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

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

Research output: Contribution to journalArticle

83 Citations (Scopus)

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)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume296
Issue number5
DOIs
StatePublished - May 1 2009

Fingerprint

Airway Remodeling
Tight Junctions
Metalloproteases
Cell Survival
Asthma
Epithelium
Anoikis
Tight Junction Proteins
Intercellular Junctions
Cellular Structures
Zinc
Peptide Hydrolases
Cell Death
Epithelial Cells
Lymphocytes
Cytokines
Viruses
Calcium
Infection

Keywords

  • Adhesion
  • Cell death
  • Protease

ASJC Scopus subject areas

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

Cite this

MMP9 modulates tight junction integrity and cell viability in human airway epithelia. / Vermeer, Paola; Denker, James; Estin, Miriam; Moninger, Thomas O.; Keshavjee, Shaf; Karp, Philip; Kline, Joel N.; Zabner, Joseph.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 296, No. 5, 01.05.2009.

Research output: Contribution to journalArticle

Vermeer, Paola ; Denker, James ; Estin, Miriam ; Moninger, Thomas O. ; Keshavjee, Shaf ; Karp, Philip ; Kline, Joel N. ; Zabner, Joseph. / MMP9 modulates tight junction integrity and cell viability in human airway epithelia. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2009 ; Vol. 296, No. 5.
@article{44b3c64b01e641a38ded1e94c03bbf91,
title = "MMP9 modulates tight junction integrity and cell viability in human airway epithelia",
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.",
keywords = "Adhesion, Cell death, Protease",
author = "Paola Vermeer and James Denker and Miriam Estin and Moninger, {Thomas O.} and Shaf Keshavjee and Philip Karp and Kline, {Joel N.} and Joseph Zabner",
year = "2009",
month = "5",
day = "1",
doi = "10.1152/ajplung.90578.2008",
language = "English (US)",
volume = "296",
journal = "American Journal of Physiology - Renal Physiology",
issn = "0363-6127",
publisher = "American Physiological Society",
number = "5",

}

TY - JOUR

T1 - MMP9 modulates tight junction integrity and cell viability in human airway epithelia

AU - Vermeer, Paola

AU - Denker, James

AU - Estin, Miriam

AU - Moninger, Thomas O.

AU - Keshavjee, Shaf

AU - Karp, Philip

AU - Kline, Joel N.

AU - Zabner, Joseph

PY - 2009/5/1

Y1 - 2009/5/1

N2 - 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.

AB - 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.

KW - Adhesion

KW - Cell death

KW - Protease

UR - http://www.scopus.com/inward/record.url?scp=66149176928&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=66149176928&partnerID=8YFLogxK

U2 - 10.1152/ajplung.90578.2008

DO - 10.1152/ajplung.90578.2008

M3 - Article

VL - 296

JO - American Journal of Physiology - Renal Physiology

JF - American Journal of Physiology - Renal Physiology

SN - 0363-6127

IS - 5

ER -