Matrix metalloprotease-9 dysregulation in lower airway secretions of cystic fibrosis patients.
Matrix metalloproteases (MMPs) are proteolytic enzymes that regulate extracellular matrix turnover and aid in restoring tissue architecture following injury. There is an emerging role for extracellular matrix destruction in the pathogenesis of chronic neutrophilic lung diseases. In this study, we examined the expression and activity profiles of MMPs in lower airway secretions from cystic fibrosis (CF) patients, patients with acute respiratory failure (ARF), and normal controls. A discrete repertoire of MMP isoforms was found in the CF samples, with robust MMP-9 expression compared with normal controls and ARF. CF samples possessed increased levels of active MMP-9, as well as decreased amounts of tissue inhibitor of metalloprotease-1 (TIMP-1), a natural inhibitor of MMP-9. The CF inpatient samples demonstrated fully active MMP-9 activity compared with CF outpatients, ARF, and normal controls. CF samples also demonstrated increased human neutrophil elastase (HNE) levels compared with ARF and normal controls. To examine potential mechanisms for the protease dysregulation seen in the CF clinical samples, in vitro studies demonstrated that HNE could activate pro-MMP-9 and also degrade TIMP-1; this HNE-based activation, however, was not seen with MMP-8. A strong correlation was seen between HNE and MMP-9 activity in CF inpatient samples. Finally, the dysregulated MMP-9 activity seen in CF inpatient sputum samples could be significantly reduced by the use of MMP-9 inhibitors. Collectively, these findings further emphasize the proposed protease/antiprotease imbalance in chronic neutrophilic lung disease, providing a potential mechanism contributing to this proteolytic dysregulation.
Gaggar
Amit
A
Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA. agaggar@uab.edu
Li
Yao
Y
Weathington
Nathaniel
N
Winkler
Margaret
M
Kong
Michele
M
Jackson
Patricia
P
Blalock
J E
JE
Clancy
J P
JP
D000293:Adolescent; D000328:Adult; D012634:Bodily Secretions / Q000201:enzymology*; D002648:Child; D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000201:enzymology* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D019272:Leukocyte Elastase / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D008954:Models, Biological; D012137:Respiratory System / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism*; D013183:Sputum / Q000187:drug effects / Q000201:enzymology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism
D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; D019272:Leukocyte Elastase; D020780:Matrix Metalloproteinase 9