title: Matrix metalloproteinases as therapeutic targets for idiopathic pulmonary fibrosis.
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.
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts.|2 Division of Pulmonary, Critical Care, and Sleep Medicine, University of California-San Diego, La Jolla, California.
authors.forename: Vanessa J
authors.initials: VJ
authors.lastname: Craig
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: 3 Division of Pediatric Respiratory Medicine, University of California-San Diego, La Jolla, California, and.|4 Rady Children's Hospital of San Diego, San Diego, California; and.
authors.forename: James S
authors.initials: JS
authors.lastname: Hagood
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts.|5 Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Owen
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D005109:Extracellular Matrix / Q000187:drug effects / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D061965:Matrix Metalloproteinase Inhibitors / Q000627:therapeutic use; D053505:Matrix Metalloproteinases, Secreted / Q000037:antagonists & inhibitors / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D058990:Molecular Targeted Therapy; D016032:Randomized Controlled Trials as Topic; D015398:Signal Transduction
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D053505:Matrix Metalloproteinases, Secreted
keywords: fibrosis; idiopathic pulmonary fibrosis; interstitial lung disease; lung; matrix metalloproteinase