Matrix metalloproteinases in emphysema

Abstract

Several studies have implicated a causative role for specific matrix metalloproteinases (MMPs) in the development and progression of cigarette smoke-induced chronic obstructive pulmonary disease (COPD) and its severe sequela, emphysema. However, the precise function of any given MMP in emphysema remains an unanswered question. Emphysema results from the degradation of alveolar elastin - among other possible mechanisms - a process that is often thought to be caused by elastolytic proteinases made by macrophages. In this article, we discuss the data suggesting, supporting, or refuting causative roles of macrophage-derived MMPs, with a focus on MMPs-7, -9, -10, -12, and 28, in both the human disease and mouse models of emphysema. Findings from experimental models suggest that some MMPs, such as MMP-12, may directly breakdown elastin, whereas others, particularly MMP-10 and MMP-28, promote the development of emphysema by influencing the proteolytic and inflammatory activities of macrophages.

Figure 1.. Graphical overview of enriched biological modules associated with obstructive lung disease.

This diagram was constructed based on gene set enrichment analysis of a large-scale GWAS of subjects with airflow obstruction. Each depicted module is an aggregate of multiple highly enriched and functionally related pathways (false discovery rate < 0.001). For select modules, a few representative pathways have been labeled (e.g., TGF-β signaling, Ceramide pathway, NOS signaling) for illustrative purposes. Note the diversity of biological processes associated with COPD, spanning developmental programs, immunity, proliferation, apoptosis and extracellular matrix (ECM). Deeper exploration of the ECM module using gene product interaction network analysis identified MMP10 as the most interconnected node and a potential orchestrator of tissue remodeling in obstructive lung disease. Other ECM network genes included collagens, laminins, fibrillins and fibulins. NOS, nitric oxide synthase; TGF-β, transforming growth factor beta; EGF, epidermal growth factor; PDGF, platelet-derived growth factor. Modified from [19].

Figure 2.. Diverse Role of Macrophage MMPs in Emphysema.

Both MMP-10 and MMP-28 have causative roles in the development of cigarette smoke-induced emphysema. These two MMPs promote the conversion of M1-biased macrophages to M2-biased cells but distinct functional consequences. Whereas MMP-10 influences the proteolytic potential of macrophages, MMP-28 shapes of the pro-inflammatory activity of these cells. In contrast, other MMPs, such as MMP-12 and possibly MMP-7 (in human macrophages), may directly degrade alveolar elastin, likely along with other macrophage enzymes, such as specific cysteine proteinases.