Aerosolization of recombinant SLPI to augment antineutrophil elastase protection of pulmonary epithelium.
In a variety of lung diseases the respiratory epithelial surface must contend with an increased burden of neutrophil elastase (NE). One candidate for augmenting epithelial anti-NE protection is the secretory leukoprotease inhibitor (SLPI). In vitro evaluation demonstrated that 96 +/- 1% of the recombinant SLPI (rSLPI) molecules were capable of inhibiting NE, with an association rate constant of 7.1 +/- 0.1 X 10(6) M-1.s-1. Evaluation of rSLPI after in vitro and in vivo aerosolization showed that aerosolization did not alter rSLPI. Aerosolization of a single dose of 50 mg rSLPI to sheep resulted in a fourfold increase of the anti-NE capacity in epithelial lining fluid (ELF) at 3 h, with a half-life in ELF of 12 h. After aerosolization some rSLPI appeared in lung lymph. Simultaneous aerosolization of rSLPI and recombinant alpha 1-antitrypsin (rAAT) demonstrated a molar ratio of the concentration in lymph to the concentration in ELF 3 h after the aerosol eightfold higher for rAAT than for rSLPI. Overall, these observations demonstrate that it is feasible to use aerosolized rSLPI to directly augment the anti-NE capacity of the lung, particularly on the pulmonary epithelial surface.
Vogelmeier
C
C
Section of Laboratory Animal Medicine and Surgery, National Heart Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892.
Buhl
R
R
Hoyt
R F
RF
Wilson
E
E
Fells
G A
GA
Hubbard
R C
RC
Schnebli
H P
HP
Thompson
R C
RC
Crystal
R G
RG
D000336:Aerosols; D000818:Animals; D001692:Biological Transport; D001826:Body Fluids / Q000378:metabolism; D004848:Epithelium / Q000502:physiology; D005240:Feasibility Studies; D006207:Half-Life; D019272:Leukocyte Elastase; D007962:Leukocytes / Q000378:metabolism / Q000502:physiology; D008168:Lung / Q000502:physiology*; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D011994:Recombinant Proteins; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D012756:Sheep; D013329:Structure-Activity Relationship
D000336:Aerosols; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D011994:Recombinant Proteins; D015842:Serine Proteinase Inhibitors; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase