Role of Mitogen-Activated Protein Kinases, Early Response Protooncogenes, and Activator Protein-1 in Cell Signaling by Asbestos

Our plain-English summary of Role of Mitogen-Activated Protein Kinases, Early Response Protooncogenes, and Activator Protein-1 in Cell Signaling by Asbestos, by B. Mossman, A. Hubbard, A. Shukla, et al (Inhalation Toxicology, 2000).

The study

• Authors: B. Mossman, A. Hubbard, A. Shukla, C.R. Timblin
• Journal: Inhalation Toxicology
• Published: 2000;12 Suppl 3:307-16
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Cell signaling by pathogenic minerals may initiate the transactivation of genes that are critical to carcinogenesis and fibroproliferative diseases of the lung and pleura. We have shown previously that stimulation of the mitogen-activated protein kinase (MAPK) cascade by asbestos fibers leads to phosphorylation events involved in transactivation of lun and Fos proteins that comprise the activator protein-1 (AP-1) transcription factor. Recently, we have also used AP-1 luciferase reporter transgenic mice and immunocytochemistry to show that transactivation of AP-1 occurs in bronchiolar and alveolar epithelial cells after inhalation of asbestos fibers. After inhalation of asbestos, epithelial cells of the lung also show increased immunoreactivity of pliosphorylated extracellular signal regulated kinases (ERKs 1/2) at sites of fibrogenesis. The availability of lung epithelial cell-specific promoters has allowed the creation of transgenic mice with mutations in the transactivation domains of key receptors and protein intermediates that comprise the MAPK signaling cascade. These rodent models may reveal whether cell signaling events initiated by mineral dusts in epithelial cells are critical to the development of cell proliferation, apoptosis, and lung disease.

In plain English

This short article mostly summarized the authors' laboratory's earlier work on how asbestos fibers switch on signaling pathways in lung and mesothelial cells. It also described one new mouse experiment. The mice were genetically modified so that their cells make a marker protein (luciferase) when a gene-control factor called AP-1 is activated. Groups of 3 to 4 mice breathed crocidolite asbestos at about 8 milligrams per cubic meter of air for 6 hours a day for 3 days. Sham mice breathed clean air. The mice were killed on day 4. In stained lung sections, sham mice showed some marker in the bronchiolar lining. Asbestos exposure markedly increased the marker in epithelial cells where the alveolar ducts branch. A crocidolite-exposed mouse without the marker gene showed none. When ground-up whole lung was tested, there was no significant increase compared with sham mice. The authors noted that only a small fraction of lung tissue is made of the cells that showed the marker. The authors concluded that AP-1 activation can be seen by staining and is increased in lung epithelial cells after asbestos inhalation.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Brief report combining a summary of the authors' laboratory's previous work with a small animal inhalation experiment (immunostaining of lungs from AP-1 luciferase reporter transgenic mice)
• Who was studied: AP-1 luciferase reporter transgenic mice, backcrossed into C57Bl/6 mice, 3 to 4 per group; sham control mice exposed to clean air; one transgene-negative crocidolite-exposed mouse lung used as a negative control
• Exposure: Inhalation of NIEHS crocidolite asbestos at approximately 8 mg per cubic meter of air, 6 hours per day for 3 days; mice killed on day 4
• Main results:
  • In asbestos-exposed mice, luciferase (the AP-1 marker) detection was markedly increased in epithelial cells at the alveolar duct bifurcation
  • Sham (clean-air) mice also showed some luciferase immunoreactivity in the bronchiolar epithelium
  • A transgene-negative mouse exposed to crocidolite showed no luciferase expression
  • The epithelium of the terminal bronchioles and alveolar duct regions were the main sites of luciferase expression
  • A biochemical luciferase assay on homogenized whole lung did not show significant increases in AP-1 activation in asbestos-exposed mice compared with sham mice
• The authors' conclusion: The authors concluded that AP-1 activation can be visualized by immunostaining and is increased in lung epithelial cells after inhalation of asbestos
• Limitations the authors state:
  • The authors noted that the whole-lung biochemical assay may have missed the effect because only a small fraction of lung tissue consists of the epithelial cells that showed luciferase on staining

Topics

Medical terms in this study, explained in our Lexicon: Carcinogenesis, Pleura, Apoptosis.

Related studies

• Oxidants and signaling by mitogen-activated protein kinases in lung epithelium — B.T. Mossman, K.M. Lounsbury, et al. (2006)
• Fibroblast growth factor-10 prevents asbestos-induced alveolar epithelial cell apoptosis by a mitogen-activated protein kinase-dependent mechanism — D. Upadhyay, V. Panduri, et al. (2005)
• Mitogen-activated protein kinase expression and activation does not differentiate benign from malignant mesothelial cells — L. Vintman, S. Nielsen, et al. (2005)
• Rat mesothelioma cell proliferation requires p38δ mitogen activated protein kinase and C/EBP-α — J. Zhong, D. Lardinois, et al. (2011)
• A phase I pharmacokinetic and pharmacodynamic study of the oral mitogen-activated protein kinase kinase (MEK) inhibitor, WX-554, in patients with advanced solid tumours — D. Jamieson, M.J. Griffin, et al. (2016)
• The duration of nuclear extracellular signal-regulated kinase 1 and 2 signaling during cell cycle reentry distinguishes proliferation from apoptosis in response to asbestos — Z. Yuan, D.J. Taatjes, et al. (2004)

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