Recent progress and perspectives on the mechanisms underlying Asbestos toxicity

Our plain-English summary of Recent progress and perspectives on the mechanisms underlying Asbestos toxicity, by A. Kuroda (Genes and Environment, 2021).

The study

• Author: A. Kuroda
• Journal: Genes and Environment
• Published: 2021;43(1):46
• Type of article: Review
• Cited by: 28 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Most cases of mesothelioma are known to result from exposure to asbestos fibers in the environment or occupational ambient air. The following questions regarding asbestos toxicity remain partially unanswered: (i) why asbestos entering the alveoli during respiration exerts toxicity in the pleura; and (ii) how asbestos causes mesothelioma, even though human mesothelial cells are easily killed upon exposure to asbestos. As for the latter question, it is now thought that the frustrated phagocytosis of asbestos fibers by macrophages prolongs inflammatory responses and gives rise to a "mutagenic microenvironment" around mesothelial cells, resulting in their malignant transformation. Based on epidemiological and genetic studies, a carcinogenic model has been proposed in which BRCA1-associated protein 1 mutations are able to suppress cell death in mesothelial cells and increase genomic instability in the mutagenic microenvironment. This leads to additional mutations, such as CDKN2A [p16], NF2, TP53, LATS2, and SETD2, which are associated with mesothelioma carcinogenesis. Regarding the former question, the receptors involved in the intracellular uptake of asbestos and the mechanism of transfer of inhaled asbestos from the alveoli to the pleura are yet to be elucidated. Further studies using live-cell imaging techniques will be critical to fully understanding the mechanisms underlying asbestos toxicity.

© 2021. The Author(s).

In plain English

This article was a single-author review of published research on how asbestos fibers harm the body and lead to mesothelioma. It reported no new study of people. The author described two open questions: why inhaled fibers harm the pleura, and how asbestos causes mesothelioma although earlier reports found human mesothelial cells exposed to asbestos died within 2–10 days. The review described cited work suggesting that fibers shorter than 5 μm were not retained in the lungs, while longer fibers were only partly engulfed by immune cells called macrophages ("frustrated phagocytosis"), causing lasting inflammation. It described a model proposed by Carbone et al. in which this inflammation creates a "mutagenic microenvironment." In that model, mesothelial cells carrying BAP1 mutations escape cell death and gather further mutations. Cited reports found somatic BAP1 mutations (arising in tumor cells, not inherited) in approximately 60% of mesotheliomas. Earlier imaging work by the author's group showed that macrophages carrying asbestos were motile. The author concluded that how asbestos enters cells and travels from the lungs to the pleura still needs to be fully understood.

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 published studies on the mechanisms of asbestos toxicity and mesothelioma
• Who was studied: No study population; the article reviewed previously published laboratory, animal, genetic and epidemiological research
• Exposure: Asbestos fibers in general. The article lists six asbestos types (printed as chrysolite, amosite, crocidolite, actinolite, tremolite, and anthophyllite) and discusses fiber length and shape.
• Main results:
  • Cited earlier reports found that human mesothelial cells were killed within 2–10 days of asbestos exposure. The author called this paradoxical for the older 'mechanical interference' model of how asbestos causes cancer.
  • Cited work reported that fibers less than 5 μm long are fully engulfed and not retained in the lungs, while longer fibers undergo 'frustrated phagocytosis' and can remain for long periods
  • The review described a 2011 study of two United States families not exposed to asbestos in which the BAP1 mutation was associated with a high incidence of mesothelioma
  • Cited studies observed somatic BAP1 mutations (those occurring during tumor cell proliferation, as distinct from inherited mutations) in approximately 60% of mesotheliomas
  • In the model the review described, credited to Carbone et al., BAP1 mutation helps mesothelial cells avoid cell death and accumulate additional mutations associated with mesothelioma
  • Prior live-cell imaging work by the author's group showed that macrophages carrying internalized asbestos were motile. The author interpreted this as indicating that macrophages are involved in moving asbestos to the pleura.
• The authors' conclusion: The author concluded that the paradoxical questions about asbestos toxicity are explained by frustrated phagocytosis of fibers by macrophages, which creates a 'mutagenic microenvironment' around mesothelial cells. The author also concluded that cell uptake of asbestos and the transfer of inhaled asbestos must be fully understood to determine the mechanism of asbestos toxicity.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Alveoli, Pleura, Mesothelial Cells, Frustrated Phagocytosis, Macrophage, Malignant Transformation, Carcinogenic.

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