Role of ADAM and ADAMTS metalloproteinases in airway diseases

Abstract

Lungs are exposed to the outside environment and therefore to toxic and infectious agents or allergens. This may lead to permanent activation of innate immune response elements. A Disintegrin And Metalloproteinases (ADAMs) and ADAMs with Thrombospondin motifs (ADAMTS) are proteinases closely related to Matrix Metalloproteinases (MMPs). These multifaceted molecules bear metalloproteinase and disintegrin domains endowing them with features of both proteinases and adhesion molecules. Proteinases of the ADAM family are associated to various physiological and pathological processes and display a wide spectrum of biological effects encompassing cell fusion, cell adhesion, "shedding process", cleavage of various substrates from the extracellular matrix, growth factors or cytokines... This review will focus on the putative roles of ADAM/ADAMTS proteinases in airway diseases such as asthma and COPD.

Figure 1

Structural organization of MMPs, ADAMs and ADAMTS. The typical structure of MMP is made of a prodomain, a furin cleavage site (all MT-MMPs, MMP-21,-23, and -28), a catalytic metalloproteinase domain with fibronectin type II repeats (MMP-2, MMP-9), a linker peptide and a haemopexin domain (except for MMP-7, -26, and -23), a linker peptide, a transmembrane domain and cytoplasmic tail (MMP-14, -15, -16, -24) or glycosylphosphatidylinositol (GPI) anchor (MMP-17, -25). MMP-23 bears C-terminal cysteine-rich (Cys-rich) and Ig-like (Ig) domains and its propeptide lacks a cystein switch motif. Common structure of ADAMs is a prodomain, a cleavage site (by a furin or furin-like proprotein convertase except for ADAM-8 and ADAM-28 which use an autocatalytic process), a metalloproteinase domain, a disintegrin domain, a cysteine-rich region (Cys-rich), an epidermal-growth factor repeat (EGF-like), a transmembrane domain (TM) and a cytoplasmic tail. ADAMTS do not possess a transmembrane domain (TM) but bear a various number of thrombospondin type I motifs (TSP-1) at their C-terminal extremity.

Figure 2

Intervention of ADAM/ADAMTS proteinases in asthma and COPD. Succinctly, in asthma, inhaled allergens provoke the degranulation of sensitized mast cells and the activation of epithelial cells (EC) while in COPD, inhaled cigarette smoke activates epithelial cells and macrophages. After a first challenge in both diseases, an inflammatory reaction occurs resulting in the recruitment of eosinophils and CD4⁺ T cells for asthma, neutrophils and CD8⁺ T cells for COPD. Following a chronic inflammation, tissue alterations such as mucus hypersecretion, bronchoconstriction appear in asthma while small airway fibrosis, alveolar destruction (emphysema) and mucus hypersecretion occur in COPD. An airway hyperresponsiveness is linked to both diseases. However, it is reversible in asthma but not in COPD. ADAM-8 plays a role in asthma-related inflammation while ADAM-33 is associated to remodeling processes and hyperresponsiveness associated to asthma. In COPD, ADAM-17 acts on mucus hypersecretion process while ADAM-33 is associated with COPD-related hyperresponsiveness.