MMP9 modulates tight junction integrity and cell viability in human airway epithelia.
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.
Vermeer
Paola D
PD
Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.
Denker
James
J
Estin
Miriam
M
Moninger
Thomas O
TO
Keshavjee
Shaf
S
Karp
Philip
P
Kline
Joel N
JN
Zabner
Joseph
J
D022005:Adherens Junctions / Q000201:enzymology; D023102:Anoikis / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D016764:Cell Polarity / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D062445:Claudin-1; D004553:Electric Conductivity; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology* / Q000821:virology; D053222:Fas Ligand Protein / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000166:cytology* / Q000201:enzymology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D062793:Occludin; D021381:Protein Transport / Q000187:drug effects; D044463:Receptor, PAR-1 / Q000378:metabolism; D012995:Solubility / Q000187:drug effects; D013917:Thrombin / Q000494:pharmacology; D019108:Tight Junctions / Q000187:drug effects / Q000201:enzymology*; D019014:fas Receptor / Q000378:metabolism
C568108:CLDN1 protein, human; D062445:Claudin-1; C491901:FAS protein, human; D053222:Fas Ligand Protein; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; D044463:Receptor, PAR-1; D019014:fas Receptor; D013917:Thrombin; D020780:Matrix Metalloproteinase 9