Molecular basis of asbestos-induced lung disease

Our plain-English summary of Molecular basis of asbestos-induced lung disease, by G. Liu, P. Cheresh, D.W. Kamp (Annual Review of Pathology, 2013).

The study

• Authors: G. Liu, P. Cheresh, D.W. Kamp
• Journal: Annual Review of Pathology
• Published: 2013;8:161-87
• Type of article: Review
• Cited by: 141 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Asbestos causes asbestosis and malignancies by molecular mechanisms that are not fully understood. The modes of action underlying asbestosis, lung cancer, and mesothelioma appear to differ depending on the fiber type, lung clearance, and genetics. After reviewing the key pathologic changes following asbestos exposure, we examine recently identified pathogenic pathways, with a focus on oxidative stress. Alveolar epithelial cell apoptosis, which is an important early event in asbestosis, is mediated by mitochondria- and p53-regulated death pathways and may be modulated by the endoplasmic reticulum. We review mitochondrial DNA (mtDNA)-damage and -repair mechanisms, focusing on 8-oxoguanine DNA glycosylase, as well as cross talk between reactive oxygen species production, mtDNA damage, p53, OGG1, and mitochondrial aconitase. These new insights into the molecular basis of asbestos-induced lung diseases may foster the development of novel therapeutic targets for managing degenerative diseases (e.g., asbestosis and idiopathic pulmonary fibrosis), tumors, and aging, for which effective management is lacking.

In plain English

This article is a review by three researchers. It summarized published cell, animal and human research on how asbestos fibers, chrysotile and amphiboles, damage the lungs, focusing mainly on asbestosis. The authors described evidence that asbestos produces iron-derived reactive oxygen species (harmful oxidants) in alveolar macrophages and in target cells such as alveolar epithelial and mesothelial cells. They described the death of alveolar epithelial cells as an early event, driven through pathways regulated by the mitochondria and the protein p53. They also described cell-culture evidence that asbestos stresses the endoplasmic reticulum, a cell compartment, in alveolar epithelial cells. They said it is unknown whether this stress matters for lung toxicity. They also reviewed their own group's earlier cell-culture work, in which a mitochondrial DNA-repair enzyme, OGG1, preserved the enzyme aconitase (ACO2) and prevented cell death. The authors concluded that strategies to protect mitochondrial DNA may prove useful in developing treatments for tumors and degenerative diseases. They noted that the relevance of these cell-culture findings in living animals and humans still needs study.

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 research on molecular mechanisms of asbestos-induced lung disease; it also mentions some preliminary findings from the authors' group
• Who was studied: No study population of its own; the review drew on cell-culture (in vitro), animal (in vivo) and human studies
• Exposure: Asbestos fibers: chrysotile (serpentine) and amphiboles (crocidolite, amosite, tremolite, anthophyllite, actinolite); oxidative stress from asbestos and hydrogen peroxide in cell studies
• Main results:
  • The review summarized evidence that asbestos induces iron-derived reactive oxygen species from alveolar macrophages and from target cells such as alveolar epithelial and mesothelial cells
  • The review described alveolar epithelial cell apoptosis (programmed cell death) as an early event in asbestosis
  • The authors reported that the evidence indicates this alveolar epithelial cell death is mediated by mitochondria- and p53-regulated pathways
  • The review summarized evidence that asbestos induces endoplasmic reticulum stress in alveolar epithelial cells in cell culture
  • The authors' group reported that asbestos-exposed human A549 and rat type II alveolar cells released endoplasmic reticulum calcium within 5 minutes and activated the stress-signaling proteins IRE-1α and XBP1 within 1 hour
  • In preliminary studies, simultaneous treatment with the chemical chaperone 4-phenyl butyric acid abolished asbestos-induced increases in IRE-1α and XBP1 but did not prevent calcium release or apoptosis
  • The review described mouse studies by another research group (Carter and colleagues) in which asbestos induced Rac1-dependent mitochondrial oxidant production in alveolar macrophages that was linked to asbestosis in mice
  • From the authors' own earlier cell-culture work: mitochondria-targeted hOGG1 preserved mitochondrial function and the enzyme ACO2 in alveolar epithelial cells and prevented cell death
  • Citing prior work, the review stated that the number of asbestos bodies in lung tissue is directly associated with lung cancer risk
• The authors' conclusion: The authors concluded that strategies promoting mitochondrial DNA integrity, by limiting oxidative stress or p53 signaling and by increasing mitochondrial OGG1 and/or ACO2, may prove useful in developing treatments for tumors and degenerative diseases
• Limitations the authors state:
  • The authors stated that the relevance of the cell-culture findings in living organisms, for asbestosis and cancers, is still unknown
  • The authors listed as an open question whether asbestos-induced endoplasmic reticulum stress is important in causing lung toxicity
  • The authors noted there is no consensus on how to define asbestos, which creates uncertainty about exposure-response relationships
  • The authors did not analyze determinants of fiber toxicity (dose, dimension, biodurability, surface reactivity, genetics) in detail
  • The authors noted that only some investigators' work is cited, because of space constraints

Topics

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

Medical terms in this study, explained in our Lexicon: Lung Cancer, Mesothelioma, Asbestos Exposure, Oxidative Stress, Apoptosis, Reactive Oxygen Species (ROS), Idiopathic, Pulmonary Fibrosis.

Related studies

• The molecular basis of asbestos induced lung injury — D.W. Kamp, S.A. Weitzman (1999)
• The pathophysiological role of mitochondrial oxidative stress in lung diseases — X. Liu, Z. Chen (2017)
• Mitochondria-targeted Ogg1 and aconitase-2 prevent oxidant-induced mitochondrial DNA damage in alveolar epithelial cells — S.J. Kim, P. Cheresh, et al. (2014)
• The role of free radicals in asbestos-induced diseases — D.W. Kamp, P. Graceffa, et al. (1992)
• 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)

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