Asbestos-induced pulmonary toxicity: role of DNA damage and apoptosis

Our plain-English summary of Asbestos-induced pulmonary toxicity: role of DNA damage and apoptosis, by D. Upadhyay, D.W. Kamp (Experimental Biology and Medicine, 2003).

The study

• Authors: D. Upadhyay, D.W. Kamp
• Journal: Experimental Biology and Medicine
• Published: 2003;228(6):650-9
• Type of article: Review
• Cited by: 73 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Asbestos causes asbestosis and various malignancies by mechanisms that are not clearly defined. Here, we review the accumulating evidence showing that asbestos is directly genotoxic by inducing DNA strand breaks (DNA-SB) and apoptosis in relevant lung target cells. Although the exact mechanisms by which asbestos causes DNA damage and apoptosis are not firmly established, some of the implicated mechanisms include the generation of iron-derived reactive oxygen species (ROS) as well as reactive nitrogen species (RNS), alteration in the mitochondrial function, and activation of the death receptor pathway. We focus on the accumulating evidence implicating ROS. DNA repair mechanisms have a key role in limiting the extent of DNA damage. Recent studies show that asbestos activates DNA repair enzymes such as apurinic/apyrimidinic endonuclease (APE) and poly (ADP-ribose) polymerase (PARP). Asbestos-induced neoplastic transformation may result in the setting where DNA damage overwhelms DNA repair in the face of a persistent proliferative signal. Strategies aimed at limiting asbestos-induced oxidative stress may reduce DNA damage and, as such, prevent malignant transformation.

In plain English

This article was a minireview, not a new study. The authors reviewed published laboratory, animal and some human tissue research on how asbestos may harm the lungs by damaging DNA and triggering programmed cell death (apoptosis) in lung epithelial cells and mesothelial cells. The review discussed chrysotile and the amphiboles crocidolite and amosite, and noted that amphiboles have a high iron content (27%-33%). Cited studies reported that asbestos caused DNA strand breaks. In one, the effect in alveolar epithelial cells was stronger with amphiboles than with chrysotile. In another, chrysotile caused more breaks than crocidolite in rat pleural mesothelial cells. The authors described evidence that iron-derived reactive oxygen species are involved. They also described evidence that cigarette smoke increased asbestos-induced DNA breaks in cultured lung cells. Their own group had found that amosite disrupted mitochondrial function in lung cells. They also reviewed DNA repair enzymes that asbestos activates. The authors concluded that all forms of asbestos are directly genotoxic to relevant lung cells. They also stated that the precise mechanisms are not presently 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: Review (minireview) of published research on asbestos-induced DNA damage and apoptosis; no new data were collected
• Who was studied: Published studies mainly of lung target cells in the laboratory and in animals (lung epithelial cells, mesothelial cells, macrophages), plus some human tumor tissue studies; no specific population, number, place or period was studied by the authors
• Exposure: Asbestos fibers in general. The review discusses chrysotile (serpentine) and the amphiboles crocidolite and amosite in detail; its table also lists anthophyllite, actinolite and tremolite. Some reviewed studies combined asbestos with cigarette smoke
• Main results:
  • A cited study by the authors' group found that asbestos-induced DNA strand breaks in alveolar epithelial cells were dose and time dependent and more pronounced with amphiboles than with chrysotile
  • A cited study in rat pleural mesothelial cells found that chrysotile caused more DNA strand breaks than crocidolite
  • The review reported that amphibole fibers have a high iron content (27%-33%), while chrysotile has a small iron content that comes mainly from surface contaminants
  • The authors described the reviewed evidence (for example, protection by iron chelators and antioxidants) as firm evidence that reactive oxygen and nitrogen species are involved in asbestos-induced DNA damage
  • Cited studies with cultured lung epithelial cells showed that cigarette smoke increased asbestos-induced DNA strand breaks
  • The authors' group found that amosite asbestos reduced mitochondrial membrane potential in A549 cells and rat ATII cells, unlike glass beads or titanium dioxide, and triggered caspase 9 activation, with minimal caspase 8 activation
  • A cited study found that asbestos-induced mesotheliomas were more common in p53-deficient mice than in wild-type mice
  • A cited study found that crocidolite induced the DNA repair enzyme APE-1/Ref-1 in mesothelial cells. The authors noted that PARP knockout mice develop normally, suggesting that PARP does not have a central role in regulating DNA repair
• The authors' conclusion: The authors concluded that accumulating evidence has established that all forms of asbestos are directly genotoxic to relevant lung target cells. They suggested that high levels of apoptosis may promote fibrosis such as asbestosis, while persistent DNA damage from defects in apoptosis may lead to bronchogenic carcinoma or mesothelioma
• Limitations the authors state:
  • The authors stated that the precise mechanisms regulating the balance of apoptosis are not presently understood, and that many detailed mechanisms await further study
  • The authors stated that the role of other p53 family members and downstream factors is unclear
  • The authors stated that the methods for assessing genotoxicity were beyond the scope of this review

Topics

The National Library of Medicine indexes this study under subjects our site covers: Asbestosis.

Medical terms in this study, explained in our Lexicon: Apoptosis, Reactive Oxygen Species (ROS), Reactive Nitrogen Species (RNS), Oxidative Stress, Malignant Transformation.

Related studies

• The Role of Mitochondrial DNA in Mediating Alveolar Epithelial Cell Apoptosis and Pulmonary Fibrosis — S.J. Kim, P. Cheresh, et al. (2015)
• SIRT3 Overexpression Ameliorates Asbestos-Induced Pulmonary Fibrosis, mt-DNA Damage, and Lung Fibrogenic Monocyte Recruitment — P. Cheresh, S.J. Kim, et al. (2021)
• Phagocytosis of crocidolite asbestos induces oxidative stress, DNA damage, and apoptosis in mesothelial cells — W. Liu, J.D. Ernst, et al. (2000)
• Asbestos induces mitochondrial DNA damage and dysfunction linked to the development of apoptosis — A. Shukla, M. Jung, et al. (2003)
• Mitochondria-targeted Ogg1 and aconitase-2 prevent oxidant-induced mitochondrial DNA damage in alveolar epithelial cells — S.J. Kim, P. Cheresh, et al. (2014)
• 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)

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