Die Genetik der neuronalen NO-Synthase (NOS1) in der Ätiologie des Asthma bronchiale

Zusammenfassung:

Das reaktive Sauerstoffradikal Stickstoffmonoxid (NO) wird von Enzymen gebildet, die NO-Synthasen (NOS) genannt werden. NO ist in den Atemwegen an einer Vielzahl pathophysiologischer Prozessen beteiligt, wie z. B. bei Entzündungen der Atemwege, bei allergischen Krankheiten und dem Asthma bronchiale. Beim Asthma handelt es sich um eine multifaktorielle Erkrankung, die Umwelteinflüssen unterliegt, aber auch genetische Ursachen hat. In so genannten Kopplungsstudien, mit familiärer DNA, konnte eine genetische Verbindung der chromosomalen Region 12q mit allergischen Krankheiten, erhöhtem Serum IgE und der Entstehung von Asthma gezeigt werden. Das Gen, das für die neuronale NOS (NOS1) kodiert, ist ein attraktives Kandidaten-Gen für das Asthma; nicht nur weil es in der chromosomalen Region 12q24 lokalisiert ist, sondern auch weil experimentelle Studien an Tieren und Menschen lassen vermuten, dass NOS1 beim Asthma eine wichtige Rolle spielt. In einem Tiermodell für allergisches Asthma, zum Beispiel, konnte gezeigt werden, dass NOS1 es für die Entwicklung einer bronchialen Hyperreagibilität wichtig ist, da nos1-defiziente Mäuse eine geringere Empfindlichkeit gegenüber der Bronchoprovokation besaßen, als Wildtyp und nos2-defiziente Mäuse. Bei Menschen wurden in Fall-Kontroll Studien allelische Assoziationen zwischen polymorphen Markern im NOS1 Gen und der Asthmadiagnose beschrieben. Zudem besteht eine enge Korrelation zwischen den bei Asthmatikern erhöhten NO-Konzentrationen in den Atemwegen und der Größe einer intronischen (AAT)_n-Wiederholungssequenz im NOS1 Gen. Ziel dieser Übersichtsarbeit ist es, Studien, aus denen sich Hinweise auf eine Beteiligung der NOS1 an der Genetik des Asthma bronchiale ergeben, zusammenfassend darzustellen.

Genetics of the Neuronal NO-Synthase (NOS1) in the Aetiology of Asthma bronchiale:

The free radical nitric oxide (NO) is endogenously produced by enzymes known as NO synthases. NO in the airways is involved in a number of pathophysiological processes, such as airway inflammation, allergic reactions, and asthma. Asthma is a multifactorial disease that is caused by environmental and genetic factors. Genome wide screening approaches in families revealed evidence for linkage between chromosomal region 12q and allergic diseases, increased serum IgE levels as well as the development of asthma. The gene encoding for neuronal NOS (NOS1) is an attractive candidate gene for asthma, not only because it is localized in chromosomal region 12q24. Experimental studies in animals and humans suggest that NOS1 plays an important role in asthma. For instance, in a murine model of allergic asthma, NOS1 has been shown to be important for the development of bronchial hyperresponsiveness, since mice deficient for the nos1 gene were less responsive to airway challenge than both wild-type mice and mice deficient for the nos2 gene. Case-control studies in humans revealed allelic associations between polymorphic markers in the NOS1 gene and the diagnosis of asthma. Furthermore, increased concentrations of NO in the airways of asthmatics are closely related to the size of an intronic (AAT)_n-repeat polymorphism in the NOS1 gene. The purpose of this review is to summarize studies that provide evidence for an involvement of NOS1 in the genetics of asthma.

Literatur

• 1 Moncada S, Higgs A. The L-arginine-nitric oxide pathway.  N Engl J Med. 1993;  329 2002-2012
• 2 Barnes P J, Belvisi M G. Nitric oxide and lung disease.  Thorax. 1993;  48 1034-1043
• 3 Michel T, Feron O. Nitric oxide synthases: which, where, how, and why?.  J Clin Invest. 1997;  100 2146-2152
• 4 Nathan C. Inducible nitric oxide synthase: what difference does it make?.  J Clin Invest. 1997;  100 2417-2423
• 5 Xu W, Gorman P, Sheer D, Bates G, Kishimoto J, Lizhi L, Emson P. Regional localization of the gene coding for human brain nitric oxide synthase (NOS1) to chromosome 12q24.2-24.31 by fluorescent in situ hybridization.  Cytogenet Cell Genet. 1993;  64 62-63
• 6 Chartrain N A, Geller D A, Koty P P, Sitrin N F, Nussler A K, Hoffmann E P, Billiar T R, Hutchinson N I, Mudgett J S. Molecular cloning, structure, and chromosomal localization of the human inducible nitric oxide synthase gene.  J Biol Chem. 1994;  269 6765-6772
• 7 Marsden P A, Heng H HQ, Scherer S W, Stewart R J, Hall A V, Shi X M, Tsui L C, Schappert K T. Structure and chromosomal localization of the human constitutive endothelial nitric oxide synthase gene.  J Biol Chem. 1993;  268 17478-17488
• 8 Asano K, Chee C B, Gaston B, Lilly C M, Gerard G, Drazen J M, Stamler J S. Constitutive and inducible nitric oxide synthase gene expression, regulation, and activity in human lung epithelial cells.  Proc Natl Acad Sci USA. 1994;  91 10089-10093
• 9 Robbins R A, Barnes P J, Springall D R, Warren J B, Kwon O J, Buttery L D, Wilson A J, Geller D A, Polak J M. Expression of inducible nitric oxide in human lung epithelial cells.  Biochem Biophys Res Commun. 1994;  203 209-218
• 10 Gutierrez H H, Pitt B R, Schwarz M, Watkins S C, Lowenstein C, Caniggia L, Chumley P, Freeman B A. Pulmonary alveolar epithelial inducible NO synthase gene expression: regulation by inflammatory mediators.  Am J Physiol. 1995;  268 L501-508
• 11 Xie Q W, Kashiwabara Y, Nathan C. Role of transcription factor NF-kappa B/Rel in induction of nitric oxide synthase.  J Biol Chem. 1994;  269 4705-4708
• 12 Nishida K, Harrison D G, Navas J P, Fisher A A, Dockery S P, Uematsu M, Nerem R M, Alexander R W, Murphy T J. Molecular cloning and characterization of the constitutive bovine arotic endothelial cell nitric oxide synthase.  J Clin Invest. 1992;  90 2092-2096
• 13 Awolesi M A, Widmann M D, Sessa W C, Sumpio B E. Cyclic strain increases endothelial nitric oxide synthase activity.  Surgery. 1994;  116 439-444
• 14 Sharma H S, Westman J, Alm P, Sjoquist P O, Cervos-Navarro I, Nyberg F. Involvement of nitric oxide in the pathophysiology of acute heat stress in the rat. Influence of a new antioxidant compound H-290/51.  Ann N Y Acad Sci. 1997;  813 581-590
• 15 Reiser P J, Kline W O, Vaghy P L. Induction of neuronal type nitric oxide synthase in skeletal muscle by chronic electrical stimulation in vivo.  J Appl Physiol. 1997;  82 1250-1255
• 16 Shaul P W, North A J, Brannon T S, Ujiie K, Wells L B, Nisen P A, Lowenstein C J, Snyder S H, Star R A. 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. 1995;  13 167-174
• 17 Prabhakar N R, Rao S, Premkumar D, Pieramici S F, Kumar G K, Kalaria R K. Regulation of neuronal nitric oxide synthase gene expression by hypoxia. Role of nitric oxide in respiratory adaptation to low pO2.  Adv Exp Med Biol. 1996;  410 345-348
• 18 Calza L, Giardino L, Pozza M, Micera A, Aloe L. 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. 1997;  94 3368-3373
• 19 Wang Y, Newton D C, Robb G B, Kau C L, Miller T L, Cheung A H, Hall A V, VanDamme S, Wilcox J N, Marsden P A. RNA diversity has profound effects on the translation of neuronal nitric oxide synthase.  Proc Natl Acad Sci USA. 1999;  96 12150-12155
• 20 Togashi H, Sasaki M, Frohman E, Taira E, Ratan R R, Dawson T M, Dawson V L. Neuronal (type I) nitric oxide synthase regulates nuclear factor kappaB activity and immunologic (type II) nitric oxide synthase expression.  Proc Natl Acad Sci USA. 1997;  94 2676-2680
• 21 Bandyopadhyay A, Chakder S, Rattan S. Regulation of inducible and neuronal nitric oxide synthase gene expression by interferon-gamma and VIP.  Am J Physiol. 1997;  272 C1790-1797
• 22 Gaston B, Drazen J M, Loscalzo J, Stamler J S. The biology of nitrogen oxides in the airways.  Am J Respir Crit Care Med. 1994;  149 538-551
• 23 Persson M G, Zetterstrom O, Agrenius V, Ihre E, Gustafsson L E. Single-breath nitric oxide measurements in asthmatic patients and smokers.  Lancet. 1994;  343 146-147
• 24 Kharitonov S A, Yates D, Robbins R A, Logan-Sinclair R, Shinebourne E A, Barnes P J. Increased nitric oxide in exhaled air of asthmatic patients.  Lancet. 1994;  343 133-135
• 25 Massaro A F, Gaston B, Kita D, Fanta C, Stamler J S, Drazen J M. Expired nitric oxide levels during treatment of acute asthma,.  Am J Respir Crit Care Med. 1995;  152 800-803
• 26 Hamid Q, Springall D R, Riveros-Moreno V, Chanez P, Howarth P, Redington A, Bousquet J, Godard P, Holgate S, Polak J M. Induction of nitric oxide synthase in asthma.  Lancet. 1993;  342 1510-1513
• 27 Bisgaard H, Loland L, Oj J A. NO in exhaled air of asthmatic children is reduced by the leukotriene receptor antagonist montelukast.  Am J Respir Crit Care Med. 1999;  160 1227-1231
• 28 Xiong Y, Karupiah G, Hogan S P, Foster P S, Ramsay A J. Inhibition of allergic airway inflammation in mice lacking nitric oxide synthase 2.  J Immunol. 1999;  162 445-452
• 29 De Sanctis G T, MacLean J A, Hamada K, Mehta S, Scott J, Jiao A, Yandava C N, Kobzic L, Wolyniec W W, Fabian A, Venugopal C S, Grasemann H, Huang P L, Drazen J M. Contribution of nitric oxide synthases 1, 2 and 3 to airway hyperresponsiveness and inflammation in a murine model of asthma.  J Exp Med. 1999;  189 1621-1630
• 30 De Sanctis G T, Mehta S, Kobzic L, Yandava C, Jiao A, Huang P L, Drazen J M. Contribution of type I NOS to expired gas NO and bronchial responsiveness in mice.  Am J Physiol. 1997;  273 L883-L888
• 31 Barnes K C, Neely J D, Duffy D L, Freidhoff L R, Breazeale D R, Schou C, Naidu R P, Levett P N, Renault B, Kucherlapati R, Iozzino S, Ehrlich E, Beaty T H, Marsh D G. Linkage of asthma and serum IgE concentration to markers on chromosome 12q: evidence from Afro-Caribbean and Caucasian populations.  Genomics. 1996;  37 41-50
• 32 The Collaborative Study on the Genetics of Asthma (CSGA) . A genome-wide search for asthma susceptibility loci in ethnically diverse populations.  Nature Genet. 1997;  15 389-392
• 33 Thomas N S, Wilkinson J, Holgate S T. The candidate gene approach to the genetics of asthma and allergy.  Am J Respir Crit Care Med. 1997;  156 S144-S151
• 34 Ober C, Cox N J, Abney M, Di Rienzo A, Lander E S, Changyaleket B, Gidley H, Kurtz B, Lee J, Nance M, Pettersson A, Prescott J, Richardson A, Schlenker E, Summerhill E, Willadsen S, Parry R. . and The Collaborative Study on the Genetics of Asthma . Genomewide search for asthma susceptibility loci in a founder population.  Hum Mol Genet. 1998;  7 1393-1398
• 35 Nickel R, Wahn U, Hizawa N, Maestri N, Duffy D L, Barnes K C, Beyer K, Forster J, Bergmann R, Zepp F, Wahn V, Marsh D G. Evidence for linkage of chromosome 12q15-q24.1 markers to high toal serum IgE concentrations in children of the German multicenter allergy study.  Genomics. 1997;  46 159-162
• 36 Dizier M H, Besse-Schmittler C, Guilloud-Bataille M, Annesi-Maesano I, Boussaha M, Bousquet J, Charpin D, Degioanni A, Gormand F, Grimfeld A, Hochez J, Hyne G, Lockhart A, Luillier-Lacombe M, Matran R, Meunier F, Neukirch F, Pacheco Y, Parent V, Paty E, Pin I, Pison C, Scheinmann P, Thobie N, Vervloet D, Kauffmann F. Genome screen for asthma and related phenotypes in the french EGEA study.  Am J Respir Crit Care Med. 2000;  162 1812-1818
• 37 Barnes K C, Freidhoff L R, Nickel R, Chiu Y F, Juo S H, Hizawa N, Naidu R P, Ehrlich E, Duffy D L, Schou C, Levett P N, Marsh D G, Beaty T H. Dense mapping of chromosome 12q13.12-q23.3 and linkage to asthma and allergy.  J Allergy Clin Immunol. 1999;  104 485-491
• 38 Hall A V, Antoniou H, Wang Y, Cheung A H, Arbus A M, Olson S L, Lu W C, Kau C L, Marsden P A. Structural organization of the human neuronal nitric oxide synthase gene (NOS1).  J Biol Chem. 1994;  269 33082-33090
• 39 Grasemann H, Yandava C N, Drazen J M. Neuronal NO synthase (NOS1) is a major candidate gene for asthma.  Clin Exp Allergy. 1999;  29 Suppl 4 39-41
• 40 Grasemann H, Yandava C N, Storm van's Gravesande K, Deykin A, Pillari A, Ma J, Sonna L A, Lilly C, Stampfer M J, Israel E, Silverman E K, Drazen J M. A neuronal NO synthase (NOS1) gene polymorphism is associated with asthma.  Biochem Biophys Res Commun. 2000;  272 391-394
• 41 Gao P S, Kawada H, Kasamatsu T, Mao X Q, Roberts M H, Miyamoto Y, Yoshimura M, Saitoh Y, Yasue H, Nakao K, Adra C N, Kun J F, Moro-oka S, Inoko H, Ho L P, Shirakawa T, Hopkin J M. Variants of NOS1, NOS2, and NOS3 genes in asthmatics.  Biochem Biophys Res Commun. 2000;  267 361-363
• 42 Steudel W, Kirmse M, Weimann J, Ullrich R, Hromi J, Zapol W M. Exhaled nitric oxide production by nitric oxide synthase-deficient mice.  Am J Respir Crit Care Med. 2000;  162 1262-1267
• 43 Wechsler M E, Grasemann H, Deykin A, Silverman E K, Yandava C N, Israel E, Wand M, Drazen J M. Exhaled nitric oxide in patients with asthma: association with NOS1 genotype.  Am J Respir Crit Care Med. 2000;  162 2043-2047
• 44 Timchenko L T, Caskey C T. Trinucleotide repeat disorders in humans: discussions of mechanisms and medical issues FASEB.  J . 1996;  10 1589-1597
• 45 Martin J B. Molecular pathobiology of neurodegenerative diseases.  N Engl J Med. 1999;  340 1970-1980
• 46 Pearson C E, Sinden R R. Trinucleotide repeat DNA structures: dynamic mutations from dynamic DNA.  Curr Opin Struct Biol. 1998;  8 321-330
• 47 Belvisi M G, Ward J K, Mitchell J A, Barnes P J. Nitric oxide as a neurotransmitter in human airways.  Arch Int Pharmacodyn. 1995;  329 97-110
• 48 Grasemann H, Deykin A, Pillari A, Israel E, Yandava C N, Drazen J M. Association of a polymorphism in the promoter region of the inducible NO synthase (NOS2) gene with asthma.  Am J Respir Crit Care Med. 1999;  159 A646
• 49 Grasemann H, Knauer N, Büscher R, Hübner K, Drazen J M, Ratjen F. Airway nitric oxide levels in cystic fibrosis patients are related to a polymorphism in the neuronal nitric oxide synthase gene.  Am J Respir Crit Care Med. 2000;  162 2172-2176