Cell signaling and transcription factor activation by asbestos in lung injury and disease

Our plain-English summary of Cell signaling and transcription factor activation by asbestos in lung injury and disease, by A. Shukla, M. Ramos-Nino, B. Mossman (The International Journal of Biochemistry & Cell Biology, 2003).

The study

• Authors: A. Shukla, M. Ramos-Nino, B. Mossman
• Journal: The International Journal of Biochemistry & Cell Biology
• Published: 2003;35(8):1198-209
• Type of article: Review
• Cited by: 56 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Signaling pathways initiated at the external cell surface or within the cytoplasm regulate transactivation of transcription factors and gene expression that are causally related to a number of critical cellular outcomes including proliferation, apoptosis, cell survival, and production of inflammatory cytokines. Asbestos, a ubiquitous pathogenic group of mineral fibers, can stimulate gene expression in a variety of cell types in the lung via intracellular signaling pathways. These cell signaling cascades may be initiated through receptor-mediated events or integrins. Alternatively, they may be stimulated by oxidants generated both during phagocytosis of minerals and/or by redox reactions on the mineral surface. Once initiated, these pathways can lead to promotion of gene expression critical to cellular injury, proliferation and inflammation-events leading to the development of fibroproliferative diseases of the lung and pleura. The elucidation and relevance of critical signaling cascades to lung injury or repair following asbestos exposure could aid in developing strategies to prevent or treat asbestos-associated lung and pleural diseases.

In plain English

This article was a review. The authors summarized laboratory research on how asbestos fibers switch on signaling pathways in lung and pleural cells. Most of it used cell cultures and rodent inhalation models; some came from the authors' own laboratory. The fibers discussed included chrysotile and the amphiboles crocidolite and amosite. In reviewed studies, asbestos fibers, but not nonpathogenic glass fibers and particles, activated a signaling pathway called ERK in mesothelial cells. Crocidolite caused persistent, dose-dependent increases in expression (messenger RNA) of the c-fos and c-jun genes in rat pleural mesothelial cells; chemically similar nonfibrous particles did not. Crocidolite also raised NF-kappa B activity in hamster tracheal epithelial cells. In the authors' rat inhalation studies of crocidolite and chrysotile, an NF-kappa B protein called p65 was located in bronchiolar and alveolar epithelial cells 5 days after inhalation and remained at sites of developing lesions for 20 days. The authors concluded that asbestos stimulates many interacting pathways. They added that blocking some of these pathways suggested possible ways to prevent or treat asbestos-associated tumors and fibrosis.

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: Narrative review of laboratory research on cell signaling and transcription factor activation by asbestos
• Who was studied: Published experimental studies, in cell cultures (in vitro) and in animals (in vivo), including rodent inhalation models and transgenic mice from the authors' laboratory; no human subjects were studied by the authors
• Exposure: Asbestos fibers, mainly chrysotile (serpentine) and the amphiboles crocidolite and amosite, compared in some studies with erionite, nonfibrous particles and nonpathogenic glass fibers or beads
• Main results:
  • In reviewed studies, asbestos fibers, but not nonpathogenic glass fibers and particles, selectively induced ERK 1/2 phosphorylation and activity in mesothelial cells
  • In mice, chrysotile inhalation was followed by a striking increase in ERK phosphorylation in pulmonary epithelial cells at sites of developing fibrotic lesions after 14 to 20 days
  • In transgenic mice with a mutant EGF receptor in lung epithelium (the authors' own work), crocidolite-induced growth of bronchiolar and alveolar epithelium depended on EGF receptor phosphorylation, but asbestos-induced inflammation still occurred
  • Crocidolite caused persistent, dose-dependent increases in c-fos and c-jun mRNA (gene expression) in rat pleural mesothelial cells
  • Nonfibrous particles chemically similar to crocidolite or erionite did not change c-fos or c-jun expression, which the authors took to mean that fibrous shape appears critical
  • Crocidolite caused a protracted, dose-responsive increase in NF-kappa B binding proteins in hamster tracheal epithelial cells
  • In the authors' rat inhalation models of crocidolite- and chrysotile-induced inflammation and asbestosis, p65 (a subunit of NF-kappa B) was localized in bronchiolar and alveolar epithelial cells at 5 days after inhalation and persisted at sites of lesion development for 20 days
  • In a rat lung fibroblast cell line (RFL-6), the antioxidant vitamin E reduced crocidolite-induced AP-1 and NF-kappa B DNA binding to background levels
• The authors' conclusion: The authors concluded that asbestos stimulates multiple cell signaling pathways involving many transcription factors and cross-talk between them. They stated that findings that inhibitors of NF-kappa B and ERK block survival and proliferation of tumor cells suggest new preventive and therapeutic approaches to asbestos-associated tumors and fibrosis.

Topics

Medical terms in this study, explained in our Lexicon: Apoptosis, Cytokine, Mineral Fiber, Phagocytosis, Inflammation, Pleura, Asbestos Exposure.

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