Aerosolized rhDNase in cystic fibrosis: effect on leucocyte proteases in sputum.
In cystic fibrosis (CF), large amounts of free leucocyte proteases are present in bronchial secretions, contributing to progressive lung damage. Recombinant, human deoxyribonuclease (rhDNase) is a new therapeutic agent that decreases sputum viscosity. However, deoxyribonuclease has been shown, in vitro, to release cationic enzymes from complexes with deoxyribonucleic acid (DNA). The present study was conducted to assess this effect in vivo. Free human leucocyte elastase (HLE), human leucocyte cathepsin G (HCG), total chemotactic activity, and interleukin-8 (IL-8) were determined in sputum from eight patients before, during and after rhDNase treatment. After 15 days of treatment, HLE activity increased by 81+/-44% (NS), and HCG by 189+/-70% (p<0.05). One week after stopping a 4-6 months treatment, HLE activity decreased by 35+/-18% (p<0.05), and HCG by 43+/-11% (p<0.05). Sputum bacterial density, chemotactic activity, and IL-8 concentration did not change. Thus, treatment with rhDNase can indeed increase the activity of HLE and HCG in the bronchial secretions of CF patients, and this effect is still detectable after several months of treatment. If this can be shown to be clinically relevant, combination therapy of recombinant human deoxyribonuclease with protease inhibitors should be considered as an approach to the problem.
Rochat
T
T
Dept of Medicine, University Hospital, Geneva, Switzerland.
Pastore
F D
FD
Schlegel-Haueter
S E
SE
Filthuth
I
I
Auckenthaler
R
R
Belli
D
D
Suter
S
S
D000328:Adult; D000336:Aerosols; D056649:Cathepsin G; D002403:Cathepsins / Q000032:analysis*; D002634:Chemotaxis, Leukocyte; D003550:Cystic Fibrosis / Q000201:enzymology / Q000628:therapy*; D003851:Deoxyribonucleases / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000032:analysis; D019272:Leukocyte Elastase / Q000032:analysis*; D008297:Male; D011550:Pseudomonas aeruginosa / Q000302:isolation & purification; D011994:Recombinant Proteins / Q000627:therapeutic use; D012697:Serine Endopeptidases / Q000032:analysis*; D013183:Sputum / Q000737:chemistry / Q000201:enzymology* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000302:isolation & purification
D000336:Aerosols; D016209:Interleukin-8; D011994:Recombinant Proteins; D003851:Deoxyribonucleases; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; D019272:Leukocyte Elastase