Matrix metalloproteinases as therapeutic targets for idiopathic pulmonary fibrosis - PubMed (original) (raw)

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Matrix metalloproteinases as therapeutic targets for idiopathic pulmonary fibrosis

Vanessa J Craig et al. Am J Respir Cell Mol Biol. 2015 Nov.

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.

Keywords: fibrosis; idiopathic pulmonary fibrosis; interstitial lung disease; lung; matrix metalloproteinase.

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Figures

Figure 1.

Figure 1.

Matrix metalloproteinase (MMP) classification by protein domain structure. MMPs can be categorized according to their protein domain structure. All MMPs share: (1) an N-terminal signal peptide and (2) a prodomain containing the consensus sequence in which a cysteine residue binds to the zinc ion in the catalytic domain to maintain enzyme latency. MMPs with the basic/simple domain structure also have a flexible linker region followed by a hemopexin-like domain (four-bladed β propeller structure), which helps determine substrate specificity. Minimal MMPs lack this linker and the hemopexin-like domain. Membrane-type MMPs are anchored to plasma membrane by either a transmembrane domain or a glycophosphatidyl inositol (GPI) anchor. Gelatin-binding MMPs contain fibronectin-binding sites in the catalytic domain. Furin-activated MMPs contain a furin cleavage site in their prodomain, allowing them to be activated intracellularly in the _trans_-Golgi network. C, carboxy terminus; Zn, zinc atom.

Figure 2.

Figure 2.

Cells that express MMPs and mechanisms or potential mechanisms by which MMPs regulate pulmonary fibrosis (PF) in murine model systems. MMPs are highly expressed in lung tissues during fibrosis but vary in their dominant cellular expression (epithelial cell, fibroblast, macrophage, fibrocyte, or peripheral blood leukocyte), compartmentalization in the lung (airway and airway/alveolar epithelium, lung interstitium, or blood), and their activity (profibrotic or antifibrotic). MMPs having overall profibrotic activities (assessed as increased total lung collagen levels) in murine models of PF include MMP-3, -7, -8, -9, -12, -13, and -28 (shown in the left panel). Based upon their in vitro activities or activities in other organs, MMP-1, -2, and -11 have potential to promote PF. MMPs having overall antifibrotic activities (assessed as decreased total lung collagen levels) in models of PF include MMP-13 and -19. Based upon its in vitro activities or activities in other organs, MMP-1 and -10 have potential to inhibit PF. Antifibrotic MMPs (or potentially antifibrotic MMPs) are shown in the right panel. The mechanisms by which MMPs promote or inhibit PF are illustrated in the middle panel. EMT, epithelial mesenchymal transition; MT1, membrane type 1 metalloprotease.

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