https://www.ncbi.nlm.nih.gov/pubmed/26121236
Matrix metalloproteinases as therapeutic targets for idiopathic pulmonary fibrosis.
Craig VJ1,2,
Zhang L1,
Hagood JS3,4,
Owen CA1,5
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
- [Indexed for MEDLINE]
Free PMC Article
Clinical Relevance
In this Translational Review,
we describe the molecular and cell biology of matrix metalloproteinases
(MMPs) and tissue inhibitors of metalloproteinases, and review the
evidence that links MMPs to idiopathic pulmonary fibrosis (IPF), the
cellular sources of MMPs, and the mechanisms involved. Although initial
studies of randomized clinical trials for nonselective MMP inhibitors as
new therapies for cancer produced disappointing results, since then,
newer approaches to target metalloproteinases more selectively have been
developed for other diseases. We have included a discussion of the
advantages (and potential limitations) of these new therapeutic
approaches targeting MMPs and their potential as therapeutics for IPF.
Idiopathic Pulmonary Fibrosis
In
the United States, approximately 50,000 patients are newly diagnosed
with idiopathic pulmonary fibrosis (IPF) each year. The median survival
of patients with IPF is only 3–5 years (
1).
Although numerous medical therapies have been evaluated in patients
with IPF, the only therapies that slow the progression of this disease,
pirfenidone (
2) and nintedanib (
3),
are associated with side effects and are not fully effective at
reducing mortality. Thus, there is an urgent need to identify novel
therapeutic targets for IPF. Herein, we review the evidence linking
members of the matrix metalloproteinase (MMP) family to the pathogenesis
of IPF, identify knowledge gaps in the field of MMPs and IPF, and
discuss potential approaches to target MMPs as novel therapeutics for
IPF.
IPF is characterized by the
deposition of excessive amounts of extracellular matrix (ECM) proteins
in the lungs, thereby replacing the normal architecture of the lung. IPF
is the most common type of idiopathic interstitial pneumonia, and is
characterized pathologically by the pattern of usual interstitial
pneumonitis. Although the etiology of IPF is still unclear, several
pathogenic mechanisms have been implicated in its development, including
aberrant repair of injured epithelium, fibroblast activation,
epithelial-to-mesenchymal transition (EMT), collagen deposition, and
immune cell dysfunction. MMPs are expressed by most of the cellular
culprits and pathologic processes implicated in IPF pathogenesis.
MMPs
MMPs
are zinc-dependent endopeptidases that, together, degrade all
components of the ECM. Consequently, it was initially thought that MMPs
would limit lung fibrosis by degrading ECM proteins in the lung.
However, recent studies have implicated MMPs in regulating the
activities of proteins other than ECM proteins, including mediators of
inflammation, latent growth factors, antifibrotic growth factors, and
cleaving cell surface molecules and receptors. However, most studies of
MMP-deficient mice in pulmonary fibrosis (PF) models have shown the
opposite—that MMPs promote pulmonary fibrotic responses to injury.
MMP Structure
MMPs are multidomain proteins ().
The signal peptide at the amino terminus targets the protein to the
cell’s secretory pathway. The propeptide domain, containing the highly
conserved cysteine switch motif, PRCGXPD, is cleaved during activation
of the latent proenzyme by yet-to-be identified peptidases. The
catalytic domain contains the highly conserved Zn2+-binding
motif, HEXXHXXGXXH, in which the three histidines (H) bind to the active
site zinc, and the nucleophilic glutamate (E) attacks the substrate’s
peptide bond. The proline-rich hinge domain connects the catalytic
domain to the C-terminal domain with a flexible segment of up to 75
residues. The carboxyterminal hemopexin-like domain regulates substrate
binding and specificity. Some MMPs contain additional domans
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