Matrix metalloprotease-9 dysregulation in lower airway secretions of cystic fibrosis patients

被引:100
作者
Gaggar, Amit
Li, Yao
Weathington, Nathaniel
Winkler, Margaret
Kong, Michele
Jackson, Patricia
Blalock, J. E.
Clancy, J. P.
机构
[1] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA
[2] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL 35294 USA
[3] Univ Alabama Birmingham, Dept Physiol Biophys, Birmingham, AL 35294 USA
关键词
matrix metalloprotease; protease; neutrophil elastase; inflammation;
D O I
10.1152/ajplung.00492.2006
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
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 metallo-protease-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.
引用
收藏
页码:L96 / L104
页数:9
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