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Collagen I and thrombin activate MMP-2 by MMP-14-dependent and -independent pathways: implications for airway smooth

Neil Henderson1, Lee J Markwick, Shona R Elshaw

  • 1Division of Therapeutics and Molecular Medicine, University Hospital, Queens Medical Centre, Nottingham, United Kingdom.

American Journal of Physiology. Lung Cellular and Molecular Physiology
|December 26, 2006
PubMed

Insights

Asthma airway components increase matrix metalloproteinase-2 (MMP-2) and MMP-14 in airway smooth muscle cells, promoting cell migration and contributing to airway remodeling.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Pulmonology

Background:

  • Asthma is characterized by airway inflammation and extracellular matrix (ECM) deposition.
  • Matrix metalloproteinases (MMPs) produced by airway smooth muscle (ASM) cells play roles in inflammation and tissue remodeling.

Purpose of the Study:

  • To investigate how asthmatic airway components stimulate MMP production and activation by ASM cells.
  • To determine the contribution of MMPs to ASM functions relevant to airway remodeling.

Main Methods:

  • Real-time RT-PCR, zymography, Western blotting, and MMP activity assays were used to measure MMPs.
  • ASM cells were treated with collagen I and thrombin to assess their effects on MMPs.
  • ASM cell migration, proliferation, adhesion, and apoptosis were evaluated in the presence of MMP inhibitors.

Main Results:

  • Collagen I and thrombin synergistically increased MMP-2 protein and total MMP activity, while decreasing MMP-2 mRNA.
  • Collagen I activated MMP-2 independently of cell surface interactions.
  • Collagen I and thrombin co-stimulation upregulated MMP-14 (an MMP-2 activator) mRNA and protein.
  • MMP inhibition reduced ASM cell migration and proliferation but not adhesion or apoptosis.

Conclusions:

  • The asthmatic airway environment enhances MMP-2 and MMP-14 protein and activity through complex mechanisms.
  • These MMP alterations may contribute to ASM migration and airway remodeling in asthma.
  • MMPs are critical mediators of ASM migration and proliferation, functions implicated in airway remodeling.

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