Infektion oder Inflammation
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Infektion oder Inflammation Tim O. Hirche Mukoviszidose-Erwachsenenambulanz Klinikum der J.W. Goethe Universität Frankfurt am Main Entstehung der CF Lungenerkrankung CF Gendefekt Gentherapie ? CFTR Ionenkanal Defekt CFTR Reparatur/Bypass ? ? PhysioTX/Mukolyse Mukostase Antibiotika Entzündung Infektion Manifeste Lungenerkrankung Resp. Insuffizienz Antientzündlich ? symptomatisch/supportiv Transplantation ? Respiratorisches Epithel Gel und Solphase x 1000 x 12000 Mukoziliäre Clearance der Atemwege 60 µM/s <50µM 7µM Hypothesen zur Entstehung der Mukostase bei CF 1. (Primär) veränderte Drüsensekrete Wine et al 2001. Submucosal gland secretions in airways from cystic fibrosis patients have normal Na and pH but elevated viscosity. Proc Natl Acad Sci 98: 8119-23 2. „high - salt“ Hypothese Welsh et al 1998. Loss of CFTR chloride channels alters salt absorption by cystic fibrosis airway epithelia in vitro. Mol Cell 2:397-403 3. „low - volume“ Hypothese Boucher et al 1998. Evidence for periciliary liquid layer depletion, not abnormal ion composition, in the pathogenesis of cystic fibrosis airway disease. Cell 95:1005-1015 CFTR Funktion Normalbefund Gelphase CFTR ENaC Solphase CFTR Funktion Mukoviszidose CFTR ENAC „low volume“-Hypothese Boucher et al. New concepts of the pathogenesis of cystic fibrosis lung disease. Eur Respir J 2004; 23: 146-158 Pulmonale Infektion 0 µM/s O2 >100 µM Doering et al. Effects of reduced mucus oxygen concentration in airway Pseudomonas infections of CF patients. JCI 2002; 109: 317-325 Chronische pulmonale Infektion 0 µM/s O2 X20.000 Recruitment von Entzündungszellen 0 µM/s O2 Pulmonale Infektion/Inflammation = Zytokine x 11.000 = Enzyme = Sauerstoffradikale Ursache der CF Lungenerkrankung: Inflammation oder Infektion? Pro Inflammation • Bonfield et al 1995. Inflammatory cytokines in cystic fibrosis lungs. Am J Respir Crit Care Med 152:2111-2118 • Khan et al 1995. Early pulmonary inflammation in infants with cystic fibrosis. Am J Respir Crit Care Med 1995; 151: 1075-1082 • Paul et al. 2004 Effect of treatment with dornase alpha on airway inflammation in patients with cystic fibrosis. Am J Respir Crit Care Med. 169:719-25 Pro Infektion • Armstrong DS et al. 1997. Lower airway inflammation in infants and young children with cystic fibrosis. Am J Respir Crit Care Med 156: 1197-1204 • Burns et al. 2001. Longitudinal assessment of Pseudomonas aeruginosa in young children with cystic fibrosis. J Infect Dis 183: 444-452 • West et al. 2002. Respiratory infection with Pseudomonas aeruginosa in children with CF: early detection by serology and assessment of risk factors. JAMA 287:2958-2967