Role of matrix metalloproteinases in models of macrophage-dependent acute lung injury - Evidence for alveolar macrophage as source of proteinases

Matrix metalloproteinases (MMPs) have been implicated in the tissue injury seen in neutrophil-dependent models of acute lung injury. However, the role of MMPs in macrophage-dependent models of lung injury is unknown. To addre ss this issue, the macrophage-dependent immunoglobulin A immune comp le x-i nduced lung injury model and the macrophage-dependent portion of the lipopo lysaccharide-induced acute lung injury model in the rat were assessed for M MP involvement and for the source of these activities. In both models, inju ry was inhibited by the recombinant human tissue inhibitor of metalloprotei nases-2. Bronchoalveolar lavage fluids (BALFs) from injured animals in both models showed increased levels of MMPs. Characterization of MMP production by isolated lung fibroblasts, endothelial cells, type II epithelial cells, and alveolar macrophages revealed that only the macrophage had the same sp ectrum of MMP activity as seen in the BALF. Further, isolated alveolar macr ophages from injured lungs showed evidence of in vivo activation with the r elease of the same spectrum of MMP activities. Together these studies show that MMPs are produced during macrophage-dependent lung injury, that these MMPs play a role in the development of the lung injury, and that the alveol ar macrophage is the likely source of these MMPs.