Molecular mechanisms of asbestos-induced lung epithelial cell apoptosis

Our plain-English summary of Molecular mechanisms of asbestos-induced lung epithelial cell apoptosis, by G. Liu, R. Beri, A. Mueller, et al (Chemico-biological Interactions, 2010).

The study

• Authors: G. Liu, R. Beri, A. Mueller, D.W. Kamp
• Journal: Chemico-biological Interactions
• Published: 2010;188(2):309-18
• Type of article: Review
• Cited by: 51 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Asbestos causes pulmonary fibrosis (asbestosis) and malignancies (bronchogenic lung cancer and mesothelioma) by mechanisms that are not fully elucidated. Accumulating evidence show that alveolar epithelial cell (AEC) apoptosis is a crucial initiating and perpetuating event in the development of pulmonary fibrosis following exposure to a wide variety of noxious stimuli, including asbestos. We review the important molecular mechanisms underlying asbestos-induced AEC apoptosis. Specifically, we focus on the role of asbestos in augmenting AEC apoptosis by the mitochondria- and p53-regulated death pathways that result from the production of iron-derived reactive oxygen species (ROS) and DNA damage. We summarize emerging evidence implicating the endoplasmic reticulum (ER) stress response in AEC apoptosis in patients with idiopathic pulmonary fibrosis (IPF), a disease with similarities to asbestosis. Finally, we discuss a recent finding that a mitochondrial oxidative DNA repair enzyme (8-oxoguanine DNA glycosylase; Ogg1) acts as a mitochondrial aconitase chaperone protein to prevent oxidant (asbestos and H(2)O(2))-induced AEC mitochondrial dysfunction and intrinsic apoptosis. The coupling of mitochondrial Ogg1 to mitochondrial aconitase is a novel mechanism linking metabolism to mitochondrial DNA that may be important in the pathophysiologic events resulting in oxidant-induced toxicity as seen in tumors, aging, and respiratory disorders (e.g. asbestosis, IPF). Collectively, these studies are illuminating the molecular basis of AEC apoptosis following asbestos exposure that may prove useful for developing novel therapeutic strategies. Importantly, the asbestos paradigm is elucidating pathophysiologic insights into other more common pulmonary diseases, such as IPF and lung cancer, for which better therapy is required.

Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

In plain English

This article is a mini-review, not a new study. The authors summarized published laboratory research, much of it from their own group, on how asbestos may trigger apoptosis (programmed cell death) in alveolar epithelial cells. These are the cells lining the lung's air sacs. The authors described their death as a key event in pulmonary fibrosis, including asbestosis. The work reviewed was mainly in cultured cells, such as human A549 lung adenocarcinoma cells and rat alveolar type II cells, and in rodents. The review described evidence that iron-derived reactive oxygen species and DNA damage from asbestos lead to cell death through pathways controlled by mitochondria and by the p53 protein. It reported the authors' preliminary finding that asbestos set off an endoplasmic reticulum stress response in A549 cells. It also reported their earlier finding that a DNA repair enzyme, Ogg1, directed into mitochondria, protected A549 cells from death caused by asbestos and hydrogen peroxide. This appeared to work by preserving an enzyme called mitochondrial aconitase. The authors concluded that the evidence points to a crucial role for both pathways. They stated that further studies, including in animals, are needed.

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: Mini-review of published laboratory (cell culture and animal) studies, including the authors' own
• Who was studied: No new population was studied. The research reviewed was mainly in cultured lung cells, such as human A549 lung adenocarcinoma cells (described as having some alveolar type II-like features) and rat primary alveolar type II cells, and in rodent models.
• Exposure: Asbestos in general, as covered by the studies reviewed (chrysotile, amosite and crocidolite are each named in individual studies). Hydrogen peroxide was used as a comparison oxidant.
• Main results:
  • The review cited Panduri et al. (cell experiments): asbestos reduced mitochondrial membrane potential in a dose- and time-dependent way, together with cytochrome c release and caspase-9 activation.
  • The review cited a study in A549 cells lacking mitochondrial DNA (A549-0 cells): asbestos-induced reactive oxygen species production, caspase-9 activation and cell death were all blocked.
  • The review cited Shukla et al.: in lung mesothelial cells, mitochondrial DNA damage occurred at a four-fold lower concentration of crocidolite than was needed for nuclear DNA damage.
  • The authors' group reported (in alveolar epithelial cells) that asbestos activated p53 promoter activity within 1 hour and p53 protein expression as early as 4 hours.
  • The review cited a rat model of asbestosis: increased p53 expression appeared where fibers collected, and the iron chelator phytic acid blocked p53 expression as well as fibrosis.
  • The authors' preliminary findings: asbestos released calcium from the endoplasmic reticulum within 5 minutes in A549 cells, with a stress response after 30 minutes.
  • The authors' earlier work in A549 cells: mitochondria-targeted Ogg1 did not reduce asbestos-induced reactive oxygen species production. Mitochondrial aconitase coprecipitated with both wild-type and mutant mitochondrial Ogg1. Reducing Ogg1 lowered aconitase levels and increased cell death from oxidants.
• The authors' conclusion: The authors concluded that the evidence implicates a crucial role for asbestos triggering alveolar epithelial cell death through both mitochondria- and p53-regulated pathways. They proposed that mitochondrial Ogg1 acts as a protective partner of mitochondrial aconitase. They also noted that there are currently no techniques to modify lung toxicity from asbestos.
• Limitations the authors state:
  • The ER stress findings are preliminary; whether the stress response causes the cell death is not established.
  • The molecules through which p53 brings about cell death after asbestos exposure are unknown.

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, Pulmonary Fibrosis, Bronchogenic Carcinoma, Lung Cancer, Mesothelioma, Reactive Oxygen Species (ROS), Idiopathic, Asbestos Exposure.

Related studies

• Apoptosis induced by crocidolite asbestos in human lung epithelial cells involves inactivation of Akt and MAPK pathways — A. Baldys, P. Pande, et al. (2007)
• P53 mediates amosite asbestos-induced alveolar epithelial cell mitochondria-regulated apoptosis — V. Panduri, S. Surapureddi, 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)
• Asbestos causes apoptosis in alveolar epithelial cells: role of iron-induced free radicals — A. Aljandali, H. Pollack, et al. (2001)
• Asbestos-induced alveolar epithelial cell apoptosis. The role of endoplasmic reticulum stress response — D.W. Kamp, G. Liu, et al. (2013)
• Indications for distinct pathogenic mechanisms of asbestos and silica through gene expression profiling of the response of lung epithelial cells — T.N. Perkins, P.M. Peeters, et al. (2015)

Browse more research in Chemico-biological Interactions, or return to medical research.