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Targeting the MEK1 cascade in lung epithelium inhibits proliferation and fibrogenesis by asbestos

Christopher B Manning1, Tara Sabo-Attwood, Raymond F Robledo

  • 1Environmental Pathology Program, University of Vermont College of Medicine, Department of Pathology, 89 Beaumont Avenue, Burlington, VT 05405, USA.

American Journal of Respiratory Cell and Molecular Biology
|January 15, 2008
PubMed

Insights

Blocking MEK1 signaling in lung epithelium reduces asbestos-induced cell proliferation and fibrogenesis. This study reveals MEK1

Area of Science:

  • Pulmonary toxicology
  • Molecular biology
  • Cell signaling

Background:

  • Asbestos inhalation triggers extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylation in lung epithelium.
  • The role of blocking this mitogen-activated protein kinase kinase-1 (MEK1) signaling pathway in asbestos-induced lung injury remains unclear.

Purpose of the Study:

  • To investigate the effect of inhibiting MEK1 signaling on lung epithelial cell responses to asbestos exposure.
  • To elucidate the role of MEK1 in asbestos-induced proliferation, inflammation, and fibrogenesis in the lung.

Main Methods:

  • Transgenic mice expressing dominant-negative MEK1 (dnMEK1) targeted to lung epithelium were exposed to crocidolite asbestos.
  • Laser capture microdissection was used to isolate distal bronchiolar epithelium for mRNA analysis of proliferation markers (histone H3, Ki-67) and CCSP.
  • Lung homogenates and bronchoalveolar lavage fluid were analyzed for inflammatory markers and fibrogenesis gene expression (procollagen, IL-6).

Main Results:

  • Asbestos-exposed wild-type mice showed increased c-fos expression, while dnMEK1 mice exhibited decreased proliferation markers.
  • In asbestos-exposed dnMEK1 mice, distal bronchioles showed altered cell composition (ciliated, mucin-secreting) and reduced CCSP levels.
  • Fibrogenesis markers were elevated in asbestos-exposed wild-type mice but reduced in asbestos-exposed dnMEK1 mice.

Conclusions:

  • MEK1 signaling is critical for epithelial cell proliferation and lung remodeling following asbestos-induced toxic injury.
  • Inhibition of MEK1 signaling mitigates asbestos-induced lung inflammation and fibrogenesis.

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