ABSTRACT
Idiopathic pulmonary fibrosis (IPF) is a restrictive lung disease that is associated with high morbidity and mortality. Current medical therapies are not fully effective at limiting mortality in patients with IPF, and new therapies are urgently needed. Matrix metalloproteinases (MMPs) are proteinases that, together, can degrade all components of the extracellular matrix and numerous nonmatrix proteins. MMPs and their inhibitors, tissue inhibitors of MMPs (TIMPs), have been implicated in the pathogenesis of IPF based upon the results of clinical studies reporting elevated levels of MMPs (including MMP-1, MMP-7, MMP-8, and MMP-9) in IPF blood and/or lung samples. Surprisingly, studies of gene-targeted mice in murine models of pulmonary fibrosis (PF) have demonstrated that most MMPs promote (rather than inhibit) the development of PF and have identified diverse mechanisms involved. These mechanisms include MMPs: (1) promoting epithelial-to-mesenchymal transition (MMP-3 and MMP-7); (2) increasing lung levels or activity of profibrotic mediators or reducing lung levels of antifibrotic mediators (MMP-3, MMP-7, and MMP-8); (3) promoting abnormal epithelial cell migration and other aberrant repair processes (MMP-3 and MMP-9); (4) inducing the switching of lung macrophage phenotypes from M1 to M2 types (MMP-10 and MMP-28); and (5) promoting fibrocyte migration (MMP-8). Two MMPs, MMP-13 and MMP-19, have antifibrotic activities in murine models of PF, and two MMPs, MMP-1 and MMP-10, have the potential to limit fibrotic responses to injury. Herein, we review what is known about the contributions of MMPs and TIMPs to the pathogenesis of IPF and discuss their potential as therapeutic targets for IPF.
Subject(s)
Idiopathic Pulmonary Fibrosis/drug therapy , Idiopathic Pulmonary Fibrosis/genetics , Lung/drug effects , Macrophages, Alveolar/drug effects , Matrix Metalloproteinases, Secreted/genetics , Animals , Cell Movement/drug effects , Disease Models, Animal , Epithelial-Mesenchymal Transition/drug effects , Epithelial-Mesenchymal Transition/genetics , Extracellular Matrix/drug effects , Extracellular Matrix/pathology , Gene Expression Regulation , Humans , Idiopathic Pulmonary Fibrosis/enzymology , Idiopathic Pulmonary Fibrosis/pathology , Lung/enzymology , Lung/pathology , Macrophages, Alveolar/enzymology , Macrophages, Alveolar/pathology , Matrix Metalloproteinase Inhibitors/therapeutic use , Matrix Metalloproteinases, Secreted/antagonists & inhibitors , Matrix Metalloproteinases, Secreted/classification , Matrix Metalloproteinases, Secreted/metabolism , Mice , Molecular Targeted Therapy , Randomized Controlled Trials as Topic , Signal TransductionABSTRACT
OBJECTIVE: The aim was to evaluate immunoexpression of matrix metalloproteinases (MMPs) 1, 2, 7, 9, and 26 in calcifying cystic odontogenic tumor (CCOT). STUDY DESIGN: Ten cases of CCOT were assessed by immunohistochemical expression of MMPs 1, 2, 7, 9, and 26 in the parenchyma and stroma. Metalloproteinase immunoexpressions and their distribution pattern were semiquantitatively scored. RESULTS: MMPs were expressed in the parenchyma and stroma in all cases of CCOT. Regarding the percentage of immunostained parenchymal cells, MMPs 1, 7, and 9 showed score 2 in 100% of cases. For MMP-2, there was a predominance of score 0 (90%), whereas for MMP-26 immunostaining was varied. CONCLUSIONS: The staining of these metalloproteinases, with the exception of MMP-2, suggests their contribution to tumor growth and expansion. The presence of these metalloproteinases in stromal cells reveals the active participation of these cells in the degradation of the extracellular matrix, contributing to the growth of the tumor studied.
