Besonderheiten im pulmonalen NO-Stoffwechsel bei Patienten mit zystischer Fibrose

Zusammenfassung

In den Atemwegen generiertes Stickstoffmonoxid (NO) und seine Metabolite sind an einer Vielzahl physiologischer und pathophysiologischer Prozesse beteiligt. Unter anderem relaxiert NO die bronchiale Muskulatur, verbessert die Motilität der Zilien, hat antimikrobielle Effekte, und erhöht die Expression des CFTR-(cystic fibrosis transmembrane regulation)Proteins in Atemwegsepithelzellen. Interessanterweise finden sich in den Atemwegen von Patienten mit zystischer Fibrose (CF) erniedrigte Konzentrationen von NO und von bioaktiven S-Nitrosothiolen (SNOs). Im Vergleich zu Patienten mit einer relativ normalen pulmonalen NO-Synthese weisen CF-Patienten mit niedrigen NO-Konzentrationen eine signifikant schlechtere Lungenfunktion auf und neigen vermehrt zu einer Besiedlung der Atemwege mit pathogenen Keimen wie P. aeruginosa. Als Konsequenz aus diesen Beobachtungen werden nun erste klinische Studien durchgeführt, die möglichen Effekte einer Erhöhung der bronchialen NO-Konzentration bei CF-Patienten untersuchen.

Abstract

Airway nitric oxide (NO) and its metabolites are involved in a number of physiological and pathophysiological processes. For instance, NO relaxes airway smooth muscle, improves airway ciliary motility, has antimicrobial effects, and increases expression of the CFTR (cystic fibrosis transmembrane regulator) protein in airway epithelial cells. Of interest, concentrations of NO and of bioactive S-nitrosothiols (SNOs) are decreased in the airways of patients with cystic fibrosis (CF). When compared to patients with relatively normal pulmonary NO formation, CF patients with low NO-concentrations have a significantly reduced pulmonary function and a higher frequency of bacterial colonisation of the airways with pathogens such as P. aeruginosa. As a consequence of these observations clinical trails have now been initiated to study possible effects of an augmented bronchial NO-concentration in CF-patients.

Literatur

• 1 Gaston B, Drazen J M, Loscalzo J. et al . The biology of nitrogen oxides in the airways.  Am J Respir Crit Care Med. 1994;  149 538-551
• 2 Paul K, Ratjen F, Schuster A. Pulmonale Manifestation der Cystischen Fibrose.  Monatsschr Kinderh. 2001;  149 222-238
• 3 Massaro A F, Gaston B, Kita D. et al . Expired nitric oxide levels during treatment of acute asthma.  Am J Respir Crit Care Med. 1995;  152 800-803
• 4 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
• 5 Worlitzsch D, Tarran R, Ulrich M. et al . Effects of reduced mucus oxygen concentration in airway Pseudomonas infections of cystic fibrosis patients.  J Clin Invest. 2002;  109 317-325
• 6 Ratjen F. Changes in strategies for optimal antibacterial therapy in cystic fibrosis.  Int J Antimicrob Agents. 2001;  17 93-96
• 7 Balfour-Lynn I M, Laverty A, Dinwiddie R. Reduced upper airway nitric oxide in cystic fibrosis.  Arch Dis Child. 1996;  75 319-322
• 8 Grasemann H, Michler E, Wallot M. et al . Decreased concentration of exhaled nitric oxide (NO) in patients with cystic fibrosis.  Pediatr Pulmonol. 1997;  24 173-177
• 9 Grasemann H, Ratjen F. Cystic fibrosis lung disease: the role of nitric oxide.  Pediatr Pulmonol. 1999;  28 442-448
• 10 Ho L P, Innes J A, Greening A P. Exhaled nitric oxide is not elevated in the inflammatory airways diseases of cystic fibrosis and bronchiectasis.  Eur Respir J. 1998;  12 1290-1294
• 11 Grasemann H, Ioannidis I, de Groot H. et al . Metabolites of nitric oxide in the lower respiratory tract of children.  Eur J Pediatr. 1997;  156 575-578
• 12 Grasemann H, Ioannidis I, Tomkiewicz R P. et al . Nitric oxide metabolites in cystic fibrosis lung disease.  Arch Dis Child. 1998;  78 49-53
• 13 Linnane S J, Keatings V M, Costello C M. et al . Total sputum nitrate plus nitrite is raised during acute pulmonary infection in cystic fibrosis.  Am J Respir Crit Care Med. 1998;  158 207-212
• 14 Grasemann H, Tomkiewicz R P, Ioannidis I. et al . Metabolites of nitric oxide and viscoelastic properties of airway secretions in cystic fibrosis.  Am J Respir Crit Care Med. 1997;  155 A46
• 15 Kelley T J, Drumm M L. Inducible nitric oxide synthase expression is reduced in cystic fibrosis murine and human airway epithelial cells.  J Clin Invest. 1998;  102 1200-1207
• 16 Meng Q H, Springall D R, Bishop A E. et al . Lack of inducible nitric oxide synthase in bronchial epithelium: a possible mechanism of susceptibility to infection in cystic fibrosis.  J Pathol. 1998;  184 323-331
• 17 Wechsler M E, Grasemann H, Deykin A. et al . Exhaled nitric oxide in patients with asthma. Association with NOS1 genotype.  Am J Respir Crit Care Med. 2000;  162 2043-2047
• 18 Grasemann H. Die Genetik der neuronalen NO-Synthase (NOS1) in der Ätiologie des Asthma bronchiale.  Pneumologie. 2001;  55 390-395
• 19 Grasemann H, Knauer N, Büscher R. et al . Airway nitric oxide levels in cystic fibrosis patients are related to a polymorphism and the neuronal nitric oxide synthase gene.  Am J Respir Crit Care Med. 2000;  162 2172-2176
• 20 Rosenfeld M, Emerson J, Accurso F. et al . Diagnostic accuracy of oropharyngeal cultures in infants and young children with cystic fibrosis.  Pediatr Pulmonol. 1999;  28 321-328
• 21 Watkins D N, Peroni D J, Basclain K A. et al . Expression and activity of nitric oxide synthase in human airway epithelium.  Am J Respir Cell Mol Biol. 1997;  16 629-539
• 22 Tasman A J, Bogatzki B, Heppt W. et al . Nitric oxide synthase in the innervation of the human nasal mucosa: correlation with neuropeptides and thyrosine hydroxylase.  Laryngoscope. 1998;  108 128-133
• 23 Riederer A, Held B, Mayer B. et al . Histochemical and immunocytochemical study of nitrergic innervation in human nasal mucosa.  Ann Otol Rhinol Laryngol. 1999;  108 869-875
• 24 Grasemann H, Storm van's Gravesande K. et al . Nasal nitric oxide levels are associated with a polymorphism in the neuronal nitric oxide synthase (NOS1) genes in cystic fibrosis patients.  Nitric Oxide. 2002;  6 236-241
• 25 Ratjen F, Kavuk I, Gärtig S. et al . Airway nitric oxide in infants with acute wheezy bronchitis.  Pediatr Allergy Immunol. 2000;  11 230-235
• 26 Grasemann H, Gärtig S S, Wiesemann H G. et al . Effect of L-arginine infusion on airway NO in cystic fibrosis and primary ciliary dyskinesia syndrome.  Eur Respir J. 1999;  13 114-118
• 27 Snyder A H, McPherson M E, Hunt J F. et al . Acute effects of aerosolized S-nitrosoglutathione in cystic fibrosis.  Am J Respir Crit Care Med. 2002;  165 922-926
• 28 Grasemann H, Gaston B, Fang K. et al . Decreased levels of nitrosothiols in the lower airways of patients with cystic fibrosis and normal pulmonary function.  J Pediatr. 1999;  135 770-772
• 29 Zaman K, McPherson M, Vaughan J. et al . S-nitrosoglutathione increases cystic fibrosis transmembrane regulator maturation.  Biochem Biophys Res Commun. 2001;  284 65-70