T. R., Curran R. D., Ferrari F. K., Williams D. L., Simmons R. L. Kupffer cell:hepatocyte cocultures release nitric oxide in response to bacterial endotoxin. J Surg Res. 1990 Apr;48(4):349–353. doi: 10.1016/0022-4804(90)90073-b. [DOI] [PubMed] [Google Scholar]
  10. Billiar T. R., Hoffman R. A., Curran R. D., Langrehr J. M., Simmons R. L. A role for inducible nitric oxide biosynthesis in the liver in inflammation and in the allogeneic immune response. J Lab Clin Med. 1992 Aug;120(2):192–197. [PubMed] [Google Scholar]
  11. Bredt D. S., Hwang P. M., Glatt C. E., Lowenstein C., Reed R. R., Snyder S. H. Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase. Nature. 1991 Jun 27;351(6329):714–718. doi: 10.1038/351714a0. [DOI] [PubMed] [Google Scholar]
  12. Bredt D. S., Snyder S. H. Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the cerebellum. Proc Natl Acad Sci U S A. 1989 Nov;86(22):9030–9033. doi: 10.1073/pnas.86.22.9030. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Cross A. H., Misko T. P., Lin R. F., Hickey W. F., Trotter J. L., Tilton R. G. Aminoguanidine, an inhibitor of inducible nitric oxide synthase, ameliorates experimental autoimmune encephalomyelitis in SJL mice. J Clin Invest. 1994 Jun;93(6):2684–2690. doi: 10.1172/JCI117282. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Curran R. D., Billiar T. R., Stuehr D. J., Hofmann K., Simmons R. L. Hepatocytes produce nitrogen oxides from L-arginine in response to inflammatory products of Kupffer cells. J Exp Med. 1989 Nov 1;170(5):1769–1774. doi: 10.1084/jem.170.5.1769. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Darley-Usmar V., Wiseman H., Halliwell B. Nitric oxide and oxygen radicals: a question of balance. FEBS Lett. 1995 Aug 7;369(2-3):131–135. doi: 10.1016/0014-5793(95)00764-z. [DOI] [PubMed] [Google Scholar]
  16. Evans CH, Stefanovic-Racic M. Nitric Oxide in Arthritis. Methods. 1996 Aug;10(1):38–42. doi: 10.1006/meth.1996.0076. [DOI] [PubMed] [Google Scholar]
  17. Fleisher L. N., Ferrell J. B., McGahan M. C. Ocular inflammatory effects of intravitreally injected tumor necrosis factor-alpha and endotoxin. Inflammation. 1990 Jun;14(3):325–335. doi: 10.1007/BF00915816. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. Gibaldi M. What is nitric oxide and why are so many people studying it? J Clin Pharmacol. 1993 Jun;33(6):488–496. doi: 10.1002/j.1552-4604.1993.tb04694.x. [DOI] [PubMed] [Google Scholar]
  20. Goureau O., Bellot J., Thillaye B., Courtois Y., de Kozak Y. Increased nitric oxide production in endotoxin-induced uveitis. Reduction of uveitis by an inhibitor of nitric oxide synthase. J Immunol. 1995 Jun 15;154(12):6518–6523. [PubMed] [Google Scholar]
  21. Grisham M. B., Yamada T. Neutrophils, nitrogen oxides, and inflammatory bowel disease. Ann N Y Acad Sci. 1992;664:103–115. doi: 10.1111/j.1749-6632.1992.tb39753.x. [DOI] [PubMed] [Google Scholar]
  22. HOGAN M. J., KIMURA S. J., THYGESON P. Signs and symptoms of uveitis. I. Anterior uveitis. Am J Ophthalmol. 1959 May;47(5 Pt 2):155–170. doi: 10.1016/s0002-9394(14)78239-x. [DOI] [PubMed] [Google Scholar]
  23. Hasan K., Heesen B. J., Corbett J. A., McDaniel M. L., Chang K., Allison W., Wolffenbuttel B. H., Williamson J. R., Tilton R. G. Inhibition of nitric oxide formation by guanidines. Eur J Pharmacol. 1993 Nov 2;249(1):101–106. doi: 10.1016/0014-2999(93)90667-7. [DOI] [PubMed] [Google Scholar]
  24. Hibbs J. B., Jr, Taintor R. R., Vavrin Z. Macrophage cytotoxicity: role for L-arginine deiminase and imino nitrogen oxidation to nitrite. Science. 1987 Jan 23;235(4787):473–476. doi: 10.1126/science.2432665. [DOI] [PubMed] [Google Scholar]
  25. Ischiropoulos H., Zhu L., Beckman J. S. Peroxynitrite formation from macrophage-derived nitric oxide. Arch Biochem Biophys. 1992 Nov 1;298(2):446–451. doi: 10.1016/0003-9861(92)90433-w. [DOI] [PubMed] [Google Scholar]
  26. Jacquemin E., de Kozak Y., Thillaye B., Courtois Y., Goureau O. Expression of inducible nitric oxide synthase in the eye from endotoxin-induced uveitis rats. Invest Ophthalmol Vis Sci. 1996 May;37(6):1187–1196. [PubMed] [Google Scholar]
  27. Kilbourn R. G., Griffith O. W. Overproduction of nitric oxide in cytokine-mediated and septic shock. J Natl Cancer Inst. 1992 Jun 3;84(11):827–831. doi: 10.1093/jnci/84.11.827. [DOI] [PubMed] [Google Scholar]
  28. Limb G. A., Little B. C., Meager A., Ogilvie J. A., Wolstencroft R. A., Franks W. A., Chignell A. H., Dumonde D. C. Cytokines in proliferative vitreoretinopathy. Eye (Lond) 1991;5(Pt 6):686–693. doi: 10.1038/eye.1991.126. [DOI] [PubMed] [Google Scholar]
  29. Liu S., Beckman J. S., Ku D. D. Peroxynitrite, a product of superoxide and nitric oxide, produces coronary vasorelaxation in dogs. J Pharmacol Exp Ther. 1994 Mar;268(3):1114–1121. [PubMed] [Google Scholar]
  30. Lorsbach R. B., Murphy W. J., Lowenstein C. J., Snyder S. H., Russell S. W. Expression of the nitric oxide synthase gene in mouse macrophages activated for tumor cell killing. Molecular basis for the synergy between interferon-gamma and lipopolysaccharide. J Biol Chem. 1993 Jan 25;268(3):1908–1913. [PubMed] [Google Scholar]
  31. Mandai M., Yoshimura N., Yoshida M., Iwaki M., Honda Y. The role of nitric oxide synthase in endotoxin-induced uveitis: effects of NG-nitro L-arginine. Invest Ophthalmol Vis Sci. 1994 Sep;35(10):3673–3680. [PubMed] [Google Scholar]
  32. Marletta M. A. Nitric oxide synthase structure and mechanism. J Biol Chem. 1993 Jun 15;268(17):12231–12234. [PubMed] [Google Scholar]
  33. 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]
  34. Meijer F., Ruijter J. M., Van Delft J. L., Van Haeringen N. J. Nitric oxide induces vascular permeability changes in the guinea pig conjunctiva. Eur J Pharmacol. 1995 Sep 15;284(1-2):61–67. doi: 10.1016/0014-2999(95)00376-v. [DOI] [PubMed] [Google Scholar]
  35. Meijer F., Van Delft J. L., Garrelds I. M., Van Haeringen N. J., Kijlstra A. Nitric oxide plays a role as a mediator of conjunctival edema in experimental allergic conjunctivitis. Exp Eye Res. 1996 Apr;62(4):359–365. doi: 10.1006/exer.1996.0041. [DOI] [PubMed] [Google Scholar]
  36. Misko T. P., Moore W. M., Kasten T. P., Nickols G. A., Corbett J. A., Tilton R. G., McDaniel M. L., Williamson J. R., Currie M. G. Selective inhibition of the inducible nitric oxide synthase by aminoguanidine. Eur J Pharmacol. 1993 Mar 16;233(1):119–125. doi: 10.1016/0014-2999(93)90357-n. [DOI] [PubMed] [Google Scholar]
  37. Moncada S., Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med. 1993 Dec 30;329(27):2002–2012. doi: 10.1056/NEJM199312303292706. [DOI] [PubMed] [Google Scholar]
  38. Moncada S., Palmer R. M., Higgs E. A. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991 Jun;43(2):109–142. [PubMed] [Google Scholar]
  39. Morris S. M., Jr, Billiar T. R. New insights into the regulation of inducible nitric oxide synthesis. Am J Physiol. 1994 Jun;266(6 Pt 1):E829–E839. doi: 10.1152/ajpendo.1994.266.6.E829. [DOI] [PubMed] [Google Scholar]
  40. Murray P. I., Hoekzema R., van Haren M. A., de Hon F. D., Kijlstra A. Aqueous humor interleukin-6 levels in uveitis. Invest Ophthalmol Vis Sci. 1990 May;31(5):917–920. [PubMed] [Google Scholar]
  41. Naseem K. M., Bruckdorfer K. R. Hydrogen peroxide at low concentrations strongly enhances the inhibitory effect of nitric oxide on platelets. Biochem J. 1995 Aug 15;310(Pt 1):149–153. doi: 10.1042/bj3100149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Nathan C. Nitric oxide as a secretory product of mammalian cells. FASEB J. 1992 Sep;6(12):3051–3064. [PubMed] [Google Scholar]
  43. Nathan C., Xie Q. W. Nitric oxide synthases: roles, tolls, and controls. Cell. 1994 Sep 23;78(6):915–918. doi: 10.1016/0092-8674(94)90266-6. [DOI] [PubMed] [Google Scholar]
  44. Nathan C., Xie Q. W. Regulation of biosynthesis of nitric oxide. J Biol Chem. 1994 May 13;269(19):13725–13728. [PubMed] [Google Scholar]
  45. Nava E., Palmer R. M., Moncada S. Inhibition of nitric oxide synthesis in septic shock: how much is beneficial? Lancet. 1991 Dec 21;338(8782-8783):1555–1557. doi: 10.1016/0140-6736(91)92375-c. [DOI] [PubMed] [Google Scholar]
  46. Nussler A. K., Billiar T. R. Inflammation, immunoregulation, and inducible nitric oxide synthase. J Leukoc Biol. 1993 Aug;54(2):171–178. [PubMed] [Google Scholar]
  47. Oku H., Yamaguchi H., Sugiyama T., Kojima S., Ota M., Azuma I. Retinal toxicity of nitric oxide released by administration of a nitric oxide donor in the albino rabbit. Invest Ophthalmol Vis Sci. 1997 Nov;38(12):2540–2544. [PubMed] [Google Scholar]
  48. Parks D. J., Cheung M. K., Chan C. C., Roberge F. G. The role of nitric oxide in uveitis. Arch Ophthalmol. 1994 Apr;112(4):544–546. doi: 10.1001/archopht.1994.01090160124032. [DOI] [PubMed] [Google Scholar]
  49. Pollock J. S., Förstermann U., Mitchell J. A., Warner T. D., Schmidt H. H., Nakane M., Murad F. Purification and characterization of particulate endothelium-derived relaxing factor synthase from cultured and native bovine aortic endothelial cells. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10480–10484. doi: 10.1073/pnas.88.23.10480. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Pryor W. A., Squadrito G. L. The chemistry of peroxynitrite: a product from the reaction of nitric oxide with superoxide. Am J Physiol. 1995 May;268(5 Pt 1):L699–L722. doi: 10.1152/ajplung.1995.268.5.L699. [DOI] [PubMed] [Google Scholar]
  51. Radi R., Beckman J. S., Bush K. M., Freeman B. A. Peroxynitrite-induced membrane lipid peroxidation: the cytotoxic potential of superoxide and nitric oxide. Arch Biochem Biophys. 1991 Aug 1;288(2):481–487. doi: 10.1016/0003-9861(91)90224-7. [DOI] [PubMed] [Google Scholar]
  52. Radomski M. W., Palmer R. M., Moncada S. The anti-aggregating properties of vascular endothelium: interactions between prostacyclin and nitric oxide. Br J Pharmacol. 1987 Nov;92(3):639–646. doi: 10.1111/j.1476-5381.1987.tb11367.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Rees D. D., Palmer R. M., Schulz R., Hodson H. F., Moncada S. Characterization of three inhibitors of endothelial nitric oxide synthase in vitro and in vivo. Br J Pharmacol. 1990 Nov;101(3):746–752. doi: 10.1111/j.1476-5381.1990.tb14151.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Schulz R., Nava E., Moncada S. Induction and potential biological relevance of a Ca(2+)-independent nitric oxide synthase in the myocardium. Br J Pharmacol. 1992 Mar;105(3):575–580. doi: 10.1111/j.1476-5381.1992.tb09021.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Sery T. W., Petrillo R. Superoxide anion radical as an indirect mediator in ocular inflammatory disease. Curr Eye Res. 1984 Jan;3(1):243–252. doi: 10.3109/02713688408997206. [DOI] [PubMed] [Google Scholar]
  56. Snyder S. H. Nitric oxide: first in a new class of neurotransmitters. Science. 1992 Jul 24;257(5069):494–496. doi: 10.1126/science.1353273. [DOI] [PubMed] [Google Scholar]
  57. Stuehr D. J., Cho H. J., Kwon N. S., Weise M. F., Nathan C. F. Purification and characterization of the cytokine-induced macrophage nitric oxide synthase: an FAD- and FMN-containing flavoprotein. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7773–7777. doi: 10.1073/pnas.88.17.7773. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Stuehr D. J., Griffith O. W. Mammalian nitric oxide synthases. Adv Enzymol Relat Areas Mol Biol. 1992;65:287–346. doi: 10.1002/9780470123119.ch8. [DOI] [PubMed] [Google Scholar]
  59. Tilton R. G., Chang K., Corbett J. A., Misko T. P., Currie M. G., Bora N. S., Kaplan H. J., Williamson J. R. Endotoxin-induced uveitis in the rat is attenuated by inhibition of nitric oxide production. Invest Ophthalmol Vis Sci. 1994 Jul;35(8):3278–3288. [PubMed] [Google Scholar]
  60. Wang Z. Y., Håkanson R. Role of nitric oxide (NO) in ocular inflammation. Br J Pharmacol. 1995 Nov;116(5):2447–2450. doi: 10.1111/j.1476-5381.1995.tb15094.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Werner-Felmayer G., Werner E. R., Fuchs D., Hausen A., Reibnegger G., Wachter H. Tetrahydrobiopterin-dependent formation of nitrite and nitrate in murine fibroblasts. J Exp Med. 1990 Dec 1;172(6):1599–1607. doi: 10.1084/jem.172.6.1599. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Wu G. S., Zhang J., Rao N. A. Peroxynitrite and oxidative damage in experimental autoimmune uveitis. Invest Ophthalmol Vis Sci. 1997 Jun;38(7):1333–1339. [PubMed] [Google Scholar]
  63. Wu M., Pritchard K. A., Jr, Kaminski P. M., Fayngersh R. P., Hintze T. H., Wolin M. S. Involvement of nitric oxide and nitrosothiols in relaxation of pulmonary arteries to peroxynitrite. Am J Physiol. 1994 May;266(5 Pt 2):H2108–H2113. doi: 10.1152/ajpheart.1994.266.5.H2108. [DOI] [PubMed] [Google Scholar]

Articles from Environmental Health Perspectives are provided here courtesy of National Institute of Environmental Health Sciences

RESOURCES