Asbestos Induces Oxidative Stress and Activation of Nrf2 Signaling in Murine Macrophages: Chemopreventive Role of the Synthetic Lignan Secoisolariciresinol Diglucoside (LGM2605)

Our plain-English summary of Asbestos Induces Oxidative Stress and Activation of Nrf2 Signaling in Murine Macrophages: Chemopreventive Role of the Synthetic Lignan Secoisolariciresinol Diglucoside (LGM2605), by R.A. Pietrofesa, A. Velalopoulou, S.M. Albelda, et al (International Journal of Molecular Sciences, 2016).

The study

• Authors: R.A. Pietrofesa, A. Velalopoulou, S.M. Albelda, M. Christofidou-Solomidou
• Journal: International Journal of Molecular Sciences
• Published: 2016;17(3):322
• Cited by: 50 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The interaction of asbestos fibers with macrophages generates harmful reactive oxygen species (ROS) and subsequent oxidative cell damage that are key processes linked to malignancy. Secoisolariciresinol diglucoside (SDG) is a non-toxic, flaxseed-derived pluripotent compound that has antioxidant properties and may thus function as a chemopreventive agent for asbestos-induced mesothelioma. We thus evaluated synthetic SDG (LGM2605) in asbestos-exposed, elicited murine peritoneal macrophages as an in vitro model of tissue phagocytic response to the presence of asbestos in the pleural space. Murine peritoneal macrophages (MFs) were exposed to crocidolite asbestos fibers (20 µg/cm²) and evaluated at various times post exposure for cytotoxicity, ROS generation, malondialdehyde (MDA), and levels of 8-iso Prostaglandin F2α (8-isoP). We then evaluated the ability of LGM2605 to mitigate asbestos-induced oxidative stress by administering LGM2605 (50 µM) 4-h prior to asbestos exposure. We observed a significant (p < 0.0001), time-dependent increase in asbestos-induced cytotoxicity, ROS generation, and the release of MDA and 8-iso Prostaglandin F2α, markers of lipid peroxidation, which increased linearly over time. LGM2605 treatment significantly (p < 0.0001) reduced asbestos-induced cytotoxicity and ROS generation, while decreasing levels of MDA and 8-isoP by 71%-88% and 41%-73%, respectively. Importantly, exposure to asbestos fibers induced cell protective defenses, such as cellular Nrf2 activation and the expression of phase II antioxidant enzymes, HO-1 and Nqo1 that were further enhanced by LGM2605 treatment. LGM2605 boosted antioxidant defenses, as well as reduced asbestos-induced ROS generation and markers of oxidative stress in murine peritoneal macrophages, supporting its possible use as a chemoprevention agent in the development of asbestos-induced malignant mesothelioma.

In plain English

This was a laboratory study of cells, not people. The authors took immune cells called peritoneal macrophages from the abdomens of mice and used them as a model of how cells respond to asbestos in the pleural space. The cells were exposed to crocidolite asbestos fibers (20 µg/cm2). Some cells were first pretreated for 4 hours with LGM2605 (50 µM), a synthetic form of a flaxseed compound. Within 30 minutes, asbestos raised the hydrogen peroxide released by the cells from 0.24 to 1.83 µM. It caused measurable cell damage from 4 hours on and raised markers of damage to cell fats. Pretreatment with LGM2605 lowered hydrogen peroxide by 54%–80% and the marker malondialdehyde by 71%–88%. At 24 hours, another marker, 8-iso prostaglandin F2a, measured 710.87 pg/mL with asbestos alone and 189.89 pg/mL with asbestos plus LGM2605. Asbestos switched on the cells' own antioxidant defenses (Nrf2 signaling and the enzymes HO-1 and Nqo1), and LGM2605 raised them further. The authors concluded that LGM2605 had potential as an agent to help prevent asbestos-induced mesothelioma. They called for further testing in chronic animal models of the disease.

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: Laboratory (in vitro) experiment on mouse cells grown in culture
• Who was studied: Peritoneal macrophages (immune cells) collected from the abdominal cavity of 13-week-old mice at the University of Pennsylvania, after the cells were drawn in with thioglycollate broth. The number of mice is not given. The authors used these cells as a model of the cell response to asbestos in the pleural space.
• Exposure: Sterile UICC crocidolite asbestos fibers at 20 µg/cm2, chosen after testing 0, 1, 5, 10 and 20 µg/cm2. Some cells were pretreated with 50 µM LGM2605 (synthetic secoisolariciresinol diglucoside, a flaxseed lignan) 4 hours before asbestos exposure; doses of 0 to 100 µM were tested first.
• Main results:
  • In the dose-finding tests, 20 µg/cm2 crocidolite produced a 2.3-fold increase in reactive oxygen species (ROS) in the macrophages.
  • In asbestos-exposed cells, 50 µM LGM2605 gave a 43% reduction in ROS compared with untreated macrophages.
  • In asbestos-exposed macrophages, hydrogen peroxide released into the culture medium rose within 30 minutes, from 0.24 (plus or minus 0.03) to 1.83 (plus or minus 0.06) µM.
  • Pretreatment with 50 µM LGM2605 reduced hydrogen peroxide levels in asbestos-exposed cells by 54%–80% (p less than 0.0001).
  • Asbestos caused a significant cell-damaging (cytotoxic) effect, measured as LDH release, starting 4 hours after exposure. LGM2605 pretreatment significantly reduced LDH release.
  • LGM2605 reduced malondialdehyde (MDA), a marker of lipid peroxidation, in asbestos-exposed cells by 71%–88% (p less than 0.0001).
  • At 24 hours, 8-iso prostaglandin F2a was 710.87 (plus or minus 5.55) pg/mL in asbestos-only cells and 189.89 (plus or minus 2.58) pg/mL in cells given asbestos plus LGM2605.
  • Asbestos alone raised the antioxidant enzyme HO-1 significantly above baseline from 4 hours after exposure. Nqo1 rose sharply after 12 hours.
  • Nuclear (active) Nrf2 was significantly higher in macrophages given LGM2605 plus asbestos than in macrophages given asbestos only.
  • Compared with asbestos alone, LGM2605 raised HO-1 and NQO1 gene expression (mRNA) by an additional 28%–31% and 25%–26%, respectively.
  • At the protein level, macrophages treated with LGM2605 showed further increases in HO-1 and Nqo1 of 39%–40% and 60%–79%, respectively.
• The authors' conclusion: The authors concluded that LGM2605's ability to act on multiple pathways (boosting antioxidant defenses and scavenging free radicals) provided evidence of its potential usefulness as a chemopreventive agent for asbestos-induced mesothelioma. They said the findings support further evaluation in chronic, in vivo models of malignant mesothelioma.

Topics

Medical terms in this study, explained in our Lexicon: Oxidative Stress, Macrophage, Reactive Oxygen Species (ROS), Mesothelioma, Crocidolite, Asbestos Exposure, Malignant Mesothelioma.

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