Matrix metalloproteases in BAL fluid of patients with cystic fibrosis and their modulation by treatment with dornase alpha

Abstract

Background: Matrix metalloproteinases (MMPs) are involved in the remodelling and degradation of extracellular matrix and may play a role in pulmonary tissue destruction in cystic fibrosis (CF). Methods: Bronchoalveolar lavage (BAL) fluid levels of MMP-8, MMP-9, and their natural inhibitor TIMP-1 were measured on two occasions within 18 months in 23 children with mild CF, 13 of whom were treated with DNase. Results: MMP-8 (39.3 (6.8) v 0.12 (0.01) ng/ml), MMP-9 (58.0 (11.4) v 0.5 (0.02) ng/ml), and the molar ratio of MMP-9/TIMP-1 (0.36 (0.05) v 0.048 (0.01)) were significantly higher in patients with CF than in control children without lung disease. Gelatine zymography showed the typical banding pattern of neutrophil derived MMP-9, including 130 kDa NGAL-MMP-9 complex and 92 kDa latent MMP-9 bands; 85 kDa bands (corresponding to active MMP-9) were seen in all patients. There was a close correlation between BAL fluid concentrations of MMPs and α 2 -macroglobulin, a marker of alveolocapillary leakage. After 18 months MMP levels were increased in untreated patients and decreased in patients treated with DNase. Conclusions: Uninhibited MMPs may contribute to pulmonary tissue destruction even in CF patients with mild lung disease that may be positively affected by treatment with DNase.

Inhibition of airway proteases in cystic fibrosis lung disease

“…HLE was found to be an activator of MMP-9 [61] and an inactivator of the MMP inhibitor TIMP-1 [44], resulting in an imbalance in MMP and TIMP. Recently, these findings have been confirmed at concentrations of HLE demonstrated in CF lung disease [62,63]. The increased activation of MMP-9 in CF lung disease has many possible downstream inflammatory effects, including activation of latent transforming growth factor (TGF)-b) [64] and the possible liberation of collagen fragments chemotactic for neutrophils [65].…”

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…In patients suffering from cystic fibrosis (CF), MMP-8 levels correlate with PMN counts (Ratjen et al, 2002) and in patients with a more advanced CF disease state there is also correlation with disease severity (Power et al, 1994). High levels of neutrophils and accompanying MMP-8 also correlate with the fibrotic state in patients suffering from hypersensitivity pneumonitis .…”

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.…”