Abstract
In the past 40 years, the mean survival of patients with cystic fibrosis (CF) has increased from less than 1 year to 30 years. The identification of the gene mutated in CF in 1989 has already been followed by the first phase of somatic gene therapy in 1993. The target organ of somatic gene therapy is the respiratory epithelium, which is progressively damaged by the chronic infection and inflammation characteristic of the disease. Since in the future, more patients may benefit from somatic gene therapy, the understanding of the mechanisms leading to chronic infection and inflammation becomes increasingly important. In the future, current therapeutic measures to protect the respiratory epithelium from damage, such as intravenous antimicrobial treatment, will be improved by the additional delivery of new drugs to the bronchial tree by aerosol. Amiloride and recombinant human DNAse administered by this route have the potential to improve mucociliary clearance. Antibiotics as well as protease inhibitors delivered by aerosol should contribute to prevent damage by infection and inflammation in order to increase the probability of successful somatic gene therapy in this disease.
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Abbreviations
- CF :
-
cystic fibrosis
- CFTR :
-
cystic fibrosis transmembrane conductance regulator
References
App EM, King M, Helfesrieder R, Köhler D, Matthys H (1990) Acute and longterm amiloride inhalation in cystic fibrosis lung disease. A rational approach to cystic fibrosis therapy. Am Rev Respir Dis 141:605–612
Auerbach HS, Kirkpatrick JA, Williams M, Colten HR (1985) Alternate-day prednisone reduces morbidity and improves pulmonary function in cystic fibrosis. Lancet II:686–688
Balough K, Fick R Jr, Weinberger M, McCubbin M, Ahrens R (1992) Inflammation in early cystic fibrosis lung lesion. Lack of correlation with infection. Am Rev Respir Dis 145:A689
Baltimore RS, Christie CDC, Walker Smith GJ (1989) Immunohistopathologic localization ofPseudomonas aeruginosa in lungs from patients with cystic fibrosis. Implications for the pathogenesis of progressive lung deterioration. Am Rev Respir Dis 140:1650–1661
Berger M, Sorensen RU, Tosi MF, Dearborn DG, Döring G (1989) Complement receptor expression on neutrophils at an inflammatory site, thePseudomonas-infected lung in cystic fibrosis. J Clin Invest 84:1302–1313
Boucher RC, Stutts MJ, Knowles MR, Cantley L, Gatzy JT (1986) Na+ transport in cystic fibrosis respiratory epithelia. Abnormal basal rate and response to adenylate cyclase activation. J Clin Invest 78:1245–1252
Breuer R, Christensen TG, Niles RM, Stone PJ, Snider GL (1989) Human neutrophil elastase causes glycoconjugate release from the epithelial cell surface of hamster trachea in organ culture. Am Rev Respir Dis 139:779–782
Brown MA, Morgan WJ, Finley PR, Scuderi P (1991) Circulating levels of tumor necrosis factor and interleukin-1 in cystic fibrosis. Pediatr Pulmonol 10:86–91
Bruce MC, Poncz L, Klinger JD, Stern RC, Thomashefski JF, Dearborn DG (1985) Biochemial and pathological evidence for proteolytic destruction of lung connective tissue in cystic fibrosis. Am Rev Respir Dis 132:529–535
Carson JL, Collier AM, Gambling TM, Knowles MR, Boucher RC (1990) Ultrastructure of airway epithelial cell membranes among patients with cystic fibrosis. Hum Pathol 21:640–647
Cerami A, Ikeda Y, Le Trang N, Hotez PJ, Beutler B (1985) Weight loss associated with an endotoxin-induced mediator from peritoneal macrophages. The role of cachectin (tumor necrosis factor). Immunol Lett 11:173–177
Coutelle C, Caplen N, Hart S, Huxley C, Williamson R (1993) Gene therapy for cystic fibrosis. Arch Dis Child 68:437–447
Davis PB, Silski CL, Liedtke CM (1992) Amiloride antagonizes betaadrenergic stimulation of cAMP synthesis and CI secretion in human tracheal epithelial cells. Am J Respir Cell Mol Biol 6:140–145
Dean TP, Dai Y, Shute JK, Church MK, Warner JO (1993) Interleukin-8 concentrations are elevated in bronchoalveolar lavage, sputum, and sera of children with cystic fibrosis. Pediatr Res 34:159–161
Di Sant'Agnese PA (1979) Cystic fibrosis. In: Vaughan VC, McKay RJ, Behrman RE (eds) Textbook of pediatrics, 11th edn. WB Saunders Company, Philadelphia, pp 1988–2001
Dorin JR, Dickinson P, Alton EWFW, Smith SN, Geddes DM, Stevenson BJ, Kimber WL, Fleming S, Clarke AR, Hooper ML, Anderson L, Beddington RSP, Porteous DJ (1992) Cystic fibromutagenesis. in the mouse by targeted insertional mutagenesis. Nature 359:211–215
Döring G, Høiby N (1983) Longitudinal study of immune response toPseudomonas aeruginosa antigens in cystic fibrosis. Infect Immun 42:197–201
Fick RB, Naegel GP, Squier SU, Wood RE, Gee JBL, Reynolds HA (1984) Proteins of the cystic fibrosis respiratory tract: fragmented immunoglobulin G opsonic antibody causing defective opsono-phagocytosis. J Clin Invest 74:236–248
Fiel SB (1993) Clinical management of pulmonary disease in cystic fibrosis. Lancet 341:1070–1074
Fomsgaard A, Høiby N, Shand GH, Conrad RS, Galanos C (1988) Longitudinal study of antibody response to lipopolysaccharides during chronicPseudomonas aeruginosa lung infection in cystic fibrosis. Infect Immun 56:2270–2278
Gaillard D, Plotkowski C, Puchelle E (1992) Mucus et protection de la muqueuse respiratoire. Edition et communication médicales. Paris
Godfrey RWA, Severs NJ, Jefferey PK (1992) Freeze-fracture morphology and quantification of human bronchial epithelial tight junctions. Am J Respir Cell Mol Biol 6:453–458
Goldstein W, Döring G (1986) Lysosomal enzymes from polymorphonuclear leukocytes and proteinase inhibitors in patients with cystic fibrosis. Am Rev Respir Dis 134:49–56
Greally P, Hussain MJ, Vergani D, Price JF (1992) Treatment with prednisolone suppresses interleukin-1, soluble interleukin-2 receptor and immunoglobulin G in cystic fibrosis patients. Am Rev Respir Dis 145:A 117
Gupta R, Jentoft N (1992) The structure of tracheobronchial mucins from cystic fibrosis and control patients. J Biol Chem 267:3160–3167
Hubbard RC, McElvaney NG, Birrer P, Shak S, Robinson WW, Jolley C, Wu M, Chernick MS, Crystal RG (1992) A preliminary study of aerosolized recombinant human deoxyribonuclease I in the treatment of cystic fibrosis. N Engl J Med 326:812–815
Hudson VL, Wielinski CL, Regelmann WE (1993) Prognostic implications of initial oropharyngeal bacterial flora in patients with cystic fibrosis diagnosed before the age of two years. J Pediatr 122:854–860
Hyde SC, Gill DR, Higgins CF, Trezise AEO (1993) Correction of the ion transport defect in cystic fibrosis transgenic mice by gene therapy. Nature 362:250–255
Jackson AH, Hill SI, Afford SC, Stockley RA (1984) Sputum sol phase proteins and elastase activity in patients with cystic fibrosis. Eur J Respir Dis 65:114–124
Jacquot J, Tournier JM, Carmona TG, Puchelle E, Chazalette JP, Sadoul P (1983) Protéines des sécrétions bronchiques dans la mucoviscidose. Rôle de l'infection. Bull Europ Physiopath Resp 19:453–458
Jeffery PK (1992) Airway epithelial structure and defence. Eur Respir J 5, [Suppl] 15:320s
Johnson DA, Carter-Hamm B, Dralle WM (1982) Inactivation of human bronchial proteinase inhibitor byPseudomonas elastase. Am Rev Respir Dis 126:1070:1073
Kronborg G, Hansen MB, Svenson M, Fomsgaard A, Høiby N, Bendtzen K (1993) Cytokines in sputum and serum from patients with cystic fibrosis and chronicPseudomonas aeruginosa infection as markers of destructive inflammation in the lungs. Pediatr Pulmonol 15:292–297
Lam J, Chan R, Lam K, Costerton JW (1980) Production of mucoid microcolonies byPseudomonas aeruginosa within infected lungs in cystic fibrosis. Infect Immun 28:546–556
Learn DB, Brestel EP, Seetharama S (1987) Hypochlorite scavenging byPseudomonas aeruginosa alginate. Infect Immun 55:1813–1818
Lethem MI, James SL, Marriott C (1990) The role of mucous glycoproteins in the rheologic properties of cystic in the rheologic properties of cystic fibrosis sputum. Am Rev Respir Dis 142:1053–1058
Levy E, Gurbindo C, Lacaille F, Paradis K, Thibault L, Seidman E (1993) Circulating tumor necrosis factor-α levels and lipid abnormalities in patients with cystic fibrosis. Pediatr Res 34:162–166
Marks MI (1981) The pathogenesis and treatment of pulmonary infections in patients with cystic fibrosis. J Pediatr 98:173–179
Mastrangeli A, Danel C, Rosenfeld MA, Stratford-Perricaudet L, Perricaudet M, Pavirani A, Lecocq J-P, Crystal RG (1993) Diversity of airway epithelial cell targets for in vivo recombinant adenovirus-mediated gene transfer. J Clin Invest 91:225–234
McElvaney NG, Hubbard RC, Birrer P, Chernick MS, Caplan DB, Frank MM, Crystal RG (1991) Aerosol α1-antitrypsin treatment for cystic fibrosis. Lancet 337:392–394
McElvaney NG, Nakamura H, Birrer P, Hébert CA, Wong WL, Alphonso M, Baker JB, Catalano MA, Crystal RG (1992) Modulation of airway inflammation in cystic fibrosis. In vivo suppression of Interleukin-8 levels on the respiratory epithelial surface by aerosolization of recombinant secretory leukoprotease inhibitor. J Clin Invest 90:1296–1301
Meshulam T, Obedeanu N, Merzbach D, Sobel JD (1984) Phagocytosis of mucoid and non mucoid strains ofPseudomonas aeruginosa. Clin Immunol Immunopathol 32:151–165
Meyer KC, Lewandoski JR, Zimmermann JJ, Nunley D, Calhoun WJ, Dopico GA (1991) Human neutrophil elastase and elastase/alpha1-antiprotease complex in cystic fibrosis. Comparison with interstitial lung disease and evaluation of the effect of intravenously administered antibiotic therapy. Am Rev Respir Dis 144:580–585
Moskowitz RW, Heinrich G (1971) Bacterial inactivation of human serum α-1 anti-trypsin. J Lab Clin Med 77:777–784
Nakamura H, Yoshimura K, McElvaney NG, Crystal RG (1992) Neutrophil elastase in respiratory epithelial lining fluid of individuals with cystic fibrosis induces Interleukin-8 gene expression in a human bronchial epithelial cell line. J Clin Invest 89:1478–1484
Norman D, Elborn JS, Cordon SM, Rayner RJ, Wiseman MS, Hiller EJ, Shale DJ (1991) Plasma tumour necrosis factor alpha in cystic fibrosis. Thorax 46:91–95
Pennington JE, Wolff SM, Puziss M (1979) Summary of a workshop on infections in patients with cystic fibrosis. J Infect Dis 140:252–256
Petersen NT, Høiby N, Mordhorst CH, Lind K, Flensborg EW, Bruun B (1981) Respiratory infections in cystic fibrosis patients caused by viruses, chlamydia and mycoplasma — possible synergism withPseudomonas aeruginosa. Acta Paediatr Scand 70:623–628
Pier GB, Saunders JM, Ames P, Edwards MS, Auerbach H, Goldfarb J, Speert DP, Hurwitch S (1987) Opsonophagocytic killing antibody toPseudomonas aeruginosa mucoid exopolysaccharide in older noncolonized patients with cystic fibrosis. N Engl J Med 317:793–798
Plotkowski MC, Beck G, Tournier JM, Bernardo-Filho M, Marques EA, Puchelle E (1989) Adherence ofPseudomonas aeruginosa to respiratory epithelium and the effect of leucocyte elastase. J Med Microbiol 30:285–293
Plotkowski MC, Chevillard M, Pierrot D, Altemayer D, Puchelle E (1992) Epithelial respiratory cells from cystic fibrosis patients do not possess specificPseudomonas aeruginosa-adhesive properties. J Med Microbiol 36:104–111
Quinton PM (1983) Chloride impermeability in cystic fibrosis. Nature 301:421–422
Ramsey BW, Dorkin HL, Eisenberg JD, Gibson RL, Harwood IR, Kravitz RM, Schidlow DV, Wilmott RW, Astley SJ, McBurnie MA, Wentz K, Smith AL (1993) Efficacy of aerosolized tobramycin in patients with cystic fibrosis. N Engl J Med 328:1740–1746
Rommens JM, Iannuzzi MC, Kerem B-S, Drumm ML, Melmer G, Dean M, Rozmahel R, Cole JL, Kennedy D, Hidaka N, Zsiga M, Buchwald M, Riordan JR, Tsui L-CH, Collins FS (1989) Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 245:1059–1065
Rosenfeld MA, Yoshimura K, Trapnell BC, Yoneyama K, Rosenthal ER, Dalemans W, Fukayama M, Bargon J, Stier LE, Stratford-Perricaudet L, Perricaudet M, Guggino WB, Pavirani A, Lecocq J-P, Crystal RG (1992) In vivo transfer of the human cystic fibrosis transmembrane conductance regulator gene to the airway epithelium. Cell 68:143–155
Rosenstein BJ, Eigen H (1991) Risks of alternate-day prednisone in patients with cystic fibrosis. Pediatrics 87:245–246
Saiman L, Cacalano G, Gruenert D, Prince A (1992) Comparison of adherence ofPseudomonas aeruginosa to respiratory epithelial cells from cystic fibrosis patients and health subjects. Infect Immun 60:2808–2814
Sajjan SU, Forstner JF (1992) Identification of the mucin-binding adhesin ofPseudomonas cepacia isolated from patients with cystic fibrosis. Infect Immun 60:1434–1440
Sajjan US, Corey M, Karmali MA, Forstner JF (1992) Binding ofPseudomonas cepacia to normal human intestinal mucin and respiratory mucin from patients with cystic fibrosis. J Clin Invest 89:648–656
Sajjan U, Reisman J, Doig P, Irvin RT, Forstner G, Forstner J (1992) Binding of nonmucoidPseudomonas aeruginosa to normal human intestinal mucin and respiratory mucin from patients with cystic fibrosis. J Clin Invest 89: 657–665
Schaad UB, Wedgwood-Krucko J, Suter S, Kraemer R (1987) Efficacy of inhaled amikacin as adjunct to intravenous combination therapy (ceftazidime and amikacin) in cystic fibrosis. J Pediatr 111:599–605
Shak S, Capon DJ, Hellmiss R, Marsters SA, Baker CL (1990) Recombinant human DNAase 1 reduces the viscosity of cystic fibrosis sputum. Proc Natl Acad Sci USA 87:9188–9192
Shimura S, Sasaki T, Ikeda K, Yamauchi K, Sasaki H, Takishima T (1990) Direct inhibitory action of glucocorticoid on glycoconjugate secretion from airway submucosal glands. Am Rev Respir Dis 141:1044–1049
Smallman LA, Hill SL, Stockley RA (1984) Reduction of ciliary beat frequency in vitro by sputum from patients with bronchiectasis: a serine proteinase effect. Thorax 39:663–667
Smith AL, Redding G, Doershuk C, Goldmann D, Gore E, Hilman B, Marks M, Moss R, Ramsey B, Rubio T, Schwartz RH, Thomassen MJ, Williams-Warren J, Weber A, Wilmott RE, Wilson HD, Yogev R (1988) Sputum changes associated with therapy for endobronchial exacerbation in cystic fibrosis. J Pediatr 112:547–554
Snouwaert JN, Brigman KK, Latour AM, Malout NN, Boucher RC, Smithies O, Koller BH (1992) An animal model for cystic fibrosis made by gene targeting. Science 257:1083–1088
Sommerhoff CP, Nadel JA, Basbaum CB, Caughey GH (1990) Neutrophil elastase and cathepsin G stimulate secretion from cultured bovine airway gland serous cells. J Clin Invest 85:682–689
Standiford TJ, Kunkel SL, Basha MA, Chensue SW, Lynch III JP, Toews GB, Westwick J, Strieter RM (1990) Interleukin-8 gene expression by a pulmonary epithelial cell line. A model for cytokine networks in the lung. J Clin Invest 86:1945–1953
Stockley RA, Hill SL, Morrison HM, Starkie CM (1984) Elastolytic activity of sputum and its relation to purulence and to lung function in patients with bronchiectasis. Thorax 39:408–413
Stolk J, Heinzel-Wieland R, Saunders D, Dijkman JH, Steffens G (1992) Potency of an oxidation-resistant mutant of secretory leukocyte proteinase inhibitor in lipopolysaccharide-induced emphysema in hamsters. Am Rev Respir Dis 145:A560
Strassmann G, Fong M, Kenney JS, Jacob CO (1992) Bvidence for the involvement of Interleukin 6 in experimental cancer cachexia. J Clin Invest 89:1681–1684
Suter S, Chevallier I (1991) Proteolytic inactivation of α1-proteinase inhibitor in infected bronchial secretions from patients with cystic fibrosis. Eur Respir J 4:40–49
Suter S, Schaad UB, Roux L, Nydegger UE, Waldvogel FA (1984) Granulocyte neutral proteases and Pseudomonas elastase as possible causes of airway damage in patients with cystic fibrosis. J Infect Dis 149:523–531
Suter S, Schaad UB, Tegner H, Ohlsson K, Desgrandchamps D, Waldvogel FA (1986) I evels of free granulocyte elastase in bronchial secretions from patients with cystic fibrosis: Effect of antimicrobial treatment againstPseudomonas aeruginosa. J Infect Dis 153:902–909
Suter S, Schaad UB, Morgenthaler JJ, Chevallier I, Schnebli HP (1988) Fibronectin-cleaving activity in bronchial secretions of patients with cystic fibrosis. J Infect Dis 158:89–100
Suter S, Schaad UB, Roux-Lombard P, Girardin E, Grau G, Dayer JM (1989) Relation between tumor necrosis factor-alpha and granulocyte elastase-αlproteinase inhibitor complexes in the plasma of patients with cystic fibrosis. Am Rev Respir Dis 140:1640–1644
Sykes DA, Wilson R, Greenstone M, Currie DC, Steinfort C, Cole PJ (1987) Deleterious effects of purulent sputum sol on human ciliary function in vitro: at least two factors identified. Thorax 42:256–261
Szaff M, Høiby N, Flensborg EW (1983) Frequent antibiotic therapy improves survival of cystic fibrosis patients with chronicPseudomonas aeruginosa infection. Acta Paediatr Scand 72:651–657
Thomassen MJ, Klinger JD, Badger SJ, Van Heeckeren DW, Stern RC (1984) Cultures of thoracotomy specimens confirm usefulness of sputum cultures in cystic fibrosis. J Pediatr 104:352–356
Tosi MF, Zakem H, Berger M (1990) Neutrophil elastase cleaves C3bi on opsonized Pseudomonas as well as CR1 on neutrophils to create a functionally important opsonin receptor mismatch. J Clin Invest 86:300–308
Tournier JM, Jacquot J, Puchelle E, Bieth JG (1985) Evidence thatPseudomonas aeruginosa elastase does not inactivate the bronchial inhibitor in the presence of leukocyte elastase. Am Rev Respir Dis 132:524–528
Valerius NH, Koch C, Høiby N (1991) Prevention of chronicPseudomonas aeruginosa colonisation in cystic fibrosis by early treatment. Lancet 338:725–726
Vogelmeier C, Hubbard RC, Fells GA, Schnebli H-P (1991) Anti-neutrophil elastase defense of the normal human respiratory epithelial surface provided by the secretory leukoprotease inhibitor. J Clin Invest 87:482–488
Wang EEL, Prober CG, Manson B, Corey M, Levison H (1984) Association of respiratory viral infections with pulmonary deterioration in patients with cystic fibrosis. N Engl J Med 311:1653–1658
Wheeler WB, Williams M, Matthews WJ jr, Colten HR (1984) Progression of cystic fibrosis lung disease as a function of serum immunoglobulin G levels: a 5-year longitudinal study. J Pediatr 104:695–699
Woods DE, Bass JA, Johanson WG, Straus DC (1980) Role of adherence in the pathogenesis ofPseudomonas aeruginosa lung infection in cystic fibrosis patients. Infect Immun 30:694–699
Woods DE, Straus DC, Johanson WG, Bass JA (1981) Role of salivary protease activity in adherence of Gramnegative bacilli to mammalian buccal epithelial cells in vivo. J Clin Invest 68:1435–1440
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Suter, S. New perspectives in understanding and management of the respiratory disease in cystic fibrosis. Eur J Pediatr 153, 144–150 (1994). https://doi.org/10.1007/BF01958972
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DOI: https://doi.org/10.1007/BF01958972