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Chapter 19 : Reactive Oxygen and Reactive Nitrogen Metabolites as Effector Molecules against Infectious Pathogens

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Abstract:

This chapter focuses on the sources, the regulation, the spectrum of activities, and the viral and microbial targets of reactive oxygen intermediates (ROIs) and reactive nitrogen intermediates (RNIs) generated by mammalian host cells. With respect to the control of infectious agents, the two most important oxygen-dependent pathways for the generation of antiviral or antimicrobial effector molecules are the phagocyte NADPH oxidase (Phox) and the inducible nitric oxide synthase (iNOS) pathways. One of the most intriguing discoveries in the field of ROIs in recent years was the observation by Wentworth and colleagues that antibodies, independent of their source or antigen specificity, can catalyze the generation of ROIs. Members of all groups of infectious pathogens (viruses, bacteria, protozoa, helminths, and fungi) were found to be controlled by RNIs. The significant improvement of certain infectious diseases after inhibition or genetic deletion of iNOS, which was without negative effects on the pathogen clearance, was unexpected. It can be explained by the inhibition of T-cell proliferation or induction of T-cell apoptosis via iNOS-positive suppressor cells (macrophages and dendritic cells) or by the tissue-damaging properties of RNIs. Transgenic mouse models have been extremely helpful to elucidate the relative contributions of ROIs and RNIs for the control of infectious pathogens. Viruses, bacteria, parasites, and fungi have developed multiple strategies to evade killing by oxygen-dependent effector mechanisms. Current research projects aim at the development of ROI or RNI precursors that enter only certain types of host cells and are activated by the infectious pathogens themselves.

Citation: Bogdan C. 2004. Reactive Oxygen and Reactive Nitrogen Metabolites as Effector Molecules against Infectious Pathogens, p 357-396. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch19

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FIGURE 1

Key pathways for the generation of ROIs and RNIs (for details see text).

Citation: Bogdan C. 2004. Reactive Oxygen and Reactive Nitrogen Metabolites as Effector Molecules against Infectious Pathogens, p 357-396. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch19
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Image of FIGURE 2
FIGURE 2

Enzymatic and nonenzymatic generation of ROIs in the phagosomes or exocytosed granules of neutrophils.The NADPH oxidase (Phox) is assembled in the plasma membrane (forming phagosomes) or in the membrane of specific granules (which can be exocytosed). The produced superoxide (O ) enters the iron (Fe)-catalyzed Fenton–Weiss reaction (which leads to the release of hydroxyl radical [OH·] or hydroxyl anions [OH]) or dismutates into hydrogen peroxide (HO) and molecular oxygen (in the triplet or singlet state). HO is a substrate for the MPO, which leads to the generation of halogen-containing oxidants. Singlet oxygen (O), which is also derived from the reaction of HO with OCl, is transformed into ozone (O) and other ROIs by catalytic antibodies that are specifically bound to phagocytosed microbes or attached to the surface of neutrophils.

Citation: Bogdan C. 2004. Reactive Oxygen and Reactive Nitrogen Metabolites as Effector Molecules against Infectious Pathogens, p 357-396. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch19
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Image of FIGURE 3
FIGURE 3

Substrates, intermediates, and products of the iNOS reaction (modified from ). -Arginine is transformed into -citrulline and nitric oxide (NO) via the intermediate -hydroxy--arginine (LOHA). The reaction involves a five-electron reduction of the guanidino-nitrogen of arginine, in which NADPH and four redox active groups (FAD, FMN, heme, and tetrahydrobiopterin [THB]) participate in the electron transport to oxygen (O).

Citation: Bogdan C. 2004. Reactive Oxygen and Reactive Nitrogen Metabolites as Effector Molecules against Infectious Pathogens, p 357-396. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch19
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Image of FIGURE 4
FIGURE 4

Cytokine regulation and function of iNOS and arginase as alternative arginineconsuming pathways. For the production of NO by iNOS, the cells (e.g., macrophages, fibroblasts) require the uptake of extracellular -arginine via cationic amino acid transporters (CAT). Arginine can enter either the iNOS pathway or the arginase pathway. Arginase degrades arginine into urea and ornithine. Ornithine is a substrate for two enzymes: the ornithine-decarboxylase (ODC), which leads to the generation of polyamines that support cell proliferation but also exert immunosuppressive functions; and the ornithine aminotransferase (OAT), which leads to the production of proline, a precursor of collagen synthesis by fibroblasts. iNOS and arginase are regulated antagonistically by overlapping sets of cytokines and also fulfill complementary functions.THB, tetrahydrobiopterin.

Citation: Bogdan C. 2004. Reactive Oxygen and Reactive Nitrogen Metabolites as Effector Molecules against Infectious Pathogens, p 357-396. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch19
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References

/content/book/10.1128/9781555817671.chap19
1. Abo, A.,, E. Pick,, A. Hall,, N. Totty,, C. G. Teahan,, and A. W. Segal. 1991. Activation of the NADPH oxidase involves the small GTP-binding protein p21rac1. Nature 353:668670.
2. Abu-Soud, H. M.,, and S. L. Hazen. 2000. Nitric oxide is a physiological substrate for mammalian peroxidases. J. Biol. Chem. 275:3752437532.
3. Adams, L. B.,, M. C. Dinauer,, D. E. Morgenstern,, and J. L. Krahenbuhl. 1997. Comparison of the roles of reactive oxygen and nitrogen intermediates in the host response to Mycobacterium tuberculosis using transgenic mice. Tuber. Lung Dis. 78:237246.
4. Adams, L. B.,, C. K. Job,, and J. L. Krahenbuhl. 2000. Role of inducible nitric oxide synthase in resistance to Mycobacterium leprae in mice. Infect. Immun. 68:54625465.
5. Ahluwalla, J.,, A. Tinker,, L. H. Clapp,, M. R. Duchen,, A.Y. Abramor,, S. Pope,, M. Nobles,, and A.W. Segal. 2004. The large-conductance Ca2+-activated K+ channel is essential for innate immunity. Nature 427:853858.
6. Akaike, T.,, S. Fujii,, A. Kato,, J. Yoshitake,, Y. Miyamoto,, T. Sawa,, S. Okamoto,, M. Suga,, M. Asakawa,, Y. Nagai,, and H. Maeda. 2000. Viral mutation accelerated by nitric oxide production during infection in vivo. FASEB J. 14:14471454.
7. Akaike, T.,, S. Okamoto,, T. Sawa,, J. Yoshitake,, F. Tamura,, K. Ichimori,, K. Miyazaki,, K. Sasamoto,, and H. Maeda. 2003. 8-Nitroguanosine formation in viral pneumonia and its implication for pathogenesis. Proc. Natl. Acad. Sci. USA 100:685690.
8. Alam, M. S.,, T. Akaike,, S. Okamoto,, T. Kubota,, J. Yoshitake,, T. Sawa,, Y. Miyamoto,, F. Tamura,, and H. Maeda. 2002. Role of nitric oxide in host defense in murine salmonellosis as a function of its antibacterial and antiapoptotic activities. Infect. Immun. 70:31303142.
9. Albina, J. E. 1995. On the expression of nitric oxide synthase by human macrophages. Why no NO? J. Leukoc. Biol. 58:643649.
10. Allen, R. C.,, R. L. Stjernholm,, and R. H. Steele. 1972. Evidence for the generation of an electronic excitation state(s) in human polymorphonuclear leukocytes and its participation in bactericidal activity. Biochem. Biophys. Res. Commun. 47:679684.
11. Amezaga, M. A.,, F. Bazzoni,, C. Sorio,, F. Rossi,, and M. A. Cassatella. 1992. Evidence for the involvement of distinct signal transduction pathways in the regulation of constitutive and interferon-g-dependent gene expression of NADPH oxidase components (gp91phox, p47phox and p22phox) and high-affinity receptor for IgG (FcγRI) in human polymorphonuclear leukocytes. Blood 79:735744.
12. Annane, D.,, S. Sanquer,, V. Sebille,, A. Faye,, D. Djuranovic,, J.-C. Raphael,, P. Gajdos,, and E. Bellisant. 2000. Compartmentalized inducible nitric-oxide synthase activity in septic shock. Lancet 355:11431148.
13. Anstey, N. M.,, J. B. Weinberg,, M.Y. Hassanali,, E. D. Mwaikambo,, D. Manyenga,, M. A. Misukonis,, D. R. Arnelle,, D. Hollis,, M. I. McDonald,, and D. L. Granger. 1996. Nitric oxide in Tanzanian children with malaria: inverse relationship between malaria severity and nitric oxide production/nitric oxide synthase type 2 expression. J. Exp. Med. 184:557567.
14. Aratani, Y.,, F. Kura,, H. Watanabe,, H. Akagawa,, Y. Takano,, K. Suzuki,, N. Maeda,, and H. Koyama. 2000. Differential host susceptibilities to pulmonary infections with bacteria and fungi in mice deficient in myeloperoxidase. J. Infect. Dis. 182:12761279.
15. Babior, B. M. 1999. NADPH oxidase: an update. Blood 93:14641476.
16. Babior, B.,, R. Kipnes,, and J. Curnette. 1973. Biological defense mechanisms. The production by leukocytes of superoxide, a potential bactericidal agent. J. Clin. Invest. 52:741744.
17. Babior, B. M.,, C. Takeuchi,, J. M. Ruedi,, A. Gutierrez,, and P. J. Wentworth. 2003. Investigating antibody-catalyzed ozone generation by human neutrophils. Proc. Natl. Acad. Sci. USA 100:30313034.
18. Badorff, C.,, B. Fichtlscherer,, A. Muelsch,, A. M. Zeiher,, and S. Dimmeler. 2002. Selective delivery of nitric oxide to a cellular target: a pseudosubstratecoupled dinitrosyl-iron complex inhibits the enteroviral protease 2A. Nitric Oxide 6:305312.
19. Baldridge, C. W.,, and R. W. Gerard. 1933. The extra respiration of phagocytosis. Am. J. Physiol. 103:235236.
20. Banerjee, R.,, J. Anguita,, and E. Fikrig. 2000. Granulocytic ehrlichiosis in mice deficient in phagocyte oxidase or inducible nitric oxide synthase. Infect. Immun. 68:43614362.
21. Barr, S. D.,, and L. Gedamu. 2003. Role of peroxidoxins in Leishmania chagasi survival. Evidence of an enzymatic defense against nitrosative stress. J. Biol. Chem. 278:1081610823.
22. Bartholdy, C.,, A. Nansen,, J. E. Christensen,, O. Marker,, and A. R. Thomsen. 1999. Inducible nitric oxide synthase plays a minimal role in LCMVinduced, T cell-mediated protective immunity and immunopathology. J. Gen.Virol. 80:29973005.
23. Beckman, J. S.,, T. W. Beckman,, J. Chen,, P. A. Marshall,, and B. A. Freeman. 1990. Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc. Natl. Acad. Sci. USA 87:16201624.
24. Beckman, J. S.,, J. Chen,, H. Ischiropoulos,, and J. P. Crow. 1994. Oxidative chemistry of peroxinitrite. Methods Enzymol. 233:229240.
25. Bevins, C. L. 2003.Antimicrobial peptides as effector molecules of mammalian host defense. Contrib. Microbiol. 10:106148.
26. Blanchard, T. G.,, F. Yu,, C. L. Hsieh,, and R.W. Redline. 2003. Severe inflammation and reduced bacteria load in murine helicobacter infection caused by lack of phagocyte oxidase activity. J. Infect. Dis. 187:16091615.
27. Blos, M.,, U. Schleicher,, F. J. Rocha,, U. Meissner,, M. Röllinghoff,, and C. Bogdan. 2003. Organspecific and stage-dependent control of Leishmania major infection by inducible nitric oxide synthase and phagocyte NADPH oxidase. Eur. J. Immunol. 33:12241234.
28. Bogdan, C. 1997. Of microbes, macrophages and NO. Behring Inst. Res. Commun. 99:5872.
29. Bogdan, C. 1998. The multiplex function of nitric oxide in (auto)immunity. J. Exp. Med. 187:13611365.
30. Bogdan, C., 2000. The function of nitric oxide in the immune system, p. 443492. In B. Mayer (ed.), Handbook of Experimental Pharmacology: Nitric Oxide. Springer, Heidelberg, Germany.
31. Bogdan, C. 2001a. Nitric oxide and the immune response. Nat. Immunol. 2:907916.
32. Bogdan, C. 2001b. Nitric oxide and the regulation of gene expression. Trends Cell Biol. 11:6675.
33. Bogdan, C.,, and C. Nathan. 1993. Modulation of macrophage function by transforming growth factor-β, interleukin 4 and interleukin 10. Ann.N.Y.Acad. Sci. 685:713739.
34. Bogdan, C.,, and M. Röllinghoff. 1998. The immune response to Leishmania: mechanisms of parasite control and evasion. Int. J. Parasitol. 28:121134.
35. Bogdan, C.,, Y. Vodovotz,, J. Paik,, Q.-W. Xie,, and C. Nathan. 1993.Traces of bacterial lipopolysaccharide suppress IFN-γ-induced nitric oxide synthase gene expression in primary mouse macrophages. J. Immunol. 151:301309.
36. Bogdan, C.,, H. Thüring,, M. Dlaska,, M. Röllinghoff,, and G. Weiss. 1997. Mechanism of suppression of macrophage nitric oxide release by IL- 13. J. Immunol. 159:45064513.
37. Bogdan, C.,, N. Donhauser,, R. Döring,, M. Röllinghoff,, A. Diefenbach,, and M. G. Rittig. 2000a. Fibroblasts as host cells in latent leishmaniosis. J. Exp. Med. 191:21212129.
38. Bogdan, C.,, M. Röllinghoff,, and A. Diefenbach. 2000b. Reactive oxygen and reactive nitrogen intermediates in innate and specific immunity. Curr. Opin. Immunol. 12:6476.
39. Borregard, N.,, and A. I. Tauber. 1984. Subcellular localization of human neutrophil NADPH oxidase: bcytochrome and associated flavoprotein. J. Biol. Chem. 259:4752.
40. Botha, T.,, and B. Ryffel. 2002. Reactivation of latent tuberculosis by an inhibitor of inducible nitric oxide synthase in an aerosol murine model. Immunology 107:350357.
41. Brennan, M. L.,, W. Wu,, X. Fu,, Z. Shen,, W. Song,, H. Frost,, C. Vadseth,, L. Narine,, E. Lenkiewicz,, M. T. Borchers,, A. J. Lusis,, J. J. Lee,, N. A. Lee,, H. M. Abu-Soud,, H. Ischiropoulos,, and S. L. Hazen. 2002. A tale of two controversies: defining both the role of peroxidases in nitrotyrosine formation in vivo using eosinophil peroxidase and myeloperoxidase- deficient mice, and the nature of peroxidasegenerated reactive nitrogen species. J. Biol. Chem. 277:1741517427.
42. Brown, C.,, and S. L. Reiner. 1999.Development of Lyme arthritis in mice deficient in inducible nitric oxide synthase. J. Infect. Dis. 179:15731576.
43. Brüne, B.,, A. von Knethen,, and K. B. Sandau. 1999. Nitric oxide (NO): an effector of apoptosis. Cell Death Differ. 6:969975.
44. Bryk, R.,, P. Griffin,, and C. Nathan. 2000. Peroxynitrite reductase activity of bacterial peroxiredoxins. Nature 407:211215.
45. Burgner, D.,, W. Xu,, K. Rockett,, M. Gravenor,, I. G. Charles,, A. V. Hill,, and D. Kwiatkowski. 1998. Inducible nitric oxide synthase polymorphism and fatal cerebral malaria. Lancet 352:11931194.
46. Caccavo, D.,, N. M. Pellegrino,, M. Altamura,, A. Rigon,, L. Amati,, A. Amoroso,, and E. Jirillo. 2002. Antimicrobial and immunoregulatory functions of lactoferrin and its potential therapeutic application. J. Endotoxin Res. 8:403417.
47. Cagan, R. H.,, and M. L. Karnovsky. 1964. Enzymatic basis of the respiratory stimulation during phagocytosis. Nature 204:255257.
48. Calzada, J. E.,, M. A. Lopez-Nevot,, Y. Beraun,, and J. Martin. 2002. No evidence for association of the inducible nitric oxide synthase promotor polymorphism with Trypanosoma cruzi infection. Tissue Antigens 59:316319.
49. Cao, W.,, C. Bao,, and C. J. Lowenstein. 2003. Inducible nitric oxide synthase expression inhibition by adenovirus E1A. Proc. Natl. Acad. Sci. USA 100:77737778.
50. Carlsson, S.,, N. P. Wiklund,, L. Engstrand,, E. Weitzberg,, and J. O. N. Lundberg. 2001. Effects of pH, nitrite, and ascorbic acid on non-enzymatic nitric oxide generation and bacterial growth in urine. Nitric Oxide 5:580586.
51. Casanova, J.-L.,, and L. Abel. 2002. Genetic dissection of immunity to mycobacteria: the human model. Annu. Rev. Immunol. 20:581620.
52. Cassatella, M. A.,, F. Bazzoni,, R. M. Flynn,, S. Dusi,, G. Trinchieri,, and F. Rossi. 1990. Molecular basis of interferon-γ and lipopolysaccharide enhancement of phagocyte respiratory burst capability. J. Biol. Chem. 265:2024120246.
53. Chakravortty, D.,, I. Hansen-Wester,, and M. Hensel. 2002. Salmonella pathogenicity island 2 mediates protection of intracellular Salmonella from reactive nitrogen intermediates. J. Exp. Med. 195:11551166.
54. Chan, E. D.,, J. Chan,, and N.W. Schluger. 2001. What is the role of nitric oxide in murine and human host defense against tuberculosis? Am. J. Respir. Cell Mol. Biol. 25:606612.
55. Chan, J.,, T. Fujiwara,, P. Brennan,, M. McNeil,, S. J. Turco,, J.-C. Sibille,, P. Snapper,, P. Aisen,, and B. R. Bloom. 1989. Microbial glycolipids: possible virulence factors that scavenge oxygen radicals. Proc. Natl. Acad. Sci. USA 86:24532457.
56. Chang, C.,, J. C. Liao,, and L. Kuo. 1998a. Arginase modulates nitric oxide production in activated macrophages. Am. J. Physiol. 274:H342H348.
57. Chang, Y. C.,, B. H. Segal,, S. M. Holland,, G. F. Miller,, and K. J. Kwon-Chung. 1998b. Virulence of catalase-deficient Aspergillus nidulans in p47phox−/− mice. Implications for fungal pathogenicity and host defense in chronic granulomatous disease. J. Clin. Invest. 101:18431850.
58. Chen, B. P.,, and T. E. Lane. 2002. Lack of nitric oxide synthase type 2 (NOS2) results in reduced neuronal apoptosis and mortality following mouse hepatitis virus infection of the central nervous system. J. Neurovirol. 8:5863.
59. Chen, L.,, Q.-W. Xie,, and C. Nathan. 1998. Alkyl hydroperoxide reductase subunit C (AhpC) protects bacterial and human cells against reactive nitrogen intermediates. Mol. Cell 1:795805.
60. Chiarugi, A.,, E. Rovida,, P. D. Sbarba,, and F. Moroni. 2003.Tryptophan availability selectively limits NO synthase induction in macrophages. J. Leukoc. Biol. 73:172177.
61. Choi, H. S.,, P. R. Rai,, H.W. Chu,, C. Cool,, and E. D. Chan. 2003. Arginine as an adjuvant to chemotherapy improves clinical outcome in active tuberculosis. Eur. Respir. J. 21:483488.
62. Clark, R. A. 1999. Activation of the neutrophil respiratory burst oxidase. J. Infect. Dis. 179(Suppl. 2):S309S317.
63. Clark, R. A.,, K. G. Leidal,, D.W. Pearson,, and W. M. Nauseef. 1987. NADPH oxidase of human neutrophils. Subcellular localization and characterization of an arachidonate-activatable superoxide-generating system. J. Biol. Chem. 262:40654074.
64. Clark, S. R.,, M. J. Coffey,, R. M. Maclean,, P.W. Collins,, M. J. Lewis,, A. R. Cross,, and V. B. O'Donnell. 2002. Characterization of nitric oxide consumption pathways by normal, chronic granulomatous disease and myeloperoxidase-deficient human neutrophils. J. Immunol. 169:58895896.
65. Closs, E. I.,, J.-S. Scheld,, M. Sharafi,, and U. Förstermann. 2000. Substrate supply for nitric oxide synthase in macrophages and endothelial cells: role of cationic amino acid transporters. Mol. Pharmacol. 57:6874.
66. Connelly, L.,, A.T. Jacobs,, M. Palacios-Callender,, S. Moncada,, and A. J. Hobbs. 2003. Macrophage endothelial nitric oxide synthase autoregulates cellular activation and proinflammatory protein expression. J. Biol. Chem. 278:2648026487.
67. Cooper, A. M.,, J. E. Pearl,, J.V. Brooks,, S. Ehlers,, and I. M. Orme. 2000a. Expression of nitric oxide synthase 2 gene is not essential for early control of Mycobacterium tuberculosis in the murine lung. Infect. Immun. 68:68796882.
68. Cooper, A. M.,, B. H. Segal,, A. A. Frank,, S. M. Holland,, and I. M. Orme. 2000b.Transient loss of resistance to pulmonary tuberculosis in p47phox−/− mice. Infect. Immun. 68:12311234.
69. Cox, G. M.,, T. S. Harrison,, H. C. McDade,, C. P. Taborda,, G. Heinrich,, A. Casadevall,, and J. R. Perfect. 2003. Superoxide dismutase influences the virulence of Cryptococcus neoformans by affecting growth within macrophages. Infect. Immun. 71:173180.
70. Crawford, M. J.,, and D. E. Goldberg. 1998. Regulation of the Salmonella typhimurium flavohemoglobin gene.A new pathway for bacterial gene expression in response to nitric oxide. J. Biol. Chem. 273:3402834032.
71. Curnutte, J.T.,, D. M. Whitten,, and B. M. Babior. 1974. Defective superoxide production by granulocytes from patients with granulomatous disease. N. Engl. J. Med. 290:593597.
72. Darrah, P. A.,, M. K. Hondalus,, Q. Chen,, H. Ischiropoulos,, and D. M. Mosser. 2000. Cooperation between reactive oxygen and nitrogen intermediates in killing of Rhodococcus equi by activated macrophages. Infect. Immun. 68:35873593.
73. Däubener, W.,, and C. R. MacKenzie. 1999. IFNgamma activated indoleamine 2,3-dioxygenase activity in human cells is an antiparasitic and an antibacterial effector mechanism. Adv. Exp. Med. Biol. 467:517524.
74. Deen, W. M.,, S. R. Tannenbaum,, and J. S. Beckman. 2002. Protein tyrosine nitration and peroxynitrite. FASEB J. 16:1144.
75. DeGroote, M. A.,, and F. C. Fang,. 1999. Antimicrobial properties of nitric oxide, p. 231261. In F. C. Fang (ed.), Nitric Oxide and Infection. Kluwer Academic, New York, N.Y.
76. DeGroote, M. A.,, T. Testerman,, Y. Xu,, G. Stauffer,, and F. C. Fang. 1996. Homocysteine antagonism of nitric oxide-related cytostasis in Salmonella typhimurium. Science 272:414417.
77. DeGroote, M. A.,, U.A. Ochsner,, M. Shiloh,, J. M. McCord,, M. C. Dinauer,, S. J. Libby,, A. Vazquez- Torres,, Y. Xu,, and F. C. Fang. 1997. Periplasmic superoxide dismutase protects Salmonella from products of phagocyte oxidase and nitric oxide synthase. Proc. Natl. Acad. Sci. USA 94:1399714001.
78. DeLeo, F. R.,, and M.T. Quinn. 1996. Assembly of the phagocyte NADPH oxidase: molecular interaction of oxidase proteins. J. Leukoc. Biol. 60:677691.
79. Denis, M. 1991.Tumor necrosis factor and granulocyte macrophage-colony stimulating factor stimulate human macrophages to restrict growth of virulent Mycobacterium avium and to kill avirulent M. avium: killing effector mechanism depends on the generation of reactive nitrogen intermediates. J. Leukoc. Biol. 49:380387.
80. Devadas, S.,, L. Zaritskaya,, S. G. Rhee,, L. Oberley,, and M. S. Williams. 2002. Discrete generation of superoxide and hydrogen peroxide by T cell receptor stimulation: selective regulation of mitogenactivated protein kinase activation and Fas ligand expression. J. Exp. Med. 195:5970.
81. Diefenbach, A.,, H. Schindler,, N. Donhauser,, E. Lorenz,, T. Laskay,, J. MacMicking,, M. Röllinghoff,, I. Gresser,, and C. Bogdan. 1998. Type 1 interferon (IFN-α/β) and type 2 nitric oxide synthase regulate the innate immune response to a protozoan parasite. Immunity 8:7787.
82. Diefenbach, A.,, H. Schindler,, M. Röllinghoff,, W. Yokoyama,, and C. Bogdan. 1999. Requirement for type 2 NO-synthase for IL-12 responsiveness in innate immunity. Science 284:951955.
83. Dinauer, M. C.,, M. B. Deck,, and E. R. Unanue. 1997. Mice lacking reduced nicotinamide adenine dinucleotide phosphate oxidase activity show increased susceptibility to early infection with Listeria monocytogenes. J. Immunol. 158:55815583.
84. Ding, A. H.,, C. F. Nathan,, and D. J. Stuehr. 1988. Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages. Comparison of activating cytokines and evidence for independent production. J. Immunol. 141:24072412.
85. Duncan, C.,, H. Dougall,, P. Johnston,, S. Green,, R. Brogan,, C. Leifert,, L. Smith,, M. Golden,, and N. Benjamin. 1995. Chemical generation of nitric oxide in the mouth from the enterosalivary circulation of dietary nitrate. Nat. Med. 1:546551.
86. Duncan, C.,, H. Li,, R. Dykhuizen,, R. Frazer,, P. Johnston,, G. MacKnight,, L. Smith,, K. Lamza,, H. McKenzie,, L. Batt,, D. Kelly,, M. Golden,, N. Benjamin,, and C. Leifert. 1997. Protection against oral and gastrointestinal diseases: importance of dietary nitrate intake, orale nitrate reduction and enterosalivary nitrate ciruclation. Comp. Biochem. Physiol. A 118:939948.
87. Dusi, S.,, M. Donini,, D. Lissandrini,, P. Mazzi,, V. D. Bianca,, and F. Rossi. 2001. Mechanisms of expression of NADPH oxidase components in human cultured monocytes: role of cytokines and transcriptional regulators involved. Eur. J. Immunol. 31:929938.
88. Eckmann, L.,, F. Laurent,, T. D. Langford,, M. L. Hetsko,, J. R. Smith,, M. F. Kagnoff,, and F. D. Gillin. 2000. Nitric oxide production by human intestinal epithelial cells and competition for arginine as potential determinants of host defense against the lumen-dwelling pathogen Giardia lamblia. J. Immunol. 164:14781487.
89. Ehlers, S.,, S. Kutsch,, J. Benini,, A. Cooper,, C. Hahn,, J. Gerdes,, I. Orme,, and C. Martin. 1999. NOS2-derived nitric oxide regulates the size, quantity, and quality of granuloma formation in Mycobacterium avium-infected mice without affecting bacterial loads. Immunology 98:313323.
90. Ehlers, S.,, J. Benini,, H.-D. Held,, C. Roeck,, G. Alber,, and S. Uhlig. 2001. αβ T cell receptor-positive cells and interferon-γ, but not inducible nitric oxide synthase, are critical for granuloma necrosis in a mouse model of Mycobacteria-induced pulmonary immunopathology. J. Exp. Med. 194:18471859.
91. Eiserich, J. P.,, M. Hristova,, C. E. Cross,, A. D. Jones,, B. A. Freeman,, B. Halliwell,, and A. van der Vliet. 1998. Formation of nitric oxide-derived inflammatory oxidants by myeloperoxidase in neutrophils. Nature 391:393397.
92. Eiserich, J. P.,, S. Baldus,, M.-L. Brennan,, W. Ma,, C. Zhang,, A. Tousson,, L. Castro,, A. J. Lusis,, W. M. Nauseef,, C. R. White,, and B. A. Freeman. 2002. Myeloperoxidase, a leukocyte-derived vascular NO synthase. Science 296:23912394.
93. Eklund, E. A.,, A. Jalava,, and R. Kakar. 1998. PU.1, interferon regulatory factor 1, and interferon consensus sequence-binding protein cooperate to increase gp91(phox) expression. J. Biol. Chem. 273:1395713965.
94. El-Gayar, S.,, H. Thüring-Nahler,, J. Pfeilschifter,, M. Röllinghoff,, and C. Bogdan. 2003. Translational control of inducible nitric oxide synthase by IL-13 and arginine availability in inflammatory macrophages. J. Immunol. 171:45614568.
95. Endres, R.,, A. Luz,, H. Schulze,, H. Neubauer,, A. Fütterer,, S. M. Holland,, H. Wagner,, and K. Pfeffer. 1997. Listeriosis in p47phox−/− and TRp55−/− mice: protection despite absence of ROI and susceptibility despite presence of RNI. Immunity 7:419432.
96. Espey, M. G.,, S. Xavier,, D. D. Thomas,, K. M. Miranda,, and D. A. Wink. 2002. Direct real-time evaluation of nitration with green fluorescent protein in solution and within human reveals the impact of nitrogen dioxide vs. peroxynitrite mechanisms. Proc. Natl. Acad. Sci. USA 99:34813486.
97. Evans, T. J.,, L. D. K. Buttery,, A. Carpenter,, D. R. Springall,, J. M. Polak,, and J. Cohen. 1996. Cytokine-treated human neutrophils contain inducible nitric oxide synthase that produces nitration of ingested bacteria. Proc. Natl. Acad. Sci. USA 93:95539558.
98. Fang, F. C.,, and A. Vazquez-Torres. 2002. Nitric oxide production by human macrophages: there's NO doubt about it. Am. J. Physiol. Lung Cell. Mol. Physiol. 282:L941L943.
99. Fang, F. C.,, M. DeGroote,, J. Foster,, A. Baumler,, U. Ochsner,, T. Testerman,, S. Bearson,, J. Giard,, Y. Xu,, G. Campbell,, and T. Laessig. 1999. Virulent Salmonella typhimurium has two periplasmic Cu,Znsuperoxide dismutases. Proc. Natl. Acad. Sci. USA 96:75027507.
100. Favre, N.,, B. Ryffel,, and W. Rudin. 1999. The development of murine cerebral malaria does not require nitric oxide production. Parasitology 118:135138.
101. Felley-Bosco, E. 1998. Role of nitric oxide in genotoxicity: implication for carcinogenesis. Cancer Metastasis Rev. 17:2537.
102. Figdor, C. G.,, Y. van Kooyk,, and G. J. Adema. 2002. C-type lectin receptors on dendritic cells and Langerhans cells. Nat. Rev. Immunol. 2:7784.
103. Flodstrom, M.,, M. S. Horwitz,, A. Maday,, D. Balakrishna,, E. Rodriguez,, and N. Sarvetnick. 2001.A critical role for inducible nitric oxide synthase in host survival following coxsackievirus B4 infection. Virology 281:205215.
104. Florquin, S.,, Z. Amraoui,, C. Dubois,, J. Decuyper,, and M. Goldman. 1994.The protective role of endogenously synthesized nitric oxide in staphylococcal enterotoxin B-induced shock in mice. J. Exp. Med. 180:11531158.
105. Flynn, J. L.,, C. A. Scanga,, K. E. Tanaka,, and J. Chan. 1998. Effects of Aminoguanidine on latent murine tuberculosis. J. Immunol. 160:17961803.
106. Forgac, M. 1999. The vacuolar H+-ATPase of clathrin-coated vesicles is reversibly inhibited by Snitrosoglutathione. J. Biol. Chem. 274:13011305.
107. Forman, H. J.,, and M. Torres. 2001. Redox signaling in macrophages. Mol. Aspects Med. 22:189216.
108. Förstermann, U.,, J. P. Boissel,, and H. Kleinert. 1998. Expressional control of the “constitutive” isoforms of nitric oxide synthase (NOSI and NOSIII). FASEB J. 12:773790.
109. Ganley, L.,, S. Babu,, and T.V. Rajan. 2001. Course of Brugia malayi infection in C57BL/6J NOS2+/+ and −/− mice. Exp. Parasitol. 98:3543.
110. Gao, J. J.,, M. B. Filla,, M. J. Fultz,, S. N. Vogel,, S. W. Russell,, and W. J. Murphy. 1998. Autocrine/ paracrine IFN-α/β mediates the lipopolysaccharideinduced activation of transcription factor Stat1α in mouse macrophages: pivotal role of Stat1α in induction of the inducible nitric oxide synthase gene. J. Immunol. 161:48034810.
111. Gao, X.-P.,, T. J. Standiford,, A. Rahman,, M. Newstead,, S. M. Holland,, M. C. Dinauer,, Q.-H. Liu,, and A. B. Malik. 2002. Role of NADPH oxidase in the mechanism of lung neutrophil sequestration and microvessel injury induced by Gram-negative sepsis: studies in p47phox−/− and gp91phox−/− mice. J. Immunol. 168:39743982.
112. Garcia, I.,, R. Guler,, D. Vesin,, M. L. Olleros,, P. Vassalli,, Y. Chvatchko,, M. Jacobs,, and B. Ryffel. 2000. Lethal Mycobacterium bovis Bacillus Calmette Guerin infection in nitric oxide synthase 2-deficient mice: cell-mediated immunity requires nitric oxide synthase 2. Lab. Invest. 80:13851397.
113. Gardner, P. R.,, A. M. Gardner,, L.A. Martin,, and A. L. Salzman. 1998. Nitric oxide dioxygenase: an enzymatic function for flavohemoglobin. Proc. Natl. Acad. Sci. USA 95:1037810383.
114. Gauss, K. A.,, P. L. Bunger,, and M. T. Quinn. 2002. AP-1 is essential for p67phox promotor activity. J. Leukoc. Biol. 71:163172.
115. Geiszt, M.,, J. B. Kopp,, P. Varnai,, and T. L. Leto. 2000. Identification of Renox, an NAD(P)H oxidase in kidney. Proc. Natl. Acad. Sci. USA 97:80108014.
116. Geiszt, M.,, A. Kapus,, and E. Ligeti. 2001. Chronic granulomatous disease: more than the lack of superoxide? J. Leukoc. Biol. 69:191196.
117. Ghosh, S.,, S. Goswami,, and S. Adhya. 2003. Role of superoxide dismutase in survival of Leishmania within the macrophage. Biochem. J. 369:447452.
118. Gobert, A. P.,, S. Daulouede,, M. Lepoivre,, J. L. Boucher,, B. Bouteille,, A. Buguet,, R. Cespuglio,, B. Veyret,, and P. Vincendeau. 2000. L-arginine availability modulates local nitric oxide production and parasite killing in experimental trypanosomiasis. Infect. Immun. 68:46534657.
119. Gobert, A. P.,, D. J. McGee,, M. Akhtar,, G. L. Mendz,, J. C. Newton,, Y. Cheng,, H. L.T. Mobley,, and K. T. Wilson. 2001. Helicobacter pylori arginase inhibits nitric oxide production by eukaryotic cells: a strategy for bacterial survival. Proc. Natl.Acad. Sci. USA 98:1384413849.
120. Gobert, A. P.,, B. D. Mersey,, Y. Cheng,, D. R. Blumberg,, J. C. Newton,, and K.T. Wilson. 2002. Urease release by Helicobacter pylori stimulates macrophage inducible nitric oxide synthase. J. Immunol. 168:60026006.
121. Gomes, M. S.,, M. Florido,, T. F. Pais,, and R. Appelberg. 1999. Improved clearance of Mycobacterium avium upon disruption of the inducible nitric oxide synthase gene. J. Immunol. 162:67346739.
122. Gonzalez, A.,, W. de Gregori,, D. Velez,, A. Restrepo,, and L. E. Cano. 2000. Nitric oxide participation in the fungicidal mechanism of gamma interferon-activated murine macrophages against Paracoccidioides brasiliensis conidia. Infect. Immun. 68:25462552.
123. Gordon, S. 2002. Pattern recognition receptors: doubling up for the innate immune response. Cell 111:927930.
124. Granger, D. L.,, J. B. Hibbs,, J. R. Perfect,, and D. T. Durack. 1988. Specific amino acid (L-arginine) requirement for the microbiostatic activity of murine macrophages. J. Clin. Invest. 81:11291136.
125. Granger, D. L.,, J. B. Hibbs,, J. R. Perfect,, and D. T. Durack. 1990. Metabolic fate of L-arginine in relation to microbiostatic capability of murine macrophages. J. Clin. Invest. 85:264273.
126. Grantt, K. R.,, T. L. Goldman,, M. L. McCormick,, M. A. Miller,, S. M. B. Jeronimo,, E. T. Nascimento,, B. E. Britigan,, and M. E. Wilson. 2001. Oxidative responses of human and murine macrophages during phagocytosis of Leishmania chagasi. J. Immunol. 167:893901.
127. Green, L. C.,, K. R. De Luzuriaga,, D. A. Wagner,, W. Rand,, N. Istfan,, V. R. Young,, and S. R. Tannenbaum. 1981a. Nitrate biosynthesis in man. Proc. Natl. Acad. Sci. USA 78:77647768.
128. Green, L. C.,, S. R. Tannenbaum,, and R. Goldman. 1981b. Nitrate synthesis in the germfree and conventional rat. Science 212:5668.
129. Green, S. P.,, J. A. Hamilton,, D. J. Uhlinger,, and W. A. Philipps. 1994. Expression of p47phox and p67phox proteins in murine bone marrow-derived macrophages: enhancement by lipopolysaccharide and tumor necrosis factor α, but not colony stimulating factor 1. J. Leukoc. Biol. 55:530535.
130. Groemping, Y.,, K. Lapouge,, S. J. Smerdon,, and K. Rittinger. 2003. Molecular basis of phosphorylation- induced activation of the NADPH oxidase. Cell 113:343355.
131. Guidotti, L. G.,, H. McClary,, J. Moorhead Loudis,, and F.V. Chisari. 2000. Nitric oxide inhibits hepatitis B virus replication in the livers of transgenic mice. J. Exp. Med. 191:12471252.
132. Gyurko, R.,, G. Boustany,, P. L. Huang,, A. Kantarci,, T. E. van Dyke,, C. A. Genco,, and F. C. I. Gibson. 2003. Mice lacking inducible nitric oxide synthase demonstrate impaired killing of Porphyromonas gingivalis. Infect. Immun. 71:49174924.
133. Hampton, M. B.,, A. J. Kettle,, and C. C. Winterboum. 1998. Inside the neutrophil phagosome: oxidants, myeloperoxidase and bacterial killing. Blood 92:30073017.
134. Hausladen, A.,, C. T. Privalle,, T. Keng,, J. DeAngelo,, and J. S. Stamler. 1996. Nitrosative stress: activation of the transcription factor oxyR. Cell 86:719729.
135. Hausladen, A.,, A. J. Gow,, and J. S. Stamler. 1998. Nitrosative stress: metabolic pathway involving the flavohemoglobin. Proc. Natl.Acad. Sci. USA 95:1410014105.
136. Hertz, C. J.,, and J. M. Mansfield. 1999. IFN-γ- dependent nitric oxide production is not linked to resistance in experimental African trypanosomiasis. Cell. Immunol. 192:2432.
137. Hevel, J. M.,, K. A. White,, and M. A. Marletta. 1991. Purification of the inducible murine macrophage nitric oxide synthase. Identification as a flavoprotein. J. Biol. Chem. 266:22789.
138. Hibbs, J. B.,, R. R. Taintor,, and Z. Vavrin. 1987a. Macrophage cytotoxicity: role of L-arginine deiminase and imino nitrogen oxidation to nitrite. Science 235:473476.
139. Hibbs, J. B.,, Z. Vavrin,, and R. R. Taintor. 1987b. L-Arginine is required for expression of the activated macrophage effector mechanism causing selective metabolic inhibition in target cells. J. Immunol. 138:550565.
140. Hibbs, J. B.,, R. R. Taintor,, Z. Vavrin,, and E. M. Rachlin. 1988. Nitric oxide: a cytotoxic activated macrophage effector molecule. Biochem. Biophys. Res. Commun. 157:8794.
141. Hickman-Davis, J.,, J. Gibbs-Erwin,, J. R. Lindsey,, and S. Matalon. 1999. Surfactant protein A mediates mycoplasmacidal activity of alveolar macrophages by production of peroxynitrite. Proc. Natl. Acad. Sci. USA 96:49534958.
142. Hickman-Davis, J. M.,, P. O'Reilly,, I. C. Davis,, J. Teti-Peterdi,, G. Davis,, K. R. Young,, R. B. Devlin,, and S. Matalon. 2002. Killing of Klebsiella pneumoniae by human alveolar macrophages. Am. J. Physiol. Lung Cell. Mol. Physiol. 282:L944L956.
143. Hobbs, M. R.,, V. Udhayakumar,, M. C. Levesque,, J. Booth,, J. M. Roberts,, A. N. Tkachuk,, A. Pole,, H. Coon,, S. Kariuki,, B. L. Nahlen,, E. D. Mwaikambo,, A. L. Lai,, D. L. Granger,, N. M. Anstey,, and J. B. Weinberg. 2002. A new NOS2 promotor polymorphism associated with increased nitric oxide production and protection from severe malaria in Tanzanian and Kenyan children. Lancet 360:14681475.
144. Holmes, B.,, A. R. Page,, and R. A. Good. 1967. Studies of the metabolic activity of leukocytes from patients with a genetic abnormality of phagocyte function. J. Clin. Invest. 46:14221432.
145. Hölscher, C.,, G. Köhler,, U. Müller,, H. Mossmann,, G. A. Schaub,, and F. Brombacher. 1998. Defective nitric oxide effector functions lead to extreme susceptibility of Trypanosoma cruzi-infected mice deficient in gamma interferon receptor or inducible nitric oxide synthase. Infect. Immun. 66:12081215.
146. Howe, D.,, L. F. Barrows,, N. M. Lindstrom,, and R. A. Heinzen. 2002. Nitric oxide inhibits Coxiella burnetii replication and parasitophorous vacuole maturation. Infect. Immun. 70:51405147.
147. Huang, H.,, J. Chan,, M. Wittner,, L. A. Jelicks,, S. A. Morris,, S. M. Factor,, L. M. Weiss,, V. L. Braunstein,, C. J. Bacchi,, N. Yarlett,, M. Chandra,, J. Shirani,, and H. B. Tanowitz. 1999. Expression of cardiac cytokines and inducible nitric oxide synthase (NOS2) in Trypanosoma cruzi-infected mice. J. Mol. Cell. Cardiol. 31:7588.
148. Huang, J.,, F. J. DeGraves,, S. D. Lenz,, D. Gao,, P. Feng,, D. Li,, T. Schlapp,, and B. Kaltenboeck. 2002. The quantity of nitric oxide released by macrophages regulates Chlamydia-induced disease. Proc. Natl. Acad. Sci. USA 99:39143919.
149. Igietseme, J. U.,, L. L. Perry,, G. A. Ananaba,, I. M. Uriri,, O. Ojior,, S.N. Kumar,, and H.D. Caldwell. 1998. Chlamydial infection in inducible nitric oxide synthase knockout mice. Infect. Immun. 66:12821286.
150. Iniesta, V.,, L. C. Gomez-Nieto,, and I. Corraliza. 2001. The inhibition of arginase by Nw-hydroxy-Larginine controls the growth of Leishmania inside macrophages. J. Exp. Med. 193:777783.
151. Inohara, N.,, Y. Ogura,, and G. Nunez. 2002. Nods: a family of cytosolic proteins that regulate the host response to pathogens. Curr. Opin. Microbiol. 5:7680.
152. Ischiropoulos, H.,, and J. S. Beckman. 2003. Oxidative stress and nitration in neurodegeneration: cause, effect or association? J. Clin. Invest. 111:163169.
153. Iyer, G.Y. N.,, D. M. F. Islam,, and J. H. Quastel. 1961. Biochemical aspects of phagocytosis. Nature 192:535541.
154. Jackson, S. H.,, J. I. Gallin,, and S. M. Holland. 1995. The p47phox mouse knock-out model of chronic granulomatous disease. J. Exp. Med. 182:751758.
155. Jacobson, E. S.,, and S. B. Tinnell. 1993. Antioxidant function of fungal melanin. J. Bacteriol. 175:71027104.
156. James, S. L.,, and J. Glavin. 1989. Macrophage cytotoxicity against schistosomula of Schistosoma mansoni involves arginine-dependent production of reactive nitrogen intermediates. J. Immunol. 143:42084212.
157. James, S. L.,, A.W. Cheever,, P. Caspar,, and T. A. Wynn. 1998. Inducible nitric oxide synthase-deficient mice develop enhanced type 1 cytokine-associated cellular and humoral immune responses after vaccination with attenuated Schistosoma mansoni cercariae but display partially reduced resistance. Infect. Immun. 66:35103518.
158. Jesaitis, A. J.,, E. S. Buescher,, D. Harrison,, M.T. Quinn,, C. A. Parkos,, S. Livesey,, and J. Linner. 1990. Ultrastructural localization of cytochrome b in the membranes of resting and phagocytosing human granulocytes. J. Clin. Invest. 85:821835.
159. Jin, Y.,, L. Dons,, K. Kristensson,, and M. E. Rottenberg. 2001. Neural route of cerebral Listeria monocytogenes murine infection: role of immune response mechanisms in controlling bacterial neuroinvasion. Infect. Immun. 69:10931100.
160. Ju, J.Y.,, C. Polhamus,, K. A. Marr,, S.M. Holland,, and J. E. Bennett. 2002. Efficacies of fluconazole, caspofungin and amphotericin B in Candida glabratainfected p47phox−/− knockout mice. Antimicrob. Agents Chemother. 46:12401245.
161. Jung, Y.-J.,, R. LaCourse,, L. Ryan,, and R. J. North. 2002.Virulent, but not avirulent Mycobacterium tuberculosis can evade the growth inhibitory action of a T helper 1-dependent, nitric oxide synthase 2-independent defense in mice. J. Exp. Med. 7:991998.
162. Karupiah, G.,, J.-H. Chen,, S. Mahalingam,, C. F. Nathan,, and J. D. MacMicking. 1998a. Rapid interferon γ-dependent clearance of influenza A virus and protection from consolidating pneumonitis in nitric oxide 2-deficient mice. J. Exp. Med. 188:15411546.
163. Karupiah, G.,, J. H. Chen,, C. F. Nathan,, S. Mahalingam,, and J. D. MacMicking. 1998b. Identification of nitric oxide synthase 2 as an innate resistance locus against ectromelia virus infection. J. Virol. 72:77037706.
164. Khan, I. A.,, J. D. Schwartzman,, T. Matsuura,, and L. H. Kasper. 1997. A dichotomous role for nitric oxide during acute Toxoplasma gondii infection in mice. Proc. Natl. Acad. Sci. USA 94:1395513960.
165. Khanolkar-Young, S.,, D. Snowdon,, and D. N. J. Lockwood. 1998. Immunocytochemical localization of inducible nitric oxide synthase and transforming growth factor-β (TGF-β) in leprosy lesions. Clin. Exp. Immunol. 113:438442.
166. Klebanoff, S. J. 1968. Myeloperoxidase-halidehydrogen peroxide antibacterial system. J. Bacteriol. 95:21312138.
167. Klebanoff, S. J. 1970. Myeloperoxidase: contribution to the microbicidal activity of intact leukocytes. Science 169:10951097.
168. Klebanoff, S. J., 1999. Oxygen metabolites from phagocytes, p. 721768. In J. I. Gallin, and R. Snyderman (ed.), Inflammation: Basic Principles and Clinical Correlates. Lippincott Williams & Wilkins, Philadelphia, Pa.
169. Klein, J. A.,, and S. L. Ackerman. 2003. Oxidative stress, cell cycle, and neurodegeneration. J. Clin. Invest. 111:785793.
170. Knaus, U. G.,, P. G. Heyworth,, T. Evans,, J. T. Curnutte,, and G. M. Bokoch. 1991. Regulation of phagocyte oxygen radical production by the GTPbinding protein Rac2. Science 254:15121515.
171. Ko, J.,, A. Gendron-Fitzpatrick,, and G. A. Splitter. 2002. Susceptibility of IFN regulatory factor-1 and IFN consensus sequence binding protein-deficient mice to brucellosis. J. Immunol. 168:24332440.
172. Kobayashi, T.,, J. M. Robinson,, and H. Seguchi. 1998. Identification of intracellular sites of superoxide production in stimulated neutrophils. J. Cell Sci. 111:8191.
173. Kolb, H.,, and V. Kolb-Bachofen. 1998. Nitric oxide in autoimmune disease: cytotoxic or regulatory mediator. Immunol.Today 19:556561.
174. Kröncke, K.-D.,, K. Fehsel,, and V. Kolb- Bachofen. 1998. Inducible nitric oxide synthase in human diseases. Clin. Exp. Immunol. 113:147156.
175. Kröncke, K.-D.,, H. Haase,, D. Beyersmann,, V. Kolb-Bachofen,, and M. K. Hayar-Hartl. 2001. Nitric oxide inhibits the cochaperone activity of the RING finger-like protein DnaJ. Nitric Oxide 5:289295.
176. Kuga, S.,, T. Otsuka,, H. Niiro,, H. Nunoi,, Y. Nemoto,, T. Nakano,, T. Ogo,, T. Umei,, and Y. Niho. 1996. Suppression of superoxide anion production by interleukin-10 is accompanied by a downregulation of the genes for subunit proteins of NADPH oxidase. Exp. Hematol. 24:151157.
177. Kun, J. F. J.,, B. Mordmüller,, B. Lell,, L. G. Lehman,, D. Luckner,, and P. G. Kremsner. 1998. Polymorphism in promotor region of inducible nitric oxide synthase gene and protection against malaria. Lancet 351:265266.
178. Kun, J. F.,, B. Mordmüller,, D. J. Perkins,, J. May,, O. Mercereau-Puijalon,, M. Alpers,, J. B. Weinberg,, and P. G. Kremsner. 2001. Nitric oxide synthase 2Lambarene (G-954C), increased nitric oxide production, and protection against malaria. J. Infect. Dis. 184:330336.
179. Lambeth, J. D. 2002. Nox/Duox family of nicotinamide adenine dinucleotide (phosphate) oxidases. Curr. Opin. Hematol. 9:1117.
180. Lambeth, J. D. 2004.NOX enzymes and the biology of reactive oxygen. Nat. Rev. Immunol. 4:181189.
181. Lancaster, J. R. J. 1997. A tutorial on the diffusibility and reactivity of free nitric oxide. Nitric Oxide 1:1830.
182. Lanza, F. 1998. Clinical manifestations of myeloperoxidase deficiency. J. Mol. Med. 76:676681.
183. Laubach, V. E.,, E. G. Shesely,, O. Smithies,, and P. A. Sherman. 1995. Mice lacking inducible nitric oxide synthase are not resistant to lipopolysaccharideinduced death. Proc. Natl. Acad. Sci. USA 92:1068810692.
184. Lee, J.,, H. Ryu,, R. J. Ferrante,, S. M. Morris,, and R. R. Ratan. 2003.Translational control of inducible nitric oxide synthase expression by arginine can explain the arginine paradox. Proc. Natl.Acad. Sci. USA 100:48434848.
185. Leitch, G. J.,, and Q. He. 1999. Reactive nitrogen and oxygen species ameliorate experimental cryptosporidiosis in the neonatal BALB/c mouse model. Infect. Immun. 67:58855891.
186. Lekstrom-Himes, J. A.,, and J. I. Gallin. 2003. Immunodeficiency diseases caused by defects in phagocytes. N. Engl. J. Med. 343:17031714.
187. Lerner, R. A.,, and A. Eschenmoser. 2003. Ozone in biology. Proc. Natl. Acad. Sci. USA 100:30133015.
188. Levesque, M. C.,, M. R. Hobbs,, N. M. Anstey,, T. N. Vaughn,, J.A. Chancellor,, A. Pole,, D. J. Perkins,, M. A. Misukonis,, S. J. Chanock,, D. L. Granger,, and J. B. Weinberg. 1999. Nitric oxide synthase type 2 promotor polymorphisms, nitric oxide production, and disease severity in Tanzanian children with malaria. J. Infect. Dis. 180:19942002.
189. Li, H.,, T. Wallerath,, and U. Förstermann. 2002a. Physiological mechanisms regulating the expression of endothelial-type NO synthase. Nitric Oxide 7:132147.
190. Li, H.,, T. Wallerath,, T. Münzel,, and U. Förstermann. 2002b. Regulation of endothelial-type NO synthase expression in pathophysiology and in response to drugs. Nitric Oxide 7:149164.
191. Liew, F.Y.,, S. Millott,, C. Parkinson,, R. M. Palmer,, and S. Moncada. 1990. Macrophage killing of Leishmania parasite in vivo is mediated by nitric oxide from L-arginine. J. Immunol. 144:47944797.
192. Locksley, R. M.,, R. M. Wilson,, and S. J. Klebanoff. 1983. Increased respiratory burst in myeloperoxidase-deficient monocytes. Blood 62:902909.
193. Lyons, C. R.,, G. J. Orloff,, and J. M. Cunningham. 1992. Molecular cloning and functional expression of an inducible nitric oxide synthase from a murine macrophage cell-line. J. Biol. Chem. 267:63706374.
194. MacMicking, J. D.,, C. Nathan,, G. Hom,, N. Chartrain,, D. S. Fletcher,, M. Trumbauer,, K. Stevens,, Q.-W. Xie,, K. Sokol,, N. Hutchinson,, H. Chen,, and J. S. Mudgett. 1995.Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell 81:641650.
195. MacMicking, J.,, Q.-W. Xie,, and C. Nathan. 1997a. Nitric oxide and macrophage function. Annu. Rev. Immunol. 15:323350.
196. MacMicking, J. D.,, R. J. North,, R. LaCourse,, J. S. Mudgett,, S. K. Shah,, and C. F. Nathan. 1997b. Identification of nitric oxide synthase as a protective locus against tuberculosis. Proc. Natl. Acad. Sci. USA 94:52435248.
197. Malkin, R.,, E. Flescher,, J. Lengy,, and Y. Keisari. 1987. On the interactions between macrophages and the developmental stages of Schistosoma mansoni: the cytotoxic mechanism involved in macrophage-mediated killing of schistosomula in vitro. Immunobiology 176: 6372.
198. Manca, C.,, S. Paul,, C. E. Barry,, V. H. Freedman,, and G. Kaplan. 1999. Mycobacterium tuberculosis catalase and peroxidase activities and resistance to oxidative killing in human monocytes in vitro. Infect.Immun. 67:7479.
199. Marletta, M. A.,, P. S. Yoon,, R. Iyengar,, C. D. Leaf,, and J. S. Wishnok. 1988. Macrophage oxidation of L-arginine to nitrite and nitrate: nitric oxide is an intermediate. Biochemistry 27:87068711.
200. Marshall, H. E.,, K. Merchant,, and J. S. Stamler. 2000. Nitrosation and oxidation in the regulation of gene expression. FASEB J. 14:18891900.
201. Martins, G. A.,, S. B. Petkova,, F. S. Machado,, R. N. Kitsis,, L. M. Weiss,, M. Wittner,, and H. B. Tanowitz. 2001. Fas-FasL interaction modulates nitric oxide production in Trypanosoma cruzi-infected mice. Immunology 103:122129.
202. Mastroeni, P.,, A. Vazquez-Torres,, F. C. Fang,, Y. Xu,, S. Khan,, C. E. Hormaeche,, and G. Dougan. 2000.Antimicrobial actions of the NADPH phagocyte oxidase and inducible nitric oxide synthase in experi- mental salmonellosis. II. Effects of microbial proliferation and host survival in vivo. J. Exp. Med. 192:237247.
203. Mauël, J. 1996. Intracellular survival of protozoan parasites with special reference to Leishmania spp., Toxoplasma gondii, and Trypanosoma cruzi. Adv. Parasitol. 38:151.
204. Messina, C. G. M.,, E. P. Reeves,, J. Roes,, and A. W. Segal. 2002. Catalase negative Staphylococcus aureus retain virulence in mouse model of chronic granulomatous disease. FEBS Lett. 518:107110.
205. Miles, A. M.,, M. W. Owens,, S. Milligan,, G. G. Johnson,, J. Z. Fields,, T. S. Ing,, V. Kottapalli,, A. Keshavarzian,, and M. B. Grisham. 1995. Nitric oxide synthase in circulating vs. extravasated polymorphonuclear leukocytes. J. Leukoc. Biol. 58:616622.
206. Mitchell, H. H.,, H. A. Shonle,, and H. S. Grindley. 1916. The origin of the nitrates in the urine. J. Biol. Chem. 24:461490.
207. Mizel, S. B.,, A. N. Honko,, M. A. Moors,, P. S. Smith,, and A. P. West. 2003. Induction of macrophage nitric oxide production by Gram-negative flagellin involves signaling via heterodimeric Tolllike receptor 5/Toll-like receptor 4 complexes. J. Immunol. 170:62176223.
208. Mnaimneh, S.,, M. Geffard,, B. Veyret,, and P. Vincendeau. 1997.Albumin nitrosylated by activated macrophages possesses antiparasitic effects neutralized by anti-NO-acetylated-cysteine antibodies. J. Immunol. 158:308314.
209. Modolell, M.,, I. M. Corraliza,, F. Link,, G. Soler,, and K. Eichmann. 1995. Reciprocal regulation of the nitric oxide synthase/arginase balance in mouse bone marrow-derived macrophages by Th1 and Th2 macrophages. Eur. J. Immunol. 25:11011104.
210. Modolell, M.,, K. Eichmann,, and G. Soler. 1997. Oxidation of N(G)-hydroxy-L-arginine to nitric oxide mediated by respiratory burst: an alternative pathway to NO synthesis. FEBS Lett. 401:123126.
211. Morgenstern, D. E.,, M. A. C. Gifford,, L. L. Li,, C. M. Doerschuk,, and M. C. Dinauer. 1997. Absence of respiratory burst in X-linked chronic granulomatous disease mice leads to abnormalities in both host defense and inflammatory response to Aspergillus fumigatus. J. Exp. Med. 185:207218.
212. Mosser, D. M. 2003.The many faces of macrophage activation. J. Leukoc. Biol. 73:209212.
213. Murray, H. W.,, and C. F. Nathan. 1999. Macrophage microbicidal mechanisms in vivo: reactive nitrogen vs. oxygen intermediates in the killing of intracellular visceral Leishmania donovani. J. Exp. Med. 189:741746.
214. Murray, H.W.,, and R. F. Teitelbaum. 1992. L-arginine- dependent reactive nitrogen intermediates and the antimicrobial effect of activated human mononuclear phagocytes. J. Infect. Dis. 165:513517.
215. Nagase, S.,, K. Takemura,, A. Ueda,, A. Hirayama,, K. Aoyagi,, M. Kondoh,, and A. Koyama. 1997.A novel non-enzymatic pathway for the generation of nitric oxide by the reaction of hydrogen peroxide and D- or L-arginine. Biochem. Biophys. Res. Commun. 233:150153.
216. Nagata, K.,, H. Yu,, M. Nishikawa,, M. Kashiba,, A. Nakamura,, E. F. Sato,, T. Tamura,, and M. Inoue. 1998. Helicobacter pylori generates superoxide radicals and modulates nitric oxide metabolism. J. Biol. Chem. 273:1407114073.
217. Nakano, T.,, H. Terato,, K. Asagoshi,, A. Masaoka,, M. Mukuta,, Y. Ohyama,, T. Suzuki,, K. Makino,, and H. Ide. 2003. DNA-protein cross-link formation mediated by oxanine. J. Biol. Chem. 278:2526425272.
218. Nathan, C. 1992. Nitric oxide as a secretory product of mammalian cells. FASEB J. 6:30513064.
219. Nathan, C. 2002. Points of control in inflammation. Nature 420:846852.
220. Nathan, C. 2003. Specificity of a third kind: reactive oxygen and nitrogen intermediates in cell signaling. J. Clin. Invest. 111:769778.
221. Nathan, C.,, and M. U. Shiloh. 2000. Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens. Proc. Natl. Acad. Sci. USA 97:88418848.
222. Nauseef, W. M. 1998. Insights into myeloperoxidase biosynthesis from its inherited deficiency. J. Mol. Med. 76:661668.
223. Nauseef, W. M.,, J. A. Metcalf,, and R. K. Root. 1983. Role of myeloperoxidase in the respiratory burst of human neutrophils. Blood 61:483492.
224. Newburger, P. E.,, R. A. B. Ezekowitz,