Anti-neutrophil elastase defense of the normal human respiratory epithelial surface provided by the secretory leukoprotease inhibitor.
Secretory leukoprotease inhibitor (SLPI), a 12-kD nonglycosylated serine antiprotease with a high capacity for inhibiting neutrophil elastase (NE), is produced by cells of mucosal surfaces including the human lung. The molar concentrations of SLPI in total respiratory tract epithelial lining fluid (ELF) were 56 +/- 10% that of alpha 1-antitrypsin, suggesting SLPI may be more important for the anti-NE protection of the pulmonary epithelial surface than previously thought. However, evaluation demonstrated that SLPI in respiratory ELF was only one-third functional. Studies aerosolizing recombinant SLPI (rSLPI) to sheep demonstrated that in the short term, neither aerosolization and alveolar deposition nor the lavage procedure inactivated the SLPI molecule. In vitro studies with rSLPI demonstrated that exposure to oxidants did not modify the form of the molecule, while exposure to oxidants and NE caused the molecule to be cleaved from 12 to 8 kD. Consistent with this, evaluation of SLPI in lavage fluid of individuals with cystic fibrosis (a condition with oxidants and NE on the respiratory epithelium) showed that the SLPI was degraded. However, evaluation of SLPI in normal ELF by molecular sieve analysis and Western analysis demonstrated an intact 12-kD molecule, suggesting that the partial inactivation of SLPI in normals in vivo is not because it is complexed to NE or exposed to oxidants + NE. Together, these observations demonstrate that SLPI is present in large amounts in respiratory ELF, but since the majority of the SLPI is inactive, it likely does not play a significant role in protecting the normal respiratory epithelium, except perhaps in the upper airways where the levels of SLPI are the highest.
Vogelmeier
C
C
Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892.
Hubbard
R C
RC
Fells
G A
GA
Schnebli
H P
HP
Thompson
R C
RC
Fritz
H
H
Crystal
R G
RG
D000328:Adult; D000336:Aerosols; D000818:Animals; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D004848:Epithelium / Q000201:enzymology; D005260:Female; D006801:Humans; D019272:Leukocyte Elastase; D008168:Lung / Q000201:enzymology*; D008297:Male; D010196:Pancreatic Elastase / Q000378:metabolism*; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D053481:Secretory Leukocyte Peptidase Inhibitor; D015842:Serine Proteinase Inhibitors / Q000502:physiology*; D012756:Sheep
D000336:Aerosols; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; C506814:SLPI protein, human; D053481:Secretory Leukocyte Peptidase Inhibitor; D015842:Serine Proteinase Inhibitors; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase