Decreased levels of secretory leucoprotease inhibitor in the Pseudomonas-infected cystic fibrosis lung are due to neutrophil elastase degradation.
Secretory leucoprotease inhibitor (SLPI) is a neutrophil serine protease inhibitor constitutively expressed at many mucosal surfaces, including that of the lung. Originally identified as a serine protease inhibitor, it is now evident that SLPI also has antimicrobial and anti-inflammatory functions, and therefore plays an important role in host defense. Previous work has shown that some host defense proteins such as SLPI and elafin are susceptible to proteolytic degradation. Consequently, we investigated the status of SLPI in the cystic fibrosis (CF) lung. A major factor that contributes to the high mortality rate among CF patients is Pseudomonas aeruginosa infection. In this study, we report that P. aeruginosa-positive CF bronchoalveolar lavage fluid, which contains lower SLPI levels and higher neutrophil elastase (NE) activity compared with P. aeruginosa-negative samples, was particularly effective at cleaving recombinant human SLPI. Additionally, we found that only NE inhibitors were able to prevent SLPI cleavage, thereby implicating NE in this process. NE in excess was found to cleave recombinant SLPI at two novel sites in the NH(2)-terminal region and abrogate its ability to bind LPS and NF-kappaB consensus binding sites but not its ability to inhibit activity of the serine protease cathepsin G. In conclusion, this study provides evidence that SLPI is cleaved and inactivated by NE present in P. aeruginosa-positive CF lung secretions and that P. aeruginosa infection contributes to inactivation of the host defense screen in the CF lung.
Weldon
Sinéad
S
Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, Northern Ireland.
McNally
Paul
P
McElvaney
Noel G
NG
Elborn
J Stuart
JS
McAuley
Danny F
DF
Wartelle
Julien
J
Belaaouaj
Abderrazzaq
A
Levine
Rodney L
RL
Taggart
Clifford C
CC
D000293:Adolescent; D000595:Amino Acid Sequence; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology / Q000382:microbiology; D002648:Child; D003550:Cystic Fibrosis / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D019272:Leukocyte Elastase / Q000378:metabolism* / Q000502:physiology; D008168:Lung / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D008969:Molecular Sequence Data; D011552:Pseudomonas Infections / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D053481:Secretory Leukocyte Peptidase Inhibitor / Q000037:antagonists & inhibitors* / Q000378:metabolism*
C506814:SLPI protein, human; D053481:Secretory Leukocyte Peptidase Inhibitor; D019272:Leukocyte Elastase