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.
Based on the knowledge that neutrophil elastase (NE) in cystic fibrosis (CF) epithelial lining fluid (ELF) can induce human bronchial epithelial cells to express the gene for interleukin 8 (IL-8), an 8.5-kD neutrophil chemoattractant, we have evaluated CF ELF for the presence of IL-8, and investigated the ability of aerosolized recombinant secretory leukoprotease inhibitor (rSLPI) to suppress NE, and hence IL-8, levels on the respiratory epithelial surface in CF. Enzyme-linked immunoassay revealed 21.9 +/- 4.8 nM IL-8 in CF ELF compared with none in normals. Active NE was detectable in ELF of all individuals with CF and was significantly decreased (P < 0.03) after aerosolization of rSLPI. Human bronchial epithelial cells exposed to CF ELF recovered before rSLPI therapy expressed IL-8 mRNA transcripts, but ELF recovered after rSLPI therapy induced far less bronchial epithelial cell IL-8 gene expression. Consistent with this, rSLPI aerosol therapy caused a marked reduction in CF ELF IL-8 levels (P < 0.05) and neutrophil number (P < 0.02). There was also a clear association between CF ELF active NE and IL-8 levels (r = 0.94). These data suggest that rSLPI therapy not only suppresses respiratory epithelial NE levels, but also breaks a cycle of inflammation on the CF epithelial surface.
Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892.
N G
NG
McElvaney
H
H
Nakamura
P
P
Birrer
C A
CA
Hébert
W L
WL
Wong
M
M
Alphonso
J B
JB
Baker
M A
MA
Catalano
R G
RG
Crystal
D000328:Adult; D000336:Aerosols; D003550:Cystic Fibrosis / Q000150:complications / Q000188:drug therapy*; D004112:Dimercaprol / Q000737:chemistry; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000517:prevention & control*; D016209:Interleukin-8 / Q000032:analysis* / Q000235:genetics; D019272:Leukocyte Elastase; D008297:Male; D010196:Pancreatic Elastase / Q000032:analysis; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D012137:Respiratory System / Q000187:drug effects* / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*
D000336:Aerosols; D016209:Interleukin-8; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D011994:Recombinant Proteins; D015842:Serine Proteinase Inhibitors; D004112:Dimercaprol; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase