Synthetic secoisolariciresinol diglucoside (LGM2605) inhibits Libby amphibole fiber-induced acute inflammation in mice

Our plain-English summary of Synthetic secoisolariciresinol diglucoside (LGM2605) inhibits Libby amphibole fiber-induced acute inflammation in mice, by M. Christofidou-Solomidou, R.A. Pietrofesa, K. Park, et al (Toxicology and Applied Pharmacology, 2019).

The study

• Authors: M. Christofidou-Solomidou, R.A. Pietrofesa, K. Park, S.M. Albelda, K.M. Serve, D.E. Keil, J.C. Pfau
• Journal: Toxicology and Applied Pharmacology
• Published: 2019;375:81-93
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Exposure to the Libby amphibole (LA) asbestos-like fibers found in Libby, Montana, is associated with inflammatory responses in mice and humans, and an increased risk of developing mesothelioma, asbestosis, pleural disease, and systemic autoimmune disease. Flaxseed-derived secoisolariciresinol diglucoside (SDG) has anti-inflammatory, anti-fibrotic, and antioxidant properties. We have previously identified potent protective properties of SDG against crocidolite asbestos exposure modeled in mice. The current studies aimed to extend those findings by evaluating the immunomodulatory effects of synthetic SDG (LGM2605) on LA-exposed mice.

Methods: Male and female C57BL/6 mice were given LGM2605 via gavage initiated 3 days prior to and continued for 3 days after a single intraperitoneal dose of LA fibers (200 μg) and evaluated on day 3 for inflammatory cell influx in the peritoneal cavity using flow cytometry.

Results: LA exposure induced a significant increase (p < 0.0001) in spleen weight and peritoneal influx of white blood cells, all of which were reduced with LGM2605 with similar trends among males and females. Levels of peritoneal PMN cells were significantly (p < 0.0001) elevated post LA exposure, and were significantly (p < 0.0001) blunted by LGM2605. Importantly, LGM2605 significantly ameliorated the LA-induced mobilization of peritoneal B1a B cells.

Conclusions: LGM2605 reduced LA-induced acute inflammation and WBC trafficking supporting its possible use in mitigating downstream LA fiber-associated diseases.

Summary: Following acute exposure to Libby amphibole (LA) asbestos-like fibers, synthetic SDG (LGM2605), a small synthetic molecule, significantly reduced the LA-induced increase in spleen weight and peritoneal inflammation in C57BL/6 male and female mice. Our findings highlight that LGM2605 has immunomodulatory properties and may, thus, likely be a chemopreventive agent for LA-induced diseases.

Copyright © 2019 Elsevier Inc. All rights reserved.

In plain English

This was an animal experiment in male and female C57BL/6 mice about 14 weeks old. The authors tested whether LGM2605, a synthetic flaxseed compound (secoisolariciresinol diglucoside), changed short-term inflammation from Libby amphibole (LA) fibers. Mice in four groups (control, LGM2605 only, LA only, LA plus LGM2605) received LGM2605 (100 mg/kg) or saline by mouth daily for 3 days before and 3 days after a single abdominal (peritoneal) injection of either 200 μg LA or saline. Three days after exposure, LA raised spleen weight and the number of abdominal white blood cells. Compared with LA-only mice, mice given LA plus LGM2605 had 44.42% fewer abdominal white blood cells. In each sex, neutrophils also made up about a 37% smaller share of those cells. LA lowered B1a B cells (a type of B cell) measured in the abdominal cavity. LGM2605 partly restored these cells, but not significantly overall; the recovery was significant in females. The authors concluded that LGM2605 significantly reduced the effects of LA exposure. Only 3-day effects were measured. The authors noted that males and females were tested in separate experiments.

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 model of acute peritoneal inflammation after injected fibers, with and without treatment)
• Who was studied: Wild-type C57BL/6 mice, 40 male and 30 female, about 14 weeks old, housed at Montana State University. They were split into four groups: control, LGM2605 only, LA only, and LA plus LGM2605.
• Exposure: The LA-only and LA plus LGM2605 groups received a single intraperitoneal injection of 200 μg Libby amphibole (LA) fibers. The fibers came from an EPA composite sample collected at the W.R. Grace mine near Libby, Montana. The control and LGM2605-only groups received a saline injection instead. Treatment was LGM2605 (synthetic secoisolariciresinol diglucoside) at 100 mg/kg by gavage, or saline gavage, from 3 days before to 3 days after the injection.
• Main results:
  • LA exposure significantly increased spleen weight (p < 0.0001). In LA-exposed mice, LGM2605 was associated with lower spleen weight: by 17.79% in males and 28.65% in females. The article calls this a reduction in the LA-induced increase. Its table values correspond to body-weight-adjusted spleen weight compared with LA-only mice.
  • LA significantly increased white blood cells in the peritoneal cavity (p < 0.0001). Mice given LA plus LGM2605 had a 44.42% lower peritoneal white blood cell count than LA-only mice (p = 0.0027).
  • LA significantly increased the percentage of peritoneal white blood cells that were neutrophils (PMN cells) (p < 0.0001). In mice given LA plus LGM2605, this percentage was 37.09% lower in males and 37.46% lower in females than in LA-only mice.
  • LA significantly increased the percentage of peritoneal macrophages (p = 0.0080). In males exposed to LA, LGM2605 significantly decreased macrophages (p = 0.0004).
  • LA lowered the percentage of peritoneal lymphocytes. Overall, LGM2605 did not significantly restore them (p = 0.3607). In males it partially protected against the decrease (p = 0.0220).
  • LA significantly decreased B1a B cells in the peritoneal cavity (p < 0.0001). LGM2605 partially but non-significantly recovered them overall. The recovery was significant in female mice (p = 0.0192).
  • The authors describe alpha-4 integrin on B1a B cells as a marker of the cells' readiness to move. It was significantly recovered in mice given LA plus LGM2605. When analyzed by sex, the recovery was significant only in females (p = 0.0026).
  • LA exposure did not significantly change total peritoneal B cells and T cells, and LGM2605 had no effect on them.
• The authors' conclusion: The authors concluded that LGM2605 significantly reduced the effects of LA exposure. They described an anti-inflammatory effect on LA-induced changes in peritoneal inflammatory cells in both male and female mice. They suggested it may protect against long-term autoimmune outcomes of LA exposure, and said further studies are needed to test this.
• Limitations the authors state:
  • Male and female mice were tested in separate experiments, so differences in the size of responses between the sexes are expected.
  • The 3-day time point was too short to see major changes in adaptive immune responses.
  • The mechanism by which LGM2605 reduced neutrophil and macrophage recruitment was not examined.

Topics

Medical terms in this study, explained in our Lexicon: Libby amphiboles, Inflammation, Mesothelioma, Crocidolite, Asbestos Exposure, Peritoneal Cavity.

Related studies

• Flaxseed lignans enriched in secoisolariciresinol diglucoside prevent acute asbestos-induced peritoneal inflammation in mice — R.A. Pietrofesa, A. Velalopoulou, et al. (2016)
• Late Inflammation Induced by Asbestiform Fibers in Mice Is Ameliorated by a Small Molecule Synthetic Lignan — R. Badger, K. Park, et al. (2021)
• 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)
• The role of iron in Libby amphibole-induced acute lung injury and inflammation — J.H. Shannahan, A.J. Ghio, et al. (2011)

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