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

doi:10.1152/ajplung.90578.2008

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

Journal article

Open access

Peer reviewed

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 and Joseph Zabner

American journal of physiology. Lung cellular and molecular physiology, Vol.296(5), pp.L751-L762

05/2009

DOI: 10.1152/ajplung.90578.2008

PMCID: PMC2681350

PMID: 19270179

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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.

protease

cell death

adhesion

Details

Title: Subtitle: MMP9 modulates tight junction integrity and cell viability in human airway epithelia
Creators: Paola D Vermeer - Department of Internal Medicine, and
James Denker - Department of Internal Medicine, and
Miriam Estin - Department of Internal Medicine, and
Thomas O Moninger - Department of Internal Medicine, and
Shaf Keshavjee - Department of Internal Medicine, and
Philip Karp - Department of Internal Medicine, and
Joel N Kline - Department of Internal Medicine, and
Joseph Zabner - Department of Internal Medicine, and
Resource Type: Journal article
Publication Details: American journal of physiology. Lung cellular and molecular physiology, Vol.296(5), pp.L751-L762
DOI: 10.1152/ajplung.90578.2008
PMID: 19270179
PMCID: PMC2681350
NLM abbreviation: Am J Physiol Lung Cell Mol Physiol
ISSN: 1040-0605
eISSN: 1522-1504
Publisher: American Physiological Society
Language: English
Date published: 05/2009
Academic Unit: Pulmonary, Critical Care, and Occupational Medicine; Occupational and Environmental Health; Internal Medicine
Record Identifier: 9984094537602771

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