Synthetic Secoisolariciresinol Diglucoside (LGM2605) Prevents Asbestos-Induced Inflammation and Genotoxic Cell Damage in Human Mesothelial Cells

Our plain-English summary of Synthetic Secoisolariciresinol Diglucoside (LGM2605) Prevents Asbestos-Induced Inflammation and Genotoxic Cell Damage in Human Mesothelial Cells, by R.A. Pietrofesa, S. Chatterjee, Y. Kadariya, et al (International Journal of Molecular Sciences, 2022).

The study

• Authors: R.A. Pietrofesa, S. Chatterjee, Y. Kadariya, J.R. Testa, S.M. Albelda, M. Christofidou-Solomidou
• Journal: International Journal of Molecular Sciences
• Published: 2022;23(17)
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Although alveolar macrophages play a critical role in malignant transformation of mesothelial cells following asbestos exposure, inflammatory and oxidative processes continue to occur in the mesothelial cells lining the pleura that may contribute to the carcinogenic process. Malignant transformation of mesothelial cells following asbestos exposure occurs over several decades; however, amelioration of DNA damage, inflammation, and cell injury may impede the carcinogenic process. We have shown in an in vitro model of asbestos-induced macrophage activation that synthetic secoisolariciresinol diglucoside (LGM2605), given preventively, reduced inflammatory cascades and oxidative/nitrosative cell damage. Therefore, it was hypothesized that LGM2605 could also be effective in reducing asbestos-induced activation and the damage of pleural mesothelial cells. LGM2605 treatment (50 µM) of huma n pleural mesothelial cells was initiated 4 h prior to exposure to asbestos (crocidolite, 20 µg/cm2). Supernatant and cells were evaluated at 0, 2, 4, and 8 h post asbestos exposure for reactive oxygen species (ROS) generation, DNA damage (oxidized guanine), inflammasome activation (caspase-1 activity) and associated pro-inflammatory cytokine release (IL-1β, IL-18, IL-6, TNFα, and HMGB1), and markers of oxidative stress (malondialdehyde (MDA) and 8-iso-prostaglandin F2a (8-iso-PGF2α). Asbestos induced a time-dependent ROS increase that was significantly (p < 0.0001) reduced (29.4%) by LGM2605 treatment. LGM2605 pretreatment also reduced levels of asbestos-induced DNA damage by 73.6% ± 1.0%. Although levels of inflammasome-activated cytokines, IL-1β and IL-18, reached 29.2 pg/mL ± 0.7 pg/mL and 43.9 pg/mL ± 0.8 pg/mL, respectively, LGM2605 treatment significantly (p < 0.0001) reduced cytokine levels comparable to baseline (non-asbestos exposed) values (3.8 pg/mL ± 0.2 pg/mL and 5.4 pg/mL ± 0.2 pg/mL, respectively). Furthermore, levels of IL-6 and TNFα in asbestos-exposed mesothelial cells were high (289.1 pg/mL ± 2.9 pg/mL and 511.3 pg/mL ± 10.2 pg/mL, respectively), while remaining undetectable with LGM2605 pretreatment. HMGB1 (a key inflammatory mediator and initiator of malignant transformation) release was reduced 75.3% ± 0.4% by LGM2605. Levels of MDA and 8-iso-PGF2α, markers of oxidative cell injury, were significantly (p < 0.001) reduced by 80.5% ± 0.1% and 76.6% ± 0.3%, respectively. LGM2605, given preventively, reduced ROS generation, DNA damage, and inflammasome-activated cytokine release and key inflammatory mediators implicated in asbestos-induced malignant transformation of normal mesothelial cells.

In plain English

This was a laboratory study of human pleural mesothelial cells grown from the pleural fluid of a single patient with congestive heart failure. The authors tested whether LGM2605 (synthetic secoisolariciresinol diglucoside) could limit damage caused by crocidolite asbestos. Cells received 50 µM LGM2605 four hours before exposure to 20 µg/cm2 crocidolite fibers and were examined up to 8 hours later. In asbestos-exposed cells, pretreatment lowered reactive oxygen species by 43.4%, 40.8% and 28.5% at 4, 6 and 8 hours. It also lowered markers of DNA damage: oxidized guanine fell by 84.4% to 90.9%, and DNA single-strand breaks by 91.8% to 97.4%. Inflammatory signals were lower too. IL-1β fell by up to 92.4%, IL-18 by up to 89.6%, and HMGB1 by 85.2% to 89.2%. IL-6 and TNFα were below detection limits. The authors wrote that their findings suggest LGM2605 may be a good candidate for preventing asbestos-related cancer, and stated their belief that it will be a safe preventive agent. They noted that in real use it would probably be given after exposure, not before. The study measured cell markers over hours, not cancer.

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 cultured human cells; results from three separate experiments
• Who was studied: Normal (non-cancerous) human pleural mesothelial cells derived from the pleural effusion fluid of one donor, a congestive heart failure patient (University of Pennsylvania)
• Exposure: Sterile UICC crocidolite asbestos fibers at 20 µg/cm2, with or without 50 µM LGM2605 given 4 hours before asbestos; cells and medium examined at 0, 2, 4 and 8 hours (some tests at 6 hours)
• Main results:
  • In asbestos-exposed cells, LGM2605 reduced intracellular reactive oxygen species by 43.4%, 40.8% and 28.5% at 4, 6 and 8 hours
  • Asbestos raised MDA (a lipid-damage marker) from 0.43 µM at baseline to 21.54 µM at 8 hours; LGM2605 reduced MDA release by 65.0% at 8 hours
  • LGM2605 reduced 8-iso-PGF2α (an oxidative stress marker) release by 92.4% at 8 hours in asbestos-exposed cells
  • LGM2605 reduced total nitrates and nitrites (markers of nitrosative stress) by 72.9%, 75.2% and 80.5% at 2, 4 and 8 hours after asbestos
  • LGM2605 reduced nuclear NF-κB by 64.1%, 68.7% and 90.8% at 2, 4 and 8 hours after asbestos
  • LGM2605 further increased nuclear Nrf2 in asbestos-exposed cells, 7.86-fold relative to asbestos-only cells at 4 hours
  • LGM2605 reduced caspase-1 activity by 51.4%, 46.5% and 56.5% at 2, 4 and 8 hours after asbestos
  • IL-1β in asbestos-exposed cells reached 29.23 pg/mL plus or minus 0.72 at 8 hours; LGM2605 reduced IL-1β release by 75.1%, 89.4% and 92.4% at 2, 4 and 8 hours
  • IL-18 in asbestos-exposed cells reached 43.90 pg/mL plus or minus 0.79 at 8 hours; LGM2605 reduced IL-18 release by 73.0%, 78.2% and 89.6% at 2, 4 and 8 hours
  • IL-6 rose to 289.05 pg/mL at 8 hours in asbestos-exposed cells but was below the detection limit in asbestos-exposed cells treated with LGM2605
  • TNFα rose to 511.32 pg/mL at 8 hours in asbestos-exposed cells but was below the detection limit in asbestos-exposed cells treated with LGM2605
  • LGM2605 reduced HMGB1 release by 85.2%, 86.9% and 89.2% at 2, 4 and 8 hours after asbestos
  • LGM2605 reduced γH2AX (a marker of DNA double-strand breaks) by 49.4% and 48.0% at 2 and 6 hours after asbestos
  • LGM2605 reduced oxidized guanine species (DNA/RNA damage markers) by 90.9%, 85.3% and 84.4% at 2, 4 and 8 hours after asbestos
  • LGM2605 reduced asbestos-induced DNA single-strand breaks (comet assay) by 94.5%, 97.4% and 91.8% at 2, 4 and 8 hours
• The authors' conclusion: The authors wrote that their findings in this cell model provide evidence that LGM2605 may be a good candidate for chemoprevention of asbestos-induced malignancy. In their conclusions they also stated a belief that it will be a safe chemopreventive agent in the context of asbestos exposures.
• Limitations the authors state:
  • LGM2605 was given 4 hours before asbestos, whereas the authors note that chemoprevention would most likely start after asbestos exposure

Topics

Medical terms in this study, explained in our Lexicon: Inflammation, Mesothelial Cells, Alveolar Macrophage, Malignant Transformation, Asbestos Exposure, Pleura, Carcinogenic, Macrophage.

Related studies

• The Synthetic Lignan Secoisolariciresinol Diglucoside Prevents Asbestos-Induced NLRP3 Inflammasome Activation in Murine Macrophages — R.A. Pietrofesa, P. Woodruff, et al. (2017)
• Flaxseed lignans enriched in secoisolariciresinol diglucoside prevent acute asbestos-induced peritoneal inflammation in mice — R.A. Pietrofesa, A. Velalopoulou, et al. (2016)
• Synthetic secoisolariciresinol diglucoside (LGM2605) inhibits Libby amphibole fiber-induced acute inflammation in mice — M. Christofidou-Solomidou, R.A. Pietrofesa, et al. (2019)
• Asbestos Induces Oxidative Stress and Activation of Nrf2 Signaling in Murine Macrophages: Chemopreventive Role of the Synthetic Lignan Secoisolariciresinol Diglucoside (LGM2605) — R.A. Pietrofesa, A. Velalopoulou, et al. (2016)
• Programmed necrosis induced by asbestos in human mesothelial cells causes high-mobility group box 1 protein release and resultant inflammation — H. Yang, Z. Rivera, et al. (2010)
• Late Inflammation Induced by Asbestiform Fibers in Mice Is Ameliorated by a Small Molecule Synthetic Lignan — R. Badger, K. Park, et al. (2021)

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