Matrix Metalloproteinases in Chronic Obstructive Pulmonary Disease

Abstract

Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade proteins of the extracellular matrix and the basement membrane. Thus, these enzymes regulate airway remodeling, which is a major pathological feature of chronic obstructive pulmonary disease (COPD). Furthermore, proteolytic destruction in the lungs may lead to loss of elastin and the development of emphysema, which is associated with poor lung function in COPD patients. In this literature review, we describe and appraise evidence from the recent literature regarding the role of different MMPs in COPD, as well as how their activity is regulated by specific tissue inhibitors. Considering the importance of MMPs in COPD pathogenesis, we also discuss MMPs as potential targets for therapeutic intervention in COPD and present evidence from recent clinical trials in this regard.

Keywords: chronic obstructive pulmonary disease (COPD); matrix metalloproteinases (MMPs); tissue inhibitors of MMPs (TIMPs).

Figure 1

The architecture of matrix metalloproteinases (MMPs). MMPs consist of an N-terminal signal peptide with variable length, a latency-maintaining pro domain, a catalytic domain with a Zn²⁺, a linker-“hinge” region and a C-terminal domain. In all MMPs, apart from MMP-7 and MMP-26, there is a hemopexin-like domain at the C-terminus. In transmembrane MMPs, there is a transmembrane domain (TM) and a short cytoplasmic domain or a glycosylphosphatidylinositol (GPI) anchor that binds them to the cell surface. Gelatinases differ from the other MMPs, as in their catalytic domain, they contain cysteine repeats that resemble collagen binding sites of type II fibronectin. Red dots represent histidines. Blue squares represent Type II fibronectin repeats. MT: membrane-type.

Figure 2

Control of MMP activity. MMPs can be found in every cellular compartment interacting with other proteins; proteoglycan core proteins and/or their glycosaminoglycan chains; extracellular matrix (ECM) molecules; integrins; CD44; CD147; and various receptors, such as epidermal growth factor receptor (EGFR). They may also be subjected to endocytosis by binding to LDL-related protein 1 (LRP-1) receptor. MMP activity is also inhibited by tissue inhibitors of MMPs (TIMPs) and α2-macroglobulin (α2M). TM: transmembrane MMP.

Figure 3

Matrix metalloproteinases (MMPs) in COPD. Various MMPs as potential biomarkers and targets in COPD. BAL: bronchoalveolar lavage; PBMCs: peripheral blood mononuclear cells; AAT: alpha-1 antitrypsin therapy; ECM: extracellular matrix; TIMPs; tissue inhibitors of MMPs.