Published ahead of print on January 10, 2008, doi:10.1165/rcmb.2007-0382OC Am. J. Respir. Cell Mol. Biol., Volume 38, Number 5, May 2008, 618-626 A more recent version of this article appeared on May 1, 2008
Submitted on October 23, 2007 Targeting the MEK1 Cascade in Lung Epithelium Inhibits Proliferation and Fibrogenesis by AsbestosChristopher B Manning1,1 Department of Pathology, University of Vermont, Burlington, VT, USA, 2 Department of Medicine, University of Vermont, Burlington, VT, USA, 3 Department of Medical Biostatistics, University of Vermont, Burlington, VT, USA, 4 Department of Civil and Environmental Engineering, University of Vermont, Burlington, VT, USA, 5 Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA * To whom correspondence should be addressed. E-mail: brooke.mossman{at}uvm.edu.
The extracellular signal-regulated kinases 1 and 2 (ERK1/2) are phosphorylated after inhalation of asbestos. The effect of blocking this signaling pathway in lung epithelium is unclear. Asbestos-exposed transgenic mice expressing a dominant-negative mitogen-activated protein kinase kinase-1 (dnMEK1), i.e., the upstream kinase necessary for phosphorylation of ERK1/2, targeted to lung epithelium exhibited morphologic and molecular changes in lung. Transgene-positive (Tg+), i.e., dnMEK1, and transgene-negative (Tg-) littermates were exposed to crocidolite asbestos for 2, 4, 9, and 32 days or maintained in clean air (sham controls). Distal bronchiolar epithelium was isolated using laser capture microdissection (LCM) and mRNA analyzed for molecular markers of proliferation and Clara cell secretory protein (CCSP). Lungs and bronchoalveolar lavage fluids (BALF) were analyzed for inflammatory and proliferative changes and molecular markers of fibrogenesis. Distal bronchiolar epithelium of asbestos-exposed wildtype mice showed increased expression of c-fos at 2 days. Elevated mRNA levels of histone H3 and numbers of Ki-67-labeled proliferating bronchiolar epithelial cells were decreased at 4 days in asbestos-exposed Tg+ mice. At 32 days, distal bronchioles normally comprised of Clara cells in asbestos-exposed Tg+ mouse lungs exhibited nonreplicating ciliated and mucin-secreting cells as well as decreased mRNA levels of CCSP. Gene expression (procollagen 3-a-1, procollagen 1-a-1, and IL-6) linked to fibrogenesis was also increased in lung homogenates of asbestos-exposed Tg- mice, but reduced in asbestos-exposed Tg+ mice. These results suggest a critical role of MEK1 signaling in epithelial cell proliferation and lung remodeling after toxic injury.
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