MMP9 modulates tight junction integrity and cell viability in human airway epithelia

Paola D. Vermeer, James Denker, Miriam Estin, Thomas O. Moninger, Shaf Keshavjee, Philip Karp, Joel N. Kline, Joseph Zabner

Research output: Contribution to journalArticlepeer-review

108 Scopus citations

Abstract

The family of zinc- and calcium-dependent matrix metalloproteases (MMPs) play an important role in remodeling of the airways in disease. Transcriptional regulation by proinflammatory 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 of 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.

Original languageEnglish (US)
Pages (from-to)L751-L762
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume296
Issue number5
DOIs
StatePublished - May 2009
Externally publishedYes

Keywords

  • Adhesion
  • Cell death
  • Protease

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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