α1-Antitrypsin inhalation reduces airway inflammation in cystic fibrosis patients

The airways of cystic fibrosis (CF) patients are characterised by neutrophils that release high amounts of elastase overwhelming the local antiprotease shield. Inhalation of α1-antitrypsin (AAT) may restore the protease–antiprotease balance and attenuate airway inflammation in CF airways. The aims of the present study were: 1) to assess the best deposition region for inhaled AAT by two different inhalation strategies; and 2) to examine the effect of 4 weeks of AAT inhalation on lung function, protease–antiprotease balance and airway inflammation in CF patients. In a prospective, randomised study, 52 CF patients received a daily deposition by inhalation of 25 mg AAT for 4 weeks targeting their peripheral or bronchial compartment. The levels of elastase activity, AAT, pro-inflammatory cytokines, neutrophils, immunoglobulin G fragments and the numbers of Pseudomonas aeruginosa were assessed in induced sputum before and after the inhalation period. Inhalation of AAT increased AAT levels and decreased the levels of elastase activity, neutrophils, pro-inflammatory cytokines and the numbers of P. aeruginosa. However, it had no effect on lung function. No difference was found between the peripheral and bronchial inhalation mode. In conclusion, although no effect on lung function was observed, the clear reduction of airway inflammation after α1-antitrypsin treatment may precede pulmonary structural changes. The α1-antitrypsin deposition region may play a minor role for α1-antitrypsin inhalation in cystic fibrosis patients.

[1]  M. Keogan,et al.  Safety and Efficacy of Recombinant Alpha1‐Antitrypsin Therapy in Cystic Fibrosis , 2006, Pediatric pulmonology.

[2]  M. Griese,et al.  Optimum peripheral drug deposition in patients with cystic fibrosis. , 2005, Journal of aerosol medicine : the official journal of the International Society for Aerosols in Medicine.

[3]  S. Janciauskiene,et al.  Prolastin, a pharmaceutical preparation of purified human α1-antitrypsin, blocks endotoxin-mediated cytokine release , 2005, Respiratory research.

[4]  H. Magnussen,et al.  Cellular profiles of induced sputum in children with stable cystic fibrosis: comparison with BAL , 2003, European Respiratory Journal.

[5]  G. Scheuch,et al.  Peripheral deposition of α1‐protease inhibitor using commercial inhalation devices , 2003, European Respiratory Journal.

[6]  F. Lottspeich,et al.  Limited proteolysis of surfactant protein D causes a loss of its calcium-dependent lectin functions. , 2003, Biochimica et biophysica acta.

[7]  M. Griese,et al.  Proteolysis of Surfactant Protein D by Cystic Fibrosis Relevant Proteases , 2003, Lung.

[8]  M. Konstan,et al.  Inflammatory mediators in CF patients. , 2002, Methods in molecular medicine.

[9]  N. Alexis,et al.  Sputum phagocytes from healthy individuals are functional and activated: a flow cytometric comparison with cells in bronchoalveolar lavage and peripheral blood. , 2000, Clinical immunology.

[10]  J. Heesemann,et al.  Specific and Rapid Detection by Fluorescent In Situ Hybridization of Bacteria in Clinical Samples Obtained from Cystic Fibrosis Patients , 2000, Journal of Clinical Microbiology.

[11]  M. Ballmann,et al.  Fractional analysis of bronchoalveolar lavage fluid cytology in cystic fibrosis patients with normal lung function. Bronchoalveolar lavage for the evaluation of anti-inflammatory treatment (BEAT) study group. , 2000, The European respiratory journal.

[12]  A. Cantin,et al.  Aerosolized prolastin suppresses bacterial proliferation in a model of chronic Pseudomonas aeruginosa lung infection. , 1999, American journal of respiratory and critical care medicine.

[13]  M. Konstan,et al.  Altered respiratory epithelial cell cytokine production in cystic fibrosis. , 1999, The Journal of allergy and clinical immunology.

[14]  Melvin Berger,et al.  Current understanding of the inflammatory process in cystic fibrosis: Onset and etiology , 1997, Pediatric pulmonology.

[15]  E. Allen.  Opportunities for the Use of Aerosolized α1-Antitrypsin for the Treatment of Cystic Fibrosis , 1996 .

[16]  E. Allen.  Opportunities for the use of aerosolized alpha 1-antitrypsin for the treatment of cystic fibrosis. , 1996, Chest.

[17]  C. Boudier,et al.  Cleavage of lymphocyte surface antigens CD2, CD4, and CD8 by polymorphonuclear leukocyte elastase and cathepsin G in patients with cystic fibrosis. , 1995, Journal of immunology.

[18]  P. Birrer.  Proteases and antiproteases in cystic fibrosis: pathogenetic considerations and therapeutic strategies. , 1995, Respiration; international review of thoracic diseases.

[19]  G. Döring.  The role of neutrophil elastase in chronic inflammation. , 1994, American journal of respiratory and critical care medicine.

[20]  R. Crystal,et al.  Protease-antiprotease imbalance in the lungs of children with cystic fibrosis. , 1994, American journal of respiratory and critical care medicine.

[21]  R. Crystal,et al.  Neutrophil elastase in respiratory epithelial lining fluid of individuals with cystic fibrosis induces interleukin-8 gene expression in a human bronchial epithelial cell line. , 1992, The Journal of clinical investigation.

[22]  K. Havemann,et al.  Regulation of neutrophil functions by elastase-generated IgG fragments. , 1992, Archivum immunologiae et therapiae experimentalis.

[23]  R. Crystal,et al.  Neutrophil accumulation in the lung in alpha 1-antitrypsin deficiency. Spontaneous release of leukotriene B4 by alveolar macrophages. , 1991, The Journal of clinical investigation.

[24]  K. Havemann,et al.  Inhibition of Neutrophil Chemotaxis by Elastase‐Generated IgG Fragments , 1991, Scandinavian journal of immunology.

[25]  R. Crystal,et al.  Aerosol α1 -antitrypsin treatment for cystic fibrosis , 1991, The Lancet.

[26]  R. Stockley,et al.  Effects of human neutrophil elastase and Pseudomonas aeruginosa proteinases on human respiratory epithelium. , 1991, American journal of respiratory cell and molecular biology.

[27]  S. Suter,et al.  Proteolytic inactivation of alpha 1-proteinase inhibitor in infected bronchial secretions from patients with cystic fibrosis. , 1991, The European respiratory journal.

[28]  R. Crystal,et al.  Aerosol alpha 1-antitrypsin treatment for cystic fibrosis. , 1991, Lancet.

[29]  K. Havemann,et al.  Inhibition of neutrophil oxidative burst by elastase-generated IgG fragments. , 1990, Biological chemistry Hoppe-Seyler.

[30]  R. Fick,et al.  Functional importance of cystic fibrosis immunoglobulin G fragments generated by Pseudomonas aeruginosa elastase. , 1989, The Journal of laboratory and clinical medicine.

[31]  D. Dearborn,et al.  Complement receptor expression on neutrophils at an inflammatory site, the Pseudomonas-infected lung in cystic fibrosis. , 1989, The Journal of clinical investigation.

[32]  S. Suter,et al.  Fibronectin-cleaving activity in bronchial secretions of patients with cystic fibrosis. , 1988, The Journal of infectious diseases.

[33]  K. Havemann,et al.  Neoantigenic group on Fc fragments in rheumatoid arthritis synovial fluids. , 1988, Scandinavian journal of rheumatology. Supplement.

[34]  A. Kharazmi,et al.  Elastase from polymorphonuclear leucocytes: a regulatory enzyme in immune complex disease. , 1986, Clinical and experimental immunology.

[35]  R. Baltimore,et al.  IgG proteolytic activity of Pseudomonas aeruginosa in cystic fibrosis. , 1985, The Journal of infectious diseases.

[36]  J. Gee,et al.  Proteins of the cystic fibrosis respiratory tract. Fragmented immunoglobulin G opsonic antibody causing defective opsonophagocytosis. , 1984, The Journal of clinical investigation.

[37]  P. Kimbel.  Proteolytic lung damage. , 1980, Chest.

[38]  J. Gustafson,et al.  Cystic Fibrosis , 2009, Journal of the Iowa Medical Society.