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

American Journal of Respiratory Cell and Molecular Biology
Christopher B ManningB T Mossman

Abstract

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 and mRNA analyzed for molecular markers of proliferation and Clara cell secretory protein (CCSP). Lungs and bronchoalveolar lavage fluids were analyzed for inflammatory and proliferative changes and molecular markers of fibrogenesis. Distal bronchiolar epithelium of asbestos-exposed wild-type 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 bro...Continue Reading

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Citations

May 3, 2011·Journal of Toxicology and Environmental Health. Part B, Critical Reviews·Brooke T MossmanJames C Bonner
May 3, 2011·Journal of Toxicology and Environmental Health. Part B, Critical Reviews·Sarah X L HuangTom K Hei
Jan 1, 2004·American Journal of Respiratory Cell and Molecular Biology·Sophie BlanchetArmelle Baeza-Squiban
Jul 23, 2004·American Journal of Respiratory Cell and Molecular Biology
Jan 14, 2010·American Journal of Respiratory Cell and Molecular Biology·Nicholas H HeintzBrooke T Mossman
Jan 14, 2010·American Journal of Respiratory Cell and Molecular Biology·Arnold R Brody
Mar 24, 2009·Translational Research : the Journal of Laboratory and Clinical Medicine·David W Kamp
Jan 6, 2010·Wiley Interdisciplinary Reviews. Nanomedicine and Nanobiotechnology·Vanesa C SanchezAgnes B Kane
Jun 29, 2011·International Journal of Cancer. Journal International Du Cancer·Arti ShuklaBrooke T Mossman
Jan 12, 2010·Wiley Interdisciplinary Reviews. Nanomedicine and Nanobiotechnology·Jedd M HillegassBrooke T Mossman
May 24, 2019·Cancer Chemotherapy and Pharmacology·Vasiliki GalaniYotanna Dalavanga
Aug 4, 2021·Journal of Cell Science·Sujin KimNam-On Ku

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