Late Inflammation Induced by Asbestiform Fibers in Mice Is Ameliorated by a Small Molecule Synthetic Lignan

Our plain-English summary of Late Inflammation Induced by Asbestiform Fibers in Mice Is Ameliorated by a Small Molecule Synthetic Lignan, by R. Badger, K. Park, R.A. Pietrofesa, et al (International Journal of Molecular Sciences, 2021).

The study

• Authors: R. Badger, K. Park, R.A. Pietrofesa, M. Christofidou-Solomidou, K.M. Serve
• Journal: International Journal of Molecular Sciences
• Published: 2021;22(20)
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Exposure to Libby amphibole (LA) asbestos-like fibers is associated with increased risk of asbestosis, mesothelioma, pulmonary disease, and systemic autoimmune disease. LGM2605 is a small molecule antioxidant and free radical scavenger, with anti-inflammatory effects in various disease models. The current study aimed to determine whether the protective effects of LGM2605 persist during the late inflammatory phase post-LA exposure. Male and female C57BL/6 mice were administered daily LGM2605 (100 mg/kg) via gel cups for 3 days before and 14 days after a 200 µg LA given via intraperitoneal (i.p.) injection. Control mice were given unsupplemented gel cups and an equivalent dose of i.p. saline. On day 14 post-LA treatment, peritoneal lavage was assessed for immune cell influx, cytokine concentrations, oxidative stress biomarkers, and immunoglobulins. During the late inflammatory phase post-LA exposure, we noted an alteration in trafficking of both innate and adaptive immune cells, increased pro-inflammatory cytokine concentrations, induction of immunoglobulin isotype switching, and increased oxidized guanine species. LGM2605 countered these changes similarly among male and female mice, ameliorating late inflammation and altering immune responses in late post-LA exposure. These data support possible efficacy of LGM2605 in the prolonged treatment of LA-associated disease and other inflammatory conditions.

In plain English

This animal experiment used 48 male and female C57BL/6 mice. Each mouse received one injection into the abdominal (peritoneal) cavity, which the authors used as a stand-in for the pleural cavity. The injection was 200 µg of Libby amphibole (LA) fibers or saline. For 3 days before and 14 days after, mice ate gel with or without LGM2605 (about 100 mg/kg daily). LGM2605 is a synthetic flaxseed lignan that the authors describe as an antioxidant. At 14 days, LA-only mice had higher spleen weight relative to body weight. Inflammatory white cells (PMN cells and macrophages) made up a larger percentage of peritoneal cells, B and T cells a smaller percentage, and antibody levels changed. IL-6 was higher in peritoneal fluid (16.84 versus 0.36 pg/mL in saline controls) and in blood. Oxidized guanine, a marker of DNA and RNA damage, was higher in peritoneal fluid. With LGM2605, most measures in LA-exposed mice returned to control levels. Total peritoneal B cells were only partly restored, and peritoneal B1a B cells fell below control levels. The authors concluded that LGM2605 ameliorated these responses. They noted that gel-cup dosing may vary between mice.

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: Animal experiment (mouse study) with four randomly assigned treatment groups
• Who was studied: 48 ten-week-old C57BL/6 mice, equal numbers of males and females (6 males and 6 females per group), housed at Idaho State University
• Exposure: A single intraperitoneal injection of 200 µg Libby amphibole (LA) fibers, or saline. The fibers came from a composite sample of rock from the W.R. Grace mine near Libby, Montana. Mice also received daily LGM2605 (about 100 mg/kg) or plain gel, for 3 days before and 14 days after the injection.
• Main results:
  • LA alone increased spleen weight relative to body weight compared with saline control (p = 0.001). LGM2605 + LA brought it back to control levels (p < 0.001).
  • LA alone increased PMN cells as a percentage of total peritoneal cells compared with saline control (p < 0.0001). LGM2605 + LA reduced the percentage to control levels (p < 0.001).
  • LA alone increased the percentage of peritoneal B1a B cells compared with saline control (p = 0.017). LGM2605, with or without LA, reduced this percentage below both the LA-only and saline control groups.
  • LA alone reduced the percentage of total peritoneal B cells compared with saline control (p < 0.0001). LGM2605 + LA only partly restored it; it remained lower than in saline controls.
  • In peritoneal fluid, LA alone lowered relative IgG1 (0.53 vs 1.00 in controls) and IgG2b (0.53 vs 1.00) and raised IgA (1.68 vs 1.00). With LGM2605 + LA the values were 1.13 for IgG1, 1.13 for IgG2b and 0.94 for IgA.
  • In peritoneal fluid, IL-6 was 16.84 plus or minus 4.16 pg/mL in LA-only mice, 0.36 plus or minus 0.17 in controls and 0.22 plus or minus 0.14 with LGM2605 + LA. The authors described the increase as more than 44-fold. MCP-1 followed the same pattern.
  • In serum, LA alone raised IL-6 compared with saline control (7.87 vs 5.47 pg/mL; p = 0.015). LGM2605 + LA lowered it to control levels (p < 0.01).
  • LA alone increased oxidized guanine species, a marker of DNA/RNA oxidative damage, in peritoneal fluid (p = 0.023). LGM2605 + LA reduced them to control levels (p = 0.022).
• The authors' conclusion: The authors concluded that LA injection promoted inflammatory responses and oxidative tissue damage in male and female mice over 14 days. In their view, oral LGM2605 ameliorated these responses, and LGM2605 may be an effective preventative treatment for exposures associated with oxidative stress.
• Limitations the authors state:
  • Dosing by gel cup does not guarantee the right dose, because individual mice may eat different amounts of gel.
  • Fibers were injected into the peritoneal cavity, which served as a surrogate for the pleural cavity, although asbestos exposures typically occur by inhalation.
  • The fall in lymphocyte numbers might partly reflect the overall rise in total peritoneal cells from the white blood cell influx.
  • Alpha-4 integrin, a marker of B cell trafficking, was not measured.
  • The physiological relevance of the κ/λ light-chain ratios in LA exposure models is not yet known.

Topics

Medical terms in this study, explained in our Lexicon: Inflammation, Asbestiform, Libby amphiboles, Mesothelioma, Cytokine, Oxidative Stress, Biomarker.

Related studies

• Synthetic secoisolariciresinol diglucoside (LGM2605) inhibits Libby amphibole fiber-induced acute inflammation in mice — M. Christofidou-Solomidou, R.A. Pietrofesa, et al. (2019)
• Flaxseed lignans enriched in secoisolariciresinol diglucoside prevent acute asbestos-induced peritoneal inflammation in mice — R.A. Pietrofesa, A. Velalopoulou, et al. (2016)
• The Synthetic Lignan Secoisolariciresinol Diglucoside Prevents Asbestos-Induced NLRP3 Inflammasome Activation in Murine Macrophages — R.A. Pietrofesa, P. Woodruff, et al. (2017)
• 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)
• Synthetic Secoisolariciresinol Diglucoside (LGM2605) Prevents Asbestos-Induced Inflammation and Genotoxic Cell Damage in Human Mesothelial Cells — R.A. Pietrofesa, S. Chatterjee, et al. (2022)
• Characterization of pulmonary responses in mice to asbestos/asbestiform fibers using gene expression profiles — N. Yanamala, E.R. Kisin, et al. (2018)

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