LOCALIZATION OF MATRIX METALLOPROTEINASE-1, METALLOPROTEINASE-2, AND METALLOPROTEINASE-9 AND TISSUE INHIBITOR OF METALLOPROTEINASE-2 IN INTERSTITIAL LUNG-DISEASES

In interstitial lung diseases, deposition of extracellular matrix (ECM ) in alveoli and degradation of ECM lead to pulmonary structural remod eling. The changes in ECM and the localization of matrix metalloprotei nases (MMPs) and a tissue inhibitor of metalloproteinases (TIMP) in th e lung tissues of patients with bronchiolitis obliterans organizing pn eumonia (BOOP) and idiopathic pulmonary fibrosis (IPF) were investigat ed. Immunohistochemical analysis for the detection of fibronectin, col lagen-I, -III, and -IV, smooth muscle actin, MMP-1 (interstitial colla genase), -2 (gelatinase A), and -9 (gelatinase B), and TIMP-2, and in situ hybridization for the detection of MMP-9 mRNA were performed. Wes tern blotting of lung tissue homogenates was performed for MMP-2 and M MP-9. The gelatinolytic activities of the homogenates were also determ ined using gelatin zymography. Fibronectin and collagen-I, -III, and - IV were detected in the intra-alveolar fibrosis in addition to the int erstitium of these diseases. MMP-1, MMP-2, MMP-9, and TIMP-2 were dete cted in the regenerated epithelial cells covering intra-alveolar fibro sis. Myofibroblasts in intra-alveolar fibrosis in BOOP showed predomin ant reaction for MMPs, and they ultrastructurally appeared to be phago cytosing collagen fibrils, and those of IPF showed a predominant react ion for TIMP-2. New vascularization in intra-alveolar fibrosis was exc lusively observed in cases of BOOP, and the endothelial cells were pos itive for MMP-2. Western blotting showed the existence of a latent for m of MMP-9 and latent and active forms of MMP-2, and gelatin zymograph y revealed that the ratio of active/latent forms of MMP-2 in BOOP is s ignificantly larger than that in the control lungs. Predominant MMPs i n BOOP may constitute the mechanism of reversibility of fibrotic chang es in this disease. TIMP-2 in myofibroblasts in IPF may contribute to the stable ECM deposition and the irreversible pulmonary structural re modeling.