Submitted on November 21, 2008
Revised on February 11, 2009
Accepted on March 1, 2009
MMP9 Modulates Tight Junction Integrity and Cell Viability in Human Airway Epithelia
Paola Drapkin Vermeer1, James Denker2, Miriam Estin1, Thomas O. Moninger1, Shaf Keshavjee3, Philip Karp1, Joel N Kline1, and Joseph Zabner1*
1 University of Iowa
2 William Mitchell College of Law
3 Toronto General Research Institute
* To whom correspondence should be addressed. E-mail: joseph-zabner{at}uiowa.edu.
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 MMP9 levels in the airway lumen of asthmatics. Moreover, the levels of the MMP9 inhibitor, tissue inhibitor of metalloprotease (TIMP1), are decreased leading to increased protease activity. The mechanism by which MMP9 activity leads to asthma pathogenesis and remodeling remains unclear. Using a model of well-differentiated human airway epithelia, we found that apical MMP9 significantly increases transepithelial conductance. Moreover, apical MMP9 treatment decreased immunostaining of tight junction proteins suggesting disruption of barrier function. Consistent with this, viruses gained access to the epithelial basolateral surface after MMP9 treatment, which increased infection efficiency. All these effects were blocked by TIMP1. In addition, loss of epithelial integrity correlated with increased epithelial cell death. Thus we hypothesized that MMP9 exerts its effects on the epithelium by cleaving one or more components of cell-cell junctions and triggering anoikis. Taken together, these data suggest that a component of airway remodeling associated with asthma may be directly regulated by MMP9.
