Nitric Oxide Functions; an Emphasis on its Diversity in Infectious Diseases

Document Type: Review Article

Authors

Department of Parasitology, Pasteur Institute of Iran, Tehran 13164, Iran

Abstract

Nitric oxide is a short-lived mediator, which can be induced in a variety of cell types and produces many physiologic and metabolic changes in target cells. It is important in many biological functions and generated from L-arginine by the enzyme nitric oxide synthase. Nitric oxide conveys a variety of messages between cells, including signals for vasorelaxation, neurotransmission and cytotoxicity. In macrophages, nitric oxide synthase activity appears slowly after exposure of the cells to cytokines and bacterial products, is sustained, and functions independently of calcium and calmodulin. The cytokine- inducible nitric oxide synthase (iNOS) is activated by several immunological stimuli, leading to the production of large quantities of nitric oxide which can be cytotoxic. To date, there have been conflicting reports concerning the clinical significance of nitric oxide in infections. Some authors have proposed that nitric oxide contributes to the development of severe and complicated cases, while others have argued that nitric oxide has a protective role. The aim of this review is to evaluate the functions of nitric oxide production toward oxidative stress induced by infections or inflammations. It is indicated that NO is an important, but possibly not essential contributor in the control of acute phase of infections and it is only part of an immunopathological chain against pathogens. The anti-microbial function does not relate only to nitric oxide action or its related molecules, a combination of nitric oxide and immune factors is required to resolve pathogenic micro-organisms. Consequently, the NO theory in infectious diseases may lead to the novel ideas for therapy and prevention.

Keywords


1.Lancaster JRJ. A tutorial on the diffusibility and reactivity of free nitric oxide. NitricOxide 1997; 1:18-30.

2. Nahrevanian H, Dascombe MJ. The role of nitric oxide and its up/downstream molecules in malaria: cytotoxic or preventive? Southeast Asian J Trop Med Public Health 2003; 4:4-50.

3. Nussler AK, Di Silvio M, Billiar TR, Hoffman RA, Geller DA, Selby R, et al. Stimulation of the nitric oxide synthase pathway in human hepatocytes by cytokines and endotoxin. J Exp Med 1992; 176:261-264.

4. Ellis G, Adatia I, Yazdanpanah  M, Makela SK. Nitrite and nitrate analyses: a clinical biochemistry perspective. Clin Biochem 1998; 31:195-220.

5. Hede George K. Ntric Oxide: From pollutant to biochemical celebrity. Duke University Research Magazine, University of Utah Dar es Salaam Tanzania. 2000. Available at: http://www.dukenews.duke.edu/dr97/nitric.htm.

6. Clark IA, Rockett KA, Cowden WB.Possible central role of nitric oxide in conditions clinically similar to cerebral malaria. Lancet 1992;340:894-896.

7. Burdon  MG, Butler AR, Renton  LM.A study of antibacterial activity of nitric oxide donor compounds. In: Moncada S, Stamler J, Gross S, Higgs EA. The biology of nitric oxide.Ed. London: Portland Press Ltd;1996.            p. 170.

8. Motard A, Landau I, Nussler A, Grau G, Baccam D, Mazier D, Targett GA. The role of reactive nitrogen intermediates in modulation of gametocyte infectivity of rodent malaria parasites. Parasite Immunol1993; 15:21-26.

9. Granger DL, Kubes P. Nitric oxide as anti-inflammatory agent. In: Packer L, editor. Nitric oxide, Part B; physiological and pathological processes. 269th ed. Academic Press; 1983. p.435-441.

10. Jourd'heuil  D,  Kang D, Grisham MB. Intreactions between superoxide and nitric oxide: Implications in DNA damage and mutagenesis. Front Biosci1997; 2:189-196.

11. Oliveira DM, Silva-Teixeira DN, Carmo SA, Goes AM. Role of nitric oxide on human Schistosomiasis mansoni: upregulation of in vitro granuloma formation by N omega-nitro-L-arginine methyl ester. Nitric Oxide1998; 2:57-65.

12. Good  MF, Doolan   DL. Immune effector mechanisms in malaria. Curr Opin Immunol  1999; 11: 412-419.

13. Hommel M. Immunology of malaria. In: WHO. Health co-operation papers, Quaderni di cooperazion sanitaria. World Health Organization 1996. p. 53-70.

14. Chiwakata CB, Hemmer CJ, Dietrich M. High levels of inducible nitric oxide synthase mRNA are associated with increased monocyte counts in blood and have a beneficial role in Plasmodium falciparum malaria. Infect Immun  2000; 68:394-399.

15. Nahrevanian H. Nitric oxide involvement during malaria infection; Immunological concepts, mechanisms and complexities; A novel review. J Trop Med Parasitol 2004;27:93-101.

16. Nahrevanian H, Dascombe MJ. Nitric oxide and reactive nitrogen intermediates in lethal and nonlethal strains of murine malaria. Parasite Immunol2001; 23:491-501.

17. Nahrevanian  H, Dascombe MJ.Expression of inducible nitric oxide synthase (iNOS) mRNA in target organs of lethal and non-lethal strains of murine malaria. Parasite Immunol 2002; 24:471-478.

18.  Dascombe MJ, Nahrevanian H.Pharmacological assessment of the role of nitric oxide in mice infected with lethal and non-ethal species of malaria. Parasite Immunol 2003; 25:149-159.

19. Nahrevanian  H,  Farahmand  M,  Aghighi Z, Assmar  M, Amirkhani  A. Pharmacological evaluation of anti-leishmanial activity by in vivo nitric oxide modulation in Balb/c mice infected with Leishmania major MRHO/IR/75/ER; An Iranian strain of cutaneous leishmaniasis. Exp Parasitol 2007; 116:233-240.

20. Klotz  FW, Scheller LF, Seguin  MC, Kumar  N, Marletta  MA, Green SJ, et al. Co-localization of inducible-nitric oxide synthase and Plasmodium berghei in hepatocytes from rats immunized with irradiated sporozoites. J Immunol 1995; 154:3391-3395.

21. Zuber M, Miesel R. Elevated levels of reactive nitrogen intermediates in serum of patients with auto-immune and inflammatory rheumatic disease. In: Moncada S, Feelisch M, Busse R, Higgs EA, editors. The biology of nitric oxide; physiopathological and clinical aspects. London and Chapel Hill, London, UK: Portland Press; 1994. p. 503-505.

22. Munzel T, Heitzer T, Harrison  DG. The physiology and pathophysiology of the nitric oxide/superoxide system. Herz 1997; 22:158-172.

23. Roitt  IM, Brostoff  J, Male D. Immunology. 5th ed. London: Mosby Publication; 1998. p. 132-314.

24. Beckman JS.Biochemistry of nitric oxide and peroxynitrite. In: Kubes P. Springer RG.Ed. Nitric oxide, A modulator of cell-cell interactions in the micro-circulations. USA:  Landes Co; 1995. p. 1-17.

25. Ferreira  SH. Direct blockade of inflammatory hyperalgesia by nitric oxide analgesics. In: Moncada  S,  Feelisch M, Busse R, Higgs EA. editors. The biology of nitric oxide; physiopatological and clinical aspects. London and Chapel Hill, London, UK: Portland Press ; 1994. p. 324-326.

26. Mellouk S, Green SJ, Nacy CA, Hoffman SL. IFN-gamma inhibits development of Plasmodium berghei exoerythrocytic stages in hepatocytes by an L-arginine-dependent effector mechanism. J Immunol 1991; 146: 3971-3976.

27. Vazquez-Torres  A, Stevanin T, Jones-Carson  J, Castor  M, Read  RC, Fang  FC. Analysis of nitric oxide-dependent antimicrobial actions in macrophages and mice. Methods Enzymol  2008; 437:521-538.

28. Poole RK. Nitric oxide and nitrosative stress tolerance in bacteria. Biochem Soc Trans 2005; 33:176-180.

29. Hussain  SMalik  M, Shi L, Gennaro  ML, Drlica  K. In vitro model of mycobacterial growth arrest using nitric oxide with limited air. Antimicrob Agents Chemother  2009; 53:157-161.

30. Alam  MS, Zaki  MH, Sawa T, Islam  S, Ahmed KA, Fujii S, et al. Nitric oxide produced in Peyer's patches exhibits antiapoptotic activity contributing to an antimicrobial effect in murine salmonellosis. Microbiol Immunol  2008; 52:197-208.

31. Refik M, Mehmet N, Durmaz R, Ersoy Y. Cytokine profile and nitric oxide levels in sera from patients with brucellosis. Braz J Med Biol Res 2004; 37:1659-1663.

32. Wang W, Xue M, Willcox M, Thakur A. Role of nitric oxide in Pseudomonas aeruginosa keratitis caused by distinct bacterial phenotypes. Eye Contact Lens 2008; 34:195-197.

33. Kim SS, Sung YJ, Park MK, Lim CH, Yang HJ, Kim TH, et al. The change of cyclooxygenase-2 and inducible nitric oxide synthase in the gastric mucosa one year after eradication of Helicobacter pylori. Korean J Gastroenterol  2008; 52:286-292.

34. Idh  J, Westman  A, Elias D, Moges F, Getachew A, Gelaw A, et al. Nitric oxide production in the exhaled air of patients with pulmonary tuberculosis in relation to HIV co-infection. BMC Infect Dis  2008 24; 8:146.

35. Kim  HA, Kim  SH, Ko  HM, Choi  JH, Kim KJ, Oh SH, et al. Nitric oxide plays a key role in the platelet-activating factor-induced enhancement of resistance against systemic candidiasis. Immunology  2008; 124:428-435.

36. Lluch P, Cortina  B, Vila JM, Segarra G, Mauricio MD, Del Olmo JA, et al. Unchanged plasma levels of dimethylarginines and nitric oxide in chronic hepatitis C. Scand J Gastroenterol  2008; 25:1-5.

37. Rockett  KA, Awburn  MM, Cowden WB, Clark  IA. Killing of Plasmodium falciparum in vitro by nitric oxide derivatives. Infect Immun1991; 59:3280-3283.

38. Modlin R, Rickinson A. Immunity to infection. Curr Opin Immunol  2000; 12: 387-389.

39. Nahrevanian H. Immune effector mechanisms of nitric oxide pathway in malaria: Cytotoxicity versus cytoprotection. Braz J Infect Dis 2006; 10:283-292.

40. Nahrevanian  H, Gholizadeh J, Farahmand  M,Assmar M, Sharifi K, Ayatollahi Mousavi SA, et al. Nitric oxide induction as a novel immunoepidemiological target in malaria-infected patients from endemic areas of the Islamic Republic of Iran. Scand J Clin Lab Invest 2006; 66:201-210.

41. Clark  IA, Al-Yaman  FM, Cowden WB, Rockett  KA.Does malarial tolerance, through nitric oxide, explain the low incidence of autoimmune disease in tropical Africa? Lancet1996; 348:1492-1494.

42. Liew FY. Regulation of nitric oxide synthase in macrophages. In: Moncada S, Stamler J, Gross S, Higgs EA, editors. The biology of nitric oxide: Enzymology, biochemistry and immunology. London, UK: Portland Press; 1992. p.223-229.

43. Tizard IR. Effector T-Cell functions. In: Tizard IR, editor. Immunology, An introduction. Chapt. 15, 3rd ed. USA: Saunders College Publishing; 1992. p. 258-273.

44. Fernandes  PD, Assreuy J. Role of nitric oxide and superoxide in Giardia lamblia killing. Braz J Med Biol Res 1997; 30: 93-99.

45. Augusto O, Linares E, Giorgio S. Possible roles of nitric oxide and peroxynitrite in murine leishmaniasis. Braz J Med Biol Res1996; 29: 853-862.

46. Haswell-Elkins M, Satarug S, Sithithaworn P, Mairiang E, Mairiang P, Elkins D. Nitrate excretion and parasite-specific T lymphocyte responses of humans infected with the liver fluke, Opisthorchis viverrini. In: Moncada S, Marletta MA, Hibbs JRJB, Higgs A, editors. The biology of nitric oxide: Physiological and clinical aspects. London, UK: Portland Press; 1992. p. 380.

47. Mannick EE, Oliver PD, Sadowska-Krowicka H, Miller MJS. Inhibition of inducible nitric oxide synthase reverse endotoxin tolerance in cultured macrophages. In: Moncada  S, Stamler J, Gross S, Higgs EA, editors. The biology of nitric oxide. London: Portland Press Ltd; 1996. p.144.

48. Ablij HC, Meinders  AE. C-reactive protein: history and revival. Eur J Intern Med 2002; 13: 412-422.

49. Jakobsen  PH, McCay V, N'Jie R, Olaleye BO, D'Alessandro U, Zhang G-H, et al. Decreased antitoxic activities among children with clinical episodes of malaria. Infect Immun 1998; 66:1654-1659.

50. McCarty MF. AMPK activation may suppress hepatic production of C-reactive protein by stimulating nitric oxide synthase. Med Hypotheses  2004; 63: 328-333.

51. Kremsner  PG, Winkler S, Wildling E, Prada J, Bienzle U, Graninger W, et al. High plasma levels of nitrogen oxides are associated with severe disease and correlate with rapid parasitological and clinical cure in Plasmodium falciparum. Trans R Soc Trop Med Hyg 1996; 90: 44-47.

52. Nahrevanian  H, Gholizadeh  J, Farahmand  M,  Assmar  M. Patterns of co-association of C-reactive protein and nitric oxide in malaria in endemic areas of Iran. Mem Inst swaldo Cruz  2008;103:39-44.

53. Gyan  B, Kurtzhals  JAL, Akanmori  BD, Ofori  M, Goka  BQ, Hviid L, et al. Elevated levels of nitric oxide and low levels of haptoglobin are associated with severe anaemia in African children. Acta Trop 2002; 83:133-140.

54. Clark  IA, Awburn  MM, Whitten  RO, Harper  CG, Liomba  NG, Molyneux  ME,  et al. Tissue distribution of migration inhibitory factor and inducible nitric oxide synthase in falciparum malaria and sepsis in African children. Malar J 2003; 2:1-17.

55. Cramer  JP, Mockenhaupt  FP, Ehrhardt  S, Burkhardt  J, Otchwemah  RN, Dietz E, et al. iNOS promoter variants and severe malaria in Ghanaian children. Trop Med Int Health 2004; 9:1074-1080.

56. Vodovotz Y. Control of nitric oxide production by transforming growth factor-beta1: mechanistic insights and potential relevance to human disease. Nitric Oxide 1997; 1:3-17.

57. Wink DA, Laval J. The Fpg protein, a DNA repair enzyme, is inhibited by the biomediator nitric oxide in vitro and in vivo. Carcinogenesis 1994; 15: 2125-29.

58. Kroncke  KD, Fehsel  K, Kolb-Bachofen V. Nitric oxide: cytotoxicity versus cytoprotection: how, why, when, and where?  Nitric Oxide 1997; 1:107-120.

59. Nguyen T, Brunson  D, Crespi  CL, Penman  BW, Wishnok JS, Tannenbaum SR. DNA damage and mutation in human cells exposed to nitric oxide in vitro. Proc Natl Acad Sci USA  1992; 89:3030-3034.

60. Zhang J, Dawson VL, Dawson TM, Snyder SH. Nitric oxide activation of poly (ADP-ribose) synthetase in neurotoxicity. Science1994;263: 687-689.

61. Kwon  NS, Stuehr  DJ, Nathan  CF. Inhibition of tumor cell ribonucleotide reductase by macrophage-derived nitric oxide. J Exp Med 1991; 174:761-767.

62. Rockett  KA, Awburn  MM, Rockett  EJ, Cowden WB, Clark  IA. Possible role of nitric oxide in malarial immunosuppression. Parasite Immunol 1994; 16: 243-249.

63. Szabo C, Ohshima  H. DNA damage induced by peroxynitrite: subsequent biological effects. Nitric Oxide 1997; 1:373-385.

64. Balakirev  MY, Khramtsov  VV, Zimmer G.Modulation of the mitochondrial permeability transition by nitric oxide.  Eur J Biochem 1997;246: 710-718.

65. Blanco FJ, Ochs  RL, Schwarz  H, Lotz  M. Chondrocyte apoptosis induced by nitric oxide.  Am J Pathol 1995; 146:75-85.

66. Bonfoco E, Krainc D, Ankarcrona  M, Nicotera  P, Lipton  SA. Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell cultures.  Proc Natl Acad Sci USA 1995; 92:7162-7166.

67. Kroncke KD, Kolb-Bachofen V, Berschick B, Burkart V, Kolb H. Activated macrophages kill pancreatic syngeneic islet cells via arginine-dependent nitric oxide generation. Biochem Biophys Res Commun 1991; 175:752-758.

68. Dimmeler S, Zeiher AM. Nitric oxide and apoptosis: another paradigm for the double-edged role of nitric oxide. Nitric Oxide 1997; 1:275-281.

69. White NJ. Malaria pathophysiology. In: Sherman IW, editor. Malaria, parasite biology, pathogenesis and protection. Washington DC, Am Soc Microbiol: ASM Press; 1998. p. 371-385.

70. Shiode  N, Morishima  N, Nakayama  K, Yamagata  T, Matsuura H, Kajiyama  G. Flow-mediated vasodilation of  human epicardial coronary arteries: effect of inhibition of nitric oxide synthesis. J Am Coll Cardiol  1996; 27:304-310.

71. Burney  S, Tamir  S, Gal  A, Tannenbaum  SR. A mechanistic analysis of nitric oxide-induced cellular toxicity. Nitric Oxide1997;1:130-144.

72. Nahrevanian H, Dascombe MJ. Reactive nitrogen intermediate (RNI) levels inside and outside Plasmodium infected red blood cells in murine malaria. J Trop Med Parasitol 2003; 26:13-19.

73. Nahrevanian H, Dascombe  MJ. Simultaneous increases in immune competent cells and nitric oxide in the spleen during Plasmodium berghei infection in mice. J Microbiol Immunol Infect 2006; 39:11-17.

74. Nahrevanian H, Gholizadeh SJ, Farahmand M,Aghighi Z, Assmar M, Abolhassani M. Reactive nitrogen intermediate production and tolerance variability in different mouse strains after in vivo treatment with lipopolysaccharide from Salmonella abortus equi. J Microbiol Immunol Infect 2005; 38:164-168.

75. Nahrevanian H. Direct monitoring of in situ and in vitro nitric oxide release in the brain during malaria infection with Plasmodium berghei N/13/1A. J Trop Med Parasitol 2004; 27:1-6.

76. Nahrevanian H. Nitric oxide and reactive nitrogen intermediates are released by immune response during malaria infection. J Commun Dis 2004; 3:23-26.

77. Nahrevanian H. The penetration of Plasmodium into red blood cell is a protective mechanism of malaria parasite against high levels of accumulated nitric oxide in blood circulation. J Parasit Dis 2004; 28:83-89.

78. Gyan B, Troye-Blomberg M, Perlmann P, Bjorkman A. Human monocytes cultured with and without interferon-gamma inhibits Plasmodium falciparum parasite growth in vitro via secretion of reactive nitrogen intermediates. Parasite Immunol 1994; 16: 371-375.

80. Playfair  JH, Taverne  J, Bate  CA, de Souza  JB. The malaria vaccine: anti-parasite or anti-disease? Immunol Today 1990; 11:25-27.