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

Abstract

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.

Flagellin Induces Myeloid-Derived Suppressor Cells: Implications for Pseudomonas aeruginosa Infection in Cystic Fibrosis Lung Disease

“…On the basis of our unexpected observation that an increase of MDSCs correlated with improved pulmonary function in P. aeruginosa-infected CF patients, we speculate that the MDSCmediated downregulation of Th17 responses dampens neutrophilic lung tissue damage and could therefore beneficially modulate the course of CF lung disease, a conception necessitating future investigations. This "anti-inflammatory" action of MDSCs could be of major relevance for progressive stages of CF lung disease, when damage-associated molecular patterns, neutrophil-derived proteases, and protease-generated extracellular breakdown products, such as proline-glycine-proline, further sustain the neutrophil influx and perpetuate IL-17-driven inflammation (48,49). As 1) P. aeruginosa-uninfected CF patients showed increased MDSCs compared with healthy controls, 2) CFTR inhibition had a slight effect on MDSC induction, and 3) flagellin induced host-derived G-CSF expression in vitro, the CFTR mutation itself and non-P. aeruginosa host-derived factors probably also contribute to MDSC induction in the course of CF lung disease.…”

Proteases and cystic fibrosis

“…Although concentrations of NE and NE activity levels are predominant in the ASL of CF patients, high levels of cathepsin G (Goldstein and Doring, 1986), and proteinase 3 are also present in bronchoalveolar lavage (BAL) fluid of CF patients (Witko-Sarsat et al, 1999). The neutrophil metalloproteases, collagenase (MMP-8) and gelatinase (MMP-9), stored in specific granules and tertiary granules respectively, are also released into the ASL of CF patients under inflammatory conditions and are found in high concentrations in the BAL (Ratjen et al, 2002, Gaggar et al, 2007.…”

Interfering with extracellular matrix degradation to blunt inflammation

“…Recently, our group has described the expression of discrete MMP isoforms (MMP's-8, 9, 11, and 12) in sputum from CF patients [14]. CF alveolar epithelium demonstrates increased MMP-7 expression [15].…”