Remodeling of the Respiratory Unit in Silica-exposed Mice

Lung remodeling is a feature of many chronic lung diseases, leading to structural changes in airways and parenchyma. An interesting feature of this remodeling is the role it may play in ongoing airway inflammation. Attention has focused on matrixderived cleavage products as chemoattractants in chronic neutrophilic lung diseases such as cystic fibrosis (CF). Our lab has characterized a collagen fragment, proline-glycine-proline (PGP), which serves as a neutrophil chemoattractant in a murine model of LPS-induced lung injury and is present in CF specimens. We hypothesized that sputum from patients with CF had the capability of generating PGP from intact collagen and that elevated matrix metalloprotease (MMP) activity in CF sputum contributed to PGP generation. CF sputum was collected from inpatients with CF with active exacerbation (n 5 10) and control subjects without CF (n 5 5). CF sputum was incubated with intact collagen, with and without MMP inhibitors. These samples were then examined for PGP generation via tandem mass spectrometry. CF sputum, when placed on intact collagen, is capable of generating PGP in quantities 10-fold greater than levels generated from the sputum of normal control subjects (P , 0.05). PGP production from CF sputum was inhibited 80% with pre-incubation with an MMP-9–specific inhibitor (P , 0.01). PGP is an important chemoattractant seen in CF. The enzymatic components necessary for the generation of PGP are elevated in CF sputum compared with sputum from normal control subjects. The use of an MMP-9 inhibitor demonstrated a significant decrease in PGP production from CF sputum and points to a central role of MMP-9 in PGP generation