Genetics of the nitric oxide synthetic pathway in asthma

  • Hartmut Grasemann
  • Jeffrey M. Drazen
Part of the Progress in Inflammation Research book series (PIR)


Nitric oxide (NO) is an endogenously formed biological mediator that has been shown to be involved in multiple biological processes including neurotransmission, vascular relaxation, micro-vascular permeability, host defense, and modulation of immune function [1-4]. NO is endogenously produced by a family of enzymes known as NO synthases (NOSs). Three distinct isoforms of NOS exist, each of which is encoded by a different gene localized in specific chromosomal regions in the human genome, which are 12q24.2 for neuronal NOS or NOS1 [5], 17gcen-q12 for inducible NOS or NOS2 [6], and 7q35-36 for endothelial NOS or NOS3 [7]. Each type of NOS has the capacity to catalyze the 5-electron oxidation of the semi-essential amino acid L-arginine to form L-citrulline and NO.


Nitric Oxide Trinucleotide Repeat Asthma Susceptibility Locus 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Moncada S, Higgs A (1993) The L-arginine-nitric oxide pathway. N Engl J Med 329: 2002–2012PubMedCrossRefGoogle Scholar
  2. 2.
    Barnes PJ, Belvisi MG (1993) Nitric oxide and lung disease. Thorax 48: 1034–1043PubMedCrossRefGoogle Scholar
  3. 3.
    Michel T, Feron O (1997) Nitric oxide synthases: which, where, how, and why? J Clin Invest 100: 2146–2152PubMedCrossRefGoogle Scholar
  4. 4.
    Nathan C (1997) Inducible nitric oxide synthase: what difference does it make? J Clin Invest 100: 2417–2423PubMedCrossRefGoogle Scholar
  5. 5.
    Xu W, Gorman P, Sheer D, Bates G, Kishimoto J, Lizhi L, Emson P (1993) Regional localization of the gene coding for human brain nitric oxide synthase (NOS1) to chromosome 12g24.2–24.31by fluorescent in situ hybridization. Cytogenet Cell Genet 64: 62–63PubMedCrossRefGoogle Scholar
  6. 6.
    Chartrain NA, Geller DA, Koty PP, Sitrin NF, Nussler AK, Hoffmann EP, Billiar TR, Hutchinson NI, Mudgett JS (1994) Molecular cloning, structure, and chromosomal localization of the human inducible nitric oxide synthase gene. J Biol Chem 269: 6765–6772PubMedGoogle Scholar
  7. 7.
    Marsden PA, Heng HHQ, Scherer SW, Stewart RJ, Hall AV, Shi XM, Tsui LC, Schap-pert KT (1993) Structure and chromosomal localization of the human constitutive endothelial nitric oxide synthase gene. J Biol Chem 268: 17478–17488PubMedGoogle Scholar
  8. 8.
    Asano K, Chee CB, Gaston B, Lilly CM, Gerard G, Drazen JM, Stamler JS (1994) Constitutive and inducible nitric oxide synthase gene expression, regulation, and activity in human lung epithelial cells. Proc Natl Acad Sci USA 91: 10089–10093PubMedCrossRefGoogle Scholar
  9. 9.
    Robbins RA, Barnes PJ, Springall DR, Warren JB, Kwon OJ, Buttery LD, Wilson AJ, Geller DA, Polak JM (1994) Expression of inducible nitric oxide in human lung epithelial cells. Biochem Biophys Res Commun 203: 209–218PubMedCrossRefGoogle Scholar
  10. 10.
    Gutierrez HH, Pitt BR, Schwarz M, Watkins SC, Lowenstein C, Caniggia I, Chumley P, Freeman BA (1995) Pulmonary alveolar epithelial inducible NO synthase gene expression: regulation by inflammatory mediators. Am J Physiol 268: L501–508PubMedGoogle Scholar
  11. 11.
    Xie QW, Kashiwabara Y, Nathan C (1994) Role of transcription factor NF-kappa B/Rel in induction of nitric oxide synthase. J Biol Chem 269: 4705–4708PubMedGoogle Scholar
  12. 12.
    Nishida K, Harrison DG, Navas JP, Fisher AA, Dockery SP, Uematsu M, Nerem RM, Alexander RW, Murphy TJ (1992) Molecular cloning and characterization of the constitutive bovine aortic endothelial cell nitric oxide synthase. J Clin Invest 90: 2092–2096PubMedCrossRefGoogle Scholar
  13. 13.
    Awolesi MA, Widmann MD, Sessa WC, Sumpio BE (1994) Cyclic strain increases endothelial nitric oxide synthase activity. Surgery 116: 439–444PubMedGoogle Scholar
  14. 14.
    Sharma HS, Westman J, Alm P, Sjoquist PO, Cervos-Navarro, Nyberg F (1997) Involvement of nitric oxide in the pathophysiology of acute heat stress in the rat. Influence of a new antioxidant compound H-290/51. Ann NY Acad Sci 813: 581–590PubMedCrossRefGoogle Scholar
  15. 15.
    Reiser PJ, Kline WO, Vaghy PL (1997) Induction of neuronal type nitric oxide synthase in skeletal muscle by chronic electrical stimulation in vivo. J Appl Physiol 82: 1250–1255Google Scholar
  16. 16.
    Shaul PW, North AJ, Brannon TS, Ujiie K, Wells LB, Nisen PA, Lowenstein CJ, Snyder SH, Star RA (1995) Prolonged in vivo hypoxia enhances nitric oxide synthase type I and type III gene expression in adult rat lung. Am J Respir Cell Mol Biol 13: 167–174PubMedCrossRefGoogle Scholar
  17. 17.
    Prabhakar NR, Rao S, Premkumar D, Pieramici SF, Kumar GK, Kalaria RK (1996) Regulation of neuronal nitric oxide synthase gene expression by hypoxia. Role of nitric oxide in respiratory adaptation to low pO2. Adv Exp Med Biol 410: 345–348PubMedCrossRefGoogle Scholar
  18. 18.
    Calza L, Giardino L, Pozza M, Micera A, Aloe L (1997) Time-course changes of nerve growth factor, corticotropin-releasing hormone, and nitric oxide synthase isoforms and their possible role in the development of inflammatory response in experimental allergic encephalomyelitis. Proc Natl Acad Sci USA 94: 3368–3373PubMedCrossRefGoogle Scholar
  19. 19.
    Wang Y, Newton DC, Robb GB, Kau CL, Miller TL, Cheung AH, Hall AV, VanDamme S, Wilcox JN, Marsden PA (1999) RNA diversity has profound effects on the translation of neuronal nitric oxide synthase. Proc Natl Acad Sci USA 96: 12150–12155PubMedCrossRefGoogle Scholar
  20. 20.
    Togashi H, Sasaki M, Frohman E, Taira E, Ratan RR, Dawson TM, Dawson VL (1997) Neuronal (type I) nitric oxide synthase regulates nuclear factor kappaB activity and immunologic (type II) nitric oxide synthase expression. Proc Natl Acad Sci USA 94: 2676–2680PubMedCrossRefGoogle Scholar
  21. 21.
    Bandyopadhyay A, Chakder S, Rattan S (1997) Regulation of inducible and neuronal nitric oxide synthase gene expression by interferon-gamma and VIP. Am J Physiol 272: C1790–1797PubMedGoogle Scholar
  22. 22.
    Gaston B, Drazen JM, Loscalzo J, Stamler JS (1994) The biology of nitrogen oxides in the airways. Am J Respir Crit Care Med 149: 538–551PubMedCrossRefGoogle Scholar
  23. 23.
    Persson MG, Zetterstrom O, Agrenius V, Ihre E, Gustafsson LE (1994) Single-breath nitric oxide measurements in asthmatic patients and smokers. Lancet 343: 146–147PubMedCrossRefGoogle Scholar
  24. 24.
    Kharitonov SA, Yates D, Robbins RA, Logan-Sinclair R, Shinebourne EA, Barnes PJ (1994) Increased nitric oxide in exhaled air of asthmatic patients. Lancet 343: 133–135PubMedCrossRefGoogle Scholar
  25. 25.
    Massaro AF, Gaston B, Kita D, Fanta C, Stamler JS, Drazen JM (1995) Expired nitric oxide levels during treatment of acute asthma. Am J Respir Crit Care Med 152: 800–803PubMedCrossRefGoogle Scholar
  26. 26.
    Hamid Q, Springall DR, Riveros-Moreno V, Chanez P, Howarth P, Redington A, Bousquet J, Godard P, Holgate S, Polak JM (1993) Induction of nitric oxide synthase in asthma. Lancet 342: 1510–1513PubMedCrossRefGoogle Scholar
  27. 27.
    Bisgaard H, Loland L, Oj JA (1999) NO in exhaled air of asthmatic children is reduced by the leukotriene receptor antagonist montelukast. Am J Respir Crit Care Med 160: 1227–1231CrossRefGoogle Scholar
  28. 28.
    Xiong Y, Karupiah G, Hogan SP, Foster PS, Ramsay AJ (1999) Inhibition of allergic airway inflammation in mice lacking nitric oxide synthase 2. J Immunol 162: 445–452PubMedGoogle Scholar
  29. 29.
    De Sanctis GT, MacLean JA, Hamada K, Mehta S, Scott J, Jiao A, Yandava CN, Kobzic L, Wolyniec WW, Fabian A et al (1999) Contribution of nitric oxide synthases 1, 2, and 3 to airway hyperresponsiveness and inflammation in a murine model of asthma. J Exp Med 189: 1621–1630PubMedCrossRefGoogle Scholar
  30. 30.
    De Sanctis GT, Mehta S, Kobzik L, Yandava C, Jiao A, Huang PL, Drazen JM (1997) Contribution of type I NOS to expired gas NO and bronchial responsiveness in mice. Am J Physiol 273: L883–L888PubMedGoogle Scholar
  31. 31.
    Barnes KC, Neely JD, Duffy DL, Freidhoff LR, Breazeale DR, Schou C, Naidu RP, Levett PN, Renault B, Kucherlapati R et al (1996) Linkage of asthma and serum IgE concentration to markers on chromosome 12q: evidence from Afro-Caribbean and Caucasian populations. Genomics 37: 41–50PubMedCrossRefGoogle Scholar
  32. 32.
    The Collaborative Study on the Genetics of Asthma (CSGA) (1997) A genome-wide search for asthma susceptibility loci in ethnically diverse populations. Nat Genet 15: 389–392CrossRefGoogle Scholar
  33. 33.
    Thomas NS, Wilkinson J, Holgate ST (1997) The candidate gene approach to the genetics of asthma and allergy. Am J Respir Crit Care Med 156: S144–S151PubMedCrossRefGoogle Scholar
  34. 34.
    Ober C, Cox NJ, Abney M, Di Rienzo A, Lander ES, Changyaleket B, Gidley H, Kurtz B, Lee J, Nance M et al and The Collaborative Study on the Genetics of Asthma (1998) Genome-wide search for asthma susceptibility loci in a founder population. Hum Mol Genet 7: 1393–1398PubMedCrossRefGoogle Scholar
  35. 35.
    Nickel R, Wahn U, Hizawa N, Maestri N, Duffy DL, Barnes KC, Beyer K, Forster J, Bergmann R, Zepp F et al (1997) Evidence for linkage of chromosome 12q15-q24.1 markers to high total serum IgE concentrations in children of the German multicenter allergy study. Genomics 46: 159–162PubMedCrossRefGoogle Scholar
  36. 36.
    Barnes KC, Freidhoff LR, Nickel R, Chiu YF, Juo SH, Hizawa N, Naidu RP, Ehrlich E, Duffy DL, Schou C et al (1999) Dense mapping of chromosome 12q13.12-q23.3 and linkage to asthma and allergy. J Allergy Clin Immunol 104: 485–491PubMedCrossRefGoogle Scholar
  37. 37.
    Hall AV, Antoniou H, Wang Y, Cheung AH, Arbus AM, Olson SL, Lu WC, Kau CL, Marsden PA (1994) Structural organization of the human neuronal nitric oxide synthase gene (NOS1). J Biol Chem 269: 33082–33090PubMedGoogle Scholar
  38. 38.
    Grasemann H, Yandava CN, Drazen JM (1999) Neuronal NO synthase (NOS1) is a major candidate gene for asthma. Clin Exp Allergy 29 (Suppl 4): 39–41PubMedGoogle Scholar
  39. 39.
    Grasemann H, Yandava CN, Storm van’s Gravesande K, Deykin A, Pillari A, Ma J, Sonna LA, Lilly C, Stampfer MJ, Israel E et al (2000) A neuronal NO synthase (NOS1) gene polymorphism is associated with asthma. Biochem Biophys Res Commun 272: 391–394PubMedCrossRefGoogle Scholar
  40. 40.
    Gao PS, Kawada H, Kasamatsu T, Mao XQ, Roberts MH, Miyamoto Y, Yoshimura M, Saitoh Y, Yasue H, Nakao K et al (2000) Variants of NOS1, NOS2, and NOS3 genes in asthmatics. Biochem Biophys Res Commun 267: 361–363CrossRefGoogle Scholar
  41. 41.
    Wechsler ME, Grasemann H, Deykin A, Silverman EK, Yandava CN, Israel E, Wand M, Drazen JM (2000) Exhaled nitric oxide in patients with asthma: association with NOS1 genotype. Am J Respir Crit Care Med 162: 2172–2176CrossRefGoogle Scholar
  42. 42.
    Timchenko LT, Caskey CT (1996) Trinucleotide repeat disorders in humans: discussions of mechanisms and medical issues. FASEB J 10: 1589–1597PubMedGoogle Scholar
  43. 43.
    Martin JB (1999) Molecular pathobiology of neurodegenerative diseases. N Engl J Med 340: 1970–1980PubMedCrossRefGoogle Scholar
  44. 44.
    Pearson CE, Sinden RR (1998) Trinucleotide repeat DNA structures: dynamic mutations from dynamic DNA. Curr Opin Struct Biol 8: 321–330PubMedCrossRefGoogle Scholar
  45. 45.
    Belvisi MG, Ward JK, Mitchell JA, Barnes PJ (1995) Nitric oxide as a neurotransmitter in human airways. Arch Int Pharmacodyn 329: 97–110PubMedGoogle Scholar

Copyright information

© Springer Basel AG 2002

Authors and Affiliations

  • Hartmut Grasemann
    • 1
  • Jeffrey M. Drazen
    • 2
  1. 1.Children’s HospitalUniversity of EssenEssenGermany
  2. 2.Division of Pulmonary and Critical Care MedicineBrigham and Women’s HospitalBostonUSA

Personalised recommendations