MMP‐9 Mediated Loss of Airway Epithelial Integrity

Abstract

The family of zinc and calcium‐dependent matrix metalloproteases (MMP's) play an important role in remodeling of the airways in disease. Transcriptional regulation by pro‐inflammatory cytokines increases lymphocyte derived MMP‐9 levels in the airway lumen of asthmatics. Moreover, the levels of the MMP‐9 inhibitor, tissue inhibitor of metalloprotease (TIMP1), are decreased leading to increased protease activity. However, the mechanism by which MMP‐9 activity leads to asthma pathogenesis and remodeling remains unclear. Using a model of well‐differentiated human airway epithelia, we found that apical MMP‐9 significantly increases transepithelial conductance that is blocked by TIMP1. Moreover, apical MMP‐9 treatment decreased immunostaining of tight junction proteins suggesting disruption of barrier function. Consistent with this, viruses gained access to the epithelial basolateral surface after MMP‐9 treatment which increased infection efficiency. In addition, loss of epithelial integrity correlated with increased epithelial cell death. Importantly, in vitro translational data suggests that MMP‐9 cleavages the tight junction protein occludin. Thus we hypothesised that MMP‐9 exerts its effects on the epithelium by cleaving occludin and triggering anoikis. Taken together, these data suggest that a component of airway remodeling associated with asthma may be directly regulated by MMP‐9.