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Nitric oxide, nitrotyrosine, and nitric oxide modulators in asthma and chronic obstructive pulmonary disease

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Abstract

Nitric oxide (NO), a simple free-radical gas, elicits a diverse range of physiologic and pathophysiologic effects, and plays an important role in pulmonary diseases. Nitrosative stress and nitration of proteins in airway epithelium may be responsible for steroid resistance in asthma and their ineffectiveness in chronic obstructive pulmonary disease (COPD), supporting the potential role of future therapeutic strategies aimed at regulating NO synthesis in asthma and COPD. In this article, we review the potential role of NO modulators (NO synthase inhibitors and NO donors), which, if given on a regular basis, may have clinical benefit in asthma and COPD.

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References and Recommended Reading

  1. Kharitonov SA, Barnes PJ: Exhaled markers of pulmonary disease. Am J Respir Crit Care Med 2001, 163:1693–1722. Review on exhaled markers in several major lung diseases.

    PubMed  CAS  Google Scholar 

  2. Saleh D, Ernst P, Lim S, et al.: Increased formation of the potent oxidant peroxynitrite in the airways of asthmatic patients is associated with induction of nitric oxide synthase: effect of inhaled glucocorticoid. FASEB J 1998, 12:929–937.

    PubMed  CAS  Google Scholar 

  3. Kharitonov SA, Donnelly LE, Montuschi P, et al.: Dose-dependent onset and cessation of action of inhaled budesonide on exhaled nitric oxide and symptoms in mild asthma. Thorax 2002, 57:889–896.

    Article  PubMed  CAS  Google Scholar 

  4. Jatakanon A, Uasuf CG, Maziak W, et al.: Neutrophilic inflammation in severe persistent asthma. Am J Respir Crit Care Med 1999, 160:1532–1539.

    PubMed  CAS  Google Scholar 

  5. Barnes PJ: New treatments for COPD. Nat Rev Drug Discov 2002, 1:437–446.

    Article  PubMed  CAS  Google Scholar 

  6. Pauwels R: Inhaled glucocorticosteroids and chronic obstructive pulmonary disease: How full is the glass? Am J Respir Crit Care Med 2002, 165:1579–1580.

    Article  PubMed  Google Scholar 

  7. Kharitonov SA, Yates DH, Robbins RA, et al.: Increased nitric oxide in exhaled air of asthmatic patients. Lancet 1994, 343:133–135.

    Article  PubMed  CAS  Google Scholar 

  8. Kharitonov SA, Robbins RA, Yates DH, et al.: Acute and chronic effects of cigarette smoking on exhaled nitric oxide. Am J Respir Crit Care Med 1995, 152:609–612.

    PubMed  CAS  Google Scholar 

  9. Ichinose M, Sugiura H, Yamagata S, et al.: Increase in reactive nitrogen species production in chronic obstructive pulmonary disease airways. Am J Respir Crit Care Med 2000, 162:701–706.

    PubMed  CAS  Google Scholar 

  10. Hutchison SJ, Sievers RE, Zhu BQ, et al.: Secondhand tobacco smoke impairs rabbit pulmonary artery endothelium-dependent relaxation. Chest 2001, 120:2004–2012.

    Article  PubMed  CAS  Google Scholar 

  11. Paska C, Maestrelli P, Formichi B, et al.: Increased expression of inducible NOS in peripheral lung of severe COPD patients. Eur Respir J 2002, 20:95S.

    Google Scholar 

  12. Maziak W, Loukides S, Culpitt SV, et al.: Exhaled nitric oxide in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998, 157(3 Pt 1):998–1002.

    PubMed  CAS  Google Scholar 

  13. Brindicci C, Cosio B, Gajdocsi R, et al.: Extended exhaled NO measurements at different exhalation flows may differentiate between bronchial and alveolar inflammation in patients with asthma and COPD. Eur Respir J 2002, 20:174S.

    Google Scholar 

  14. Kamisaki Y, Wada K, Bian K, et al.: An activity in rat tissues that modifies nitrotyrosine-containing proteins. Proc Natl Acad Sci U S A 1998, 95:11584–11589.

    Article  PubMed  CAS  Google Scholar 

  15. Bartberger MD, Liu W, Ford E, et al.: The reduction potential of nitric oxide (NO) and its importance to NO biochemistry. Proc Natl Acad Sci U S A 2002, 99:10958–10963.

    Article  PubMed  CAS  Google Scholar 

  16. Hanazawa T, Kharitonov SA, Barnes PJ: Increased nitrotyrosine in exhaled breath condensate of patients with asthma. Am J Respir Crit Care Med 2000, 162(4 Pt 1):1273–1276.

    PubMed  CAS  Google Scholar 

  17. Gunther MR, Sturgeon BE, Mason RP: Nitric oxide trapping of the tyrosyl radical-chemistry and biochemistry. Toxicol 2002, 177:1–9.

    Article  CAS  Google Scholar 

  18. Kuo WN, Kocis JM: Nitration/S-nitrosation of proteins by peroxynitrite-treatment and subsequent modification by glutathione S-transferase and glutathione peroxidase. Mol Cell Biochem 2002, 233:57–63.

    Article  PubMed  CAS  Google Scholar 

  19. Aulak KS, Miyagi M, Yan L, et al.: Proteomic method identifies proteins nitrated in vivo during inflammatory challenge. Proc Natl Acad Sci U S A 2001, 98:12056–12061. Nitration can cause protein dysfunction and is implicated in pathogenesis, but few proteins that appear nitrated in vivo have been identified. To understand how this modification impacts physiology and disease, we used a proteomic approach toward targets of protein nitration in both in vivo and cell culture inflammatory disease models.

    Article  PubMed  CAS  Google Scholar 

  20. Brown GC, Borutaite V: Nitric oxide, mitochondria, and cell death. IUBMB Life 2001, 52:189–195.

    Article  PubMed  CAS  Google Scholar 

  21. Bucchieri F, Puddicombe SM, Lordan JL, et al.: Asthmatic bronchial epithelium is more susceptible to oxidant-induced apoptosis. Am J Respir Cell Mol Biol 2002, 27:179–185.

    PubMed  CAS  Google Scholar 

  22. Tomita K, Caramori G, Lim S, et al.: Increased p21(CIP1/ WAF1) and B cell lymphoma leukemia-x(L) expression and reduced apoptosis in alveolar macrophages from smokers. Am J Respir Crit Care Med 2002, 166:724–731.

    Article  PubMed  Google Scholar 

  23. Harju T, Kaarteenaho-Wiik R, Soini Y, et al.: Diminished immunoreactivity of gamma-glutamylcysteine synthetase in the airways of smokers’ lung. Am J Respir Crit Care Med 2002, 166:754–759.

    Article  PubMed  Google Scholar 

  24. Yang S, Milla C, Panoskaltsis-Mortari A, et al.: Human surfactant protein A suppresses T cell-dependent inflammation and attenuates the manifestations of idiopathic pneumonia syndrome in mice. Am J Respir Cell Mol Biol 2001, 24:527–536.

    PubMed  CAS  Google Scholar 

  25. Souza JM, Choi I, Chen Q, et al.: Proteolytic degradation of tyrosine nitrated proteins. Arch Biochem Biophys 2000, 380:360–366. The steady-state levels of tyrosine hydroxylase were restored by selective inhibition of the proteasome activity with lactacystin. These data indicate that nitration of tyrosine residue in proteins is sufficient to induce an accelerated degradation of the modified proteins by the proteasome and that the proteasome may be critical for the removal of nitrated proteins in vivo.

    Article  PubMed  CAS  Google Scholar 

  26. Davis KL, Martin E, Turko IV, Murad F: Novel effects of nitric oxide. Annu Rev Pharmacol Toxicol 2001, 41:203–236.

    Article  PubMed  CAS  Google Scholar 

  27. Eiserich JP, Baldus S, Brennan ML, et al.: Myeloperoxidase, a leukocyte-derived vascular NO oxidase. Science 2002, 296:2391–2394.

    Article  PubMed  CAS  Google Scholar 

  28. Hanazawa T, Kharitonov SA, Barnes PJ: Increased nitrotyrosine in exhaled breath condensate of patients with asthma. Am J Respir Crit Care Med 2000, 162:1273–1276.

    PubMed  CAS  Google Scholar 

  29. Cooke CL, Davidge ST: Peroxynitrite increases iNOS through NF-kappaB and decreases prostacyclin synthase in endothelial cells. Am J Physiol Cell Physiol 2002, 282:C395-C402.

    PubMed  CAS  Google Scholar 

  30. Ashutosh K, Phadke K, Jackson JF, Steele D: Use of nitric oxide inhalation in chronic obstructive pulmonary disease. Thorax 2000, 55:109–113.

    Article  PubMed  CAS  Google Scholar 

  31. Guo X, Lin HM, Lin Z, et al.: Surfactant protein gene A, B, and D marker alleles in chronic obstructive pulmonary disease of a Mexican population. Eur Respir J 2001, 18:482–490.

    Article  PubMed  CAS  Google Scholar 

  32. Lawler JM, Song W: Specificity of antioxidant enzyme inhibition in skeletal muscle to reactive nitrogen species donors. Biochem Biophys Res Commun 2002, 294:1093–1100.

    Article  PubMed  CAS  Google Scholar 

  33. Gow AJ, Chen Q, Hess DT, et al.: Basal and stimulated protein S-nitrosylation in multiple cell types and tissues. J Biol Chem 2002, 277:9637–9640.

    Article  PubMed  CAS  Google Scholar 

  34. Glare EM, Divjak M, Bailey MJ, Walters EH: b-Actin and GAPDH housekeeping gene expression in asthmatic airways is variable and not suitable for normalising mRNA levels. Thorax 2002, 57:765–770.

    Article  PubMed  CAS  Google Scholar 

  35. Kasahara Y, Tuder RM, Taraseviciene-Stewart L, et al.: Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. J Clin Invest 2000, 106:1311–1319.

    PubMed  CAS  Google Scholar 

  36. Gaston B, Sears S, Woods J, et al.: Bronchodilator S-nitrosothiol deficiency in asthmatic respiratory failure. Lancet 1998, 351:1317–1319.

    Article  PubMed  CAS  Google Scholar 

  37. Haqqani AS, Kelly JF, Birnboim HC: Selective nitration of histone tyrosine residues in vivo in mutatect tumors. J Biol Chem 2002, 277:3614–3621.

    Article  PubMed  CAS  Google Scholar 

  38. Ito K, Adcock IM: Histone acetylation and histone deacetylation. Mol Biotechnol 2002, 20:99–106.

    Article  PubMed  CAS  Google Scholar 

  39. Ito K, Caramori G, Lim S, et al.: Expression and activity of histone deacetylases in human asthmatic airways. Am J Respir Crit Care Med 2002, 166:392–396. The increase in HAT activity and reduced HDAC activity in asthma may underlie the increased expression of multiple inflammatory genes. This is reversed, at least in part, by treatment with inhaled steroids.

    Article  PubMed  Google Scholar 

  40. Sapienza MA, Kharitonov SA, Horvath I, et al.: Effect of inhaled l-arginine on exhaled nitric oxide in normal and asthmatic subjects. Thorax 1998, 53:172–175.

    Article  PubMed  CAS  Google Scholar 

  41. Loukides S, Kharitonov SA, Wodehouse T, et al.: Effect of l-arginine on mucociliary function in primary ciliary dyskinesia. Lancet 1998, 352:371–372.

    Article  PubMed  CAS  Google Scholar 

  42. Shahid SK, Kharitonov SA, Wilson NM, et al.: Increased interleukin-4 and decreased interferon-gamma in exhaled breath condensate of children with asthma. Am J Respir Crit Care Med 2002, 165:1290–1293.

    Article  PubMed  Google Scholar 

  43. Corne JM, Marshall C, Smith S, et al.: Frequency, severity, and duration of rhinovirus infections in asthmatic and nonasthmatic individuals: a longitudinal cohort study. Lancet 2002, 359:831–834.

    Article  PubMed  Google Scholar 

  44. Kharitonov SA, Yates DH, Barnes PJ: Increased nitric oxide in exhaled air of normal human subjects with upper respiratory infections. Eur Respir J 1995, 8:295–297.

    Article  PubMed  CAS  Google Scholar 

  45. Wang PG, Xian M, Tang X, et al.: Nitric oxide donors, chemical activities and biological applications. Chem Rev 2002, 102:1091–1134.

    Article  PubMed  CAS  Google Scholar 

  46. Hattori R, Otani H, Maulik N, Das DK: Pharmacological preconditioning with resveratrol: role of nitric oxide. Am J Physiol Heart Circ Physiol 2002, 282:H1988-H1995.

    PubMed  CAS  Google Scholar 

  47. Michelakis E, Tymchak W, Lien D, et al.: Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide. Circulation 2002, 105:2398–2403.

    Article  PubMed  CAS  Google Scholar 

  48. Moya MP, Gow AJ, Califf RM, et al.: Inhaled ethyl nitrite gas for persistent pulmonary hypertension of the newborn. Lancet 2002, 360:141–143.

    Article  PubMed  CAS  Google Scholar 

  49. Richardson G, Benjamin N: Potential therapeutic uses for Snitrosothiols. Clin Sci (Lond) 2002, 102:99–105.

    Article  CAS  Google Scholar 

  50. Ewing JF, Young DV, Janero DR, et al.: Nitrosylated bovine serum albumin derivatives as pharmacologically active nitric oxide congeners. J Pharmacol Exp Ther 1997, 283:947–954.

    PubMed  CAS  Google Scholar 

  51. Xian M, Fujiwara N, Wen Z, et al.: Novel substrates for nitric oxide synthases. Bioorg Med Chem 2002, 10:3049–3055. This work demonstrates that N-alkyl-substituted hydroxyguanidine compounds are novel NOS substrates that ’short-circuit’ the first oxidation step of NOS, and N-aryl-substituted hydroxyguanidine compounds are isoform-selective NOS substrate.

    Article  PubMed  CAS  Google Scholar 

  52. Kharitonov SA, Lubec G, Lubec B, et al.: l-arginine increases exhaled nitric oxide in normal human subjects. Clin Sci 1995, 88:135–139.

    PubMed  CAS  Google Scholar 

  53. Janero DR, Ewing JF: Nitric oxide and postangioplasty restenosis: pathological correlates and therapeutic potential. Free Radic Biol Med 2000, 29:1199–1221.

    Article  PubMed  CAS  Google Scholar 

  54. Lass A, Suessenbacher A, Wolkart G, et al.: Functional and analytical evidence for scavenging of oxygen radicals by l-arginine. Mol Pharmacol 2002, 61:1081–1088.

    Article  PubMed  CAS  Google Scholar 

  55. Wallner S, Hermetter A, Mayer B, Wascher TC: The alphaamino group of l-arginine mediates its antioxidant effect. Eur J Clin Invest 2001, 31:98–102.

    Article  PubMed  CAS  Google Scholar 

  56. Yates DH, Kharitonov SA, Robbins RA, et al.: Effect of a nitric oxide synthase inhibitor and a glucocorticosteroid on exhaled nitric oxide. Am J Respir Crit Care Med 1995, 152:892–896.

    PubMed  CAS  Google Scholar 

  57. Taylor DA, McGrath JL, O’Connor BJ, Barnes PJ: Allergeninduced early and late asthmatic responses are not affected by inhibition of endogenous nitric oxide. Am J Respir Crit Care Med 1998, 158:99–106.

    PubMed  CAS  Google Scholar 

  58. Yates DH, Kharitonov SA, Thomas PS, Barnes PJ: Endogenous nitric oxide is decreased in asthmatic patients by an inhibitor of inducible nitric oxide synthase. Am J Respir Crit Care Med 1996, 154:247–250.

    PubMed  CAS  Google Scholar 

  59. Kawanaka Y, Kobayashi K, Kusuda S, et al.: Design and synthesis of orally bioavailable inhibitors of inducible nitric oxide synthase. Part 1: synthesis and biological evaluation of dihydropyridin-2-imines. Bioorg Med Chem Lett 2002, 12:2291.

    Article  PubMed  CAS  Google Scholar 

  60. Erin EM, Hansel T, Kharitonov SA, et al.: A selective inhibitor of iNOS inhibits exhaled breath NO in asthma [abstract]. Am J Respir Crit Care Med 2002, 165:187.

    Google Scholar 

  61. Adachi T, Matsui R, Xu S, et al.: Antioxidant improves smooth muscle sarco/endoplasmic reticulum Ca(2+)-ATPase function and lowers tyrosine nitration in hypercholesterolemia and improves nitric oxide-induced relaxation. Circ Res 2002, 90:1114–1121.

    Article  PubMed  CAS  Google Scholar 

  62. Kharitonov SA, Barnes PJ: Clinical aspects of exhaled nitric oxide. Eur Respir J 2000, 16:781–792.

    Article  PubMed  CAS  Google Scholar 

  63. Garey KW, Neuhauser MM, Rafice AL, et al.: Protein, nitrite/ nitrate, and cytokine concentration in exhaled breath condensate of young smokers [abstract]. Am J Respir Crit Care Med 2000, 161:175.

    Google Scholar 

  64. Griese M, Noss J, Bredow CC: Protein pattern of exhaled breath condensate and saliva. Proteomics 2002, 2:690–696.

    Article  PubMed  CAS  Google Scholar 

  65. Balint B, Kharitonov SA, Hanazawa T, et al.: Increase nitrotyrosine in exhaled breath condensate in cystic fibrosis. Eur Respir J 2001, 17:1201–1207.

    Article  PubMed  CAS  Google Scholar 

  66. Hanazawa T, Antuni JD, Kharitonov SA, Barnes PJ: Intranasal administration of eotaxin increases nasal eosinophils and nitric oxide in patients with allergic rhinitis. J Allergy Clin Immunol 2000, 105(1 Pt 1):58–64.

    Article  PubMed  CAS  Google Scholar 

  67. Gaut JP, Byun J, Tran HD, Heinecke JW: Artifact-free quantification of free 3-chlorotyrosine, 3-bromotyrosine, and 3-nitrotyrosine in human plasma by electron capture-negative chemical ionization gas chromatography mass spectrometry and liquid chromatography-electrospray ionization tandem mass spectrometry. Anal Biochem 2002, 300:252–259.

    Article  PubMed  CAS  Google Scholar 

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Kharitonov, S.A., Barnes, P.J. Nitric oxide, nitrotyrosine, and nitric oxide modulators in asthma and chronic obstructive pulmonary disease. Curr Allergy Asthma Rep 3, 121–129 (2003). https://doi.org/10.1007/s11882-003-0024-7

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