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

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 al-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 onethird 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. (J. Clin. Invest. 1991. 87:482-488.)

Oxidized mucus proteinase inhibitor: a fairly potent neutrophil elastase inhibitor

“…This result is new and does not fully agree with previous reports demonstrating full oxidative inactivation of the inhibitor (Carp and Janoff, 1980;Kramps et al, 1990;Vogelmeier et al, 1991). These authors used NE concentrations in the nanomolar range to assess the elastase inhibitory capacity of the modified inhibitor.…”

“…This may explain why oxidants depress its anti-NE capacities (Carp and Janoff, 1980;Smith et al, 1987;Kramps et al, 1990;Vogelmeier et al, 1991). The kinetic consequences of MPI oxidation on its interaction with NE have however never been investigated, and a possible anti-elastase function of the oxidized inhibitor in vivo was therefore impossible to predict.…”

Transforming growth factor-β1 is a potent inhibitor of secretory leukoprotease inhibitor expression in a bronchial epithelial cell line

“…SLPI is the major antielastase of the conducting airways [18]. SLPI is a 12-kDa, nonglycosylated, disulphide-linked antiprotease secreted by cells of mucosal surfaces including the epithelium of the airways [17]. SLPI inhibits a variety of proteases, such as cathepsin G, trypsin, chymotrypsin, chymase, trypase, and NE.…”

Secretory Leukoprotease Inhibitor in Mucosal Lymph Node Dendritic Cells Regulates the Threshold for Mucosal Tolerance

“…Expression of SLPI in LN is surprising as the protein is predominantly found in fluids lining the mucosa, consistent with its role in protecting against elastase-induced damage during mucosal inflammation (35). To unravel the function of SLPI in cervical LN, we determined the cellular location of SLPI in these mucosa-draining nodes.…”