We report that matrilysin, a matrix metalloproteinase, is constitutively expressed in the epithelium of peribronchial glands and conducting airways in normal lung. Matrilysin expression was increased in airway epithelial cells and was induced in alveolar type II cells in cystic fibrosis. Other metalloproteinases (collagenase-1, stromelysin-1, and 92-kD gelatinase) were not produced by normal or injured lung epithelium. These observations suggest that matrilysin functions in injury-mediated responses of the lung. Indeed, matrilysin expression was increased in migrating airway epithelial cells in wounded human and mouse trachea. In human tissue, epithelial migration was reduced by Ͼ 80% by a hydroxamate inhibitor, and in mouse tissue, reepithelialization in trachea from matrilysin-null mice was essentially blocked. In vivo observations and cell culture studies demonstrated that matrilysin was secreted lumenally by lung epithelium, but upon activation or while migrating over wounds, some matrilysin was released basally. The constitutive production of matrilysin in conducting airways, its upregulation after injury, its induction by alveolar epithelium, and its release into both lumenal and matrix compartments suggest that this metalloproteinase serves multiple functions in intact and injured lung, one of which is to facilitate reepithelialization. ( J. Clin. Invest. 1998. 102:1321-1331.)
The lung and other organs are comprised of both cellular and extracellular compartments. Interaction of these components modulates physiological function at the organ, cellular, and subcellular levels. Extracellular components in the gas-exchange region of the lung include both noncellular interstitium and basement membranes. Connective tissue elements of the interstitium in part determine ventilatory function by contributions to tissue compliance and to resistance of the diffusion barrier. The basement membrane underlies cells of both the alveolar epithelium and the capillary endothelium; basement membrane components exert biological effects on adjacent cells through receptor-mediated interactions. This review emphasizes current knowledge concerning the composition and biological activity of extracellular matrix in the alveolar region of the lung. Matrix synthesis and turnover are also considered. Directions for future research are suggested in the context of current knowledge of the lung and other model systems.
Neutrophil elastase is a serine protease stored in the azurophilic granules of leukocytes. It has been implicated in the pathology of several lung diseases and is generally presumed to contribute to the tissue destruction and extracellular matrix damage associated with these conditions. To delineate the role of neutrophil elastase in pulmonary inflammation and fibrosis, neutrophil elastase-null mice were intratracheally instilled with bleomycin. In neutrophil elastase-null mice, biochemical and morphological characteristics of pulmonary fibrosis were attenuated for at least 60 days after bleomycin administration despite a typical response to bleomycin as evidenced by assessment of indices of DNA and cell damage. Neutrophil burden of bleomycin-treated wild-type and neutrophil elastasenull mice was comparable, and marked neutrophilic alveolitis was manifest in bleomycin-treated neutrophil elastase-null mice. An absence of immunostaining for active transforming growth factor (TGF)- in lung tissue from bleomycin-treated neutrophil elastase-null mice suggested a defect in TGF- activation, which was confirmed by biochemical assessment of TGF- levels in bronchoalveolar lavage fluid and lung tissue. These data point to novel and unexpected fibrogenic consequences of neutrophil elastase activity in the inflamed lung.
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