The effects of recombinant human DNase on neutrophil elastase activity and interleukin-8 levels in the sputum of patients with cystic fibrosis.
In cystic fibrosis (CF), neutrophil-dominated airway inflammation results in high levels of neutrophil elastase (NE). Some of these proteases are sequestered by the large amounts of deoxyribonucleic acid (DNA) present in purulent sputum. Recombinant human deoxyribonuclease (rhDNase), a new treatment in CF, depolymerizes DNA. Our concerns were that this might release proteases bound to DNA, which could be potentially harmful. The in vitro and in vivo effects of rhDNase on NE and interleukin-8 (IL-8) were evaluated. The acute effects of rhDNase were evaluated in CF patients during the first 6 days of treatment. Medium-term effects were evaluated in stable CF patients observed in rhDNase over 6 months. Sputum samples were collected at regular intervals and NE activity was measured by a fluorimetric assay and IL-8 with a radioimmunoassay. In vitro addition of rhDNase resulted in a twofold increase in protease activity and this was reflected in an acute transient rise on initiation of treatment with rhDNase. Medium-term treatment was associated with a decline in NE activity and IL-8. These in vivo results are encouraging, since the increase in protease activity was transient and the trend over 6 months was a reduction in both inflammatory markers.
Shah
P L
PL
Dept of Cystic Fibrosis, Royal Brompton Hospital, London, UK.
Scott
S F
SF
Knight
R A
RA
Hodson
M E
ME
D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000503:physiopathology; D003850:Deoxyribonuclease I / Q000494:pharmacology / Q000627:therapeutic use*; D005100:Expectorants / Q000008:administration & dosage / Q000627:therapeutic use*; D005470:Fluorometry; D006801:Humans; D016209:Interleukin-8 / Q000032:analysis / Q000378:metabolism*; D019272:Leukocyte Elastase; D010196:Pancreatic Elastase / Q000187:drug effects / Q000378:metabolism*; D011863:Radioimmunoassay; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D013183:Sputum / Q000187:drug effects; D016896:Treatment Outcome
D005100:Expectorants; D016209:Interleukin-8; D011994:Recombinant Proteins; C085693:DNASE1 protein, human; D003850:Deoxyribonuclease I; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase