Anti-neutrophil elastase defense of the normal human respiratory epithelial surface provided by the secretory leukoprotease inhibitor

C. Vogelmeier, R. C. Hubbard, G. A. Fells, H. P. Schnebli, R. C. Thompson, H. Fritz, Ronald Crystal

Research output: Contribution to journalArticle

155 Citations (Scopus)

Abstract

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 α1-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.

Original languageEnglish
Pages (from-to)482-488
Number of pages7
JournalJournal of Clinical Investigation
Volume87
Issue number2
DOIs
Publication statusPublished - 1 Jan 1991
Externally publishedYes

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Secretory Leukocyte Peptidase Inhibitor
Leukocyte Elastase
Oxidants
Respiratory Mucosa
Therapeutic Irrigation
Lung
Protease Inhibitors

Keywords

  • antiprotease
  • bronchoalveolar lavage
  • α1-antitrypsin

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Anti-neutrophil elastase defense of the normal human respiratory epithelial surface provided by the secretory leukoprotease inhibitor. / Vogelmeier, C.; Hubbard, R. C.; Fells, G. A.; Schnebli, H. P.; Thompson, R. C.; Fritz, H.; Crystal, Ronald.

In: Journal of Clinical Investigation, Vol. 87, No. 2, 01.01.1991, p. 482-488.

Research output: Contribution to journalArticle

Vogelmeier, C. ; Hubbard, R. C. ; Fells, G. A. ; Schnebli, H. P. ; Thompson, R. C. ; Fritz, H. ; Crystal, Ronald. / Anti-neutrophil elastase defense of the normal human respiratory epithelial surface provided by the secretory leukoprotease inhibitor. In: Journal of Clinical Investigation. 1991 ; Vol. 87, No. 2. pp. 482-488.
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abstract = "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 α1-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.",
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