title: Asbestos Induces Oxidative Stress and Activation of Nrf2 Signaling in Murine Macrophages: Chemopreventive Role of the Synthetic Lignan Secoisolariciresinol Diglucoside (LGM2605).
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.
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine and the Department of Medicine, University of Pennsylvania Perelman School of Medicine, 3615 Civic Center Boulevard, Abramson Research Center, Office Suite 1016C, Philadelphia, PA 19104, USA. ralphp@mail.med.upenn.edu.
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Pietrofesa
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine and the Department of Medicine, University of Pennsylvania Perelman School of Medicine, 3615 Civic Center Boulevard, Abramson Research Center, Office Suite 1016C, Philadelphia, PA 19104, USA. avela@mail.med.upenn.edu.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Velalopoulou
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine and the Department of Medicine, University of Pennsylvania Perelman School of Medicine, 3615 Civic Center Boulevard, Abramson Research Center, Office Suite 1016C, Philadelphia, PA 19104, USA. albelda@mail.med.upenn.edu.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Albelda
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine and the Department of Medicine, University of Pennsylvania Perelman School of Medicine, 3615 Civic Center Boulevard, Abramson Research Center, Office Suite 1016C, Philadelphia, PA 19104, USA. melpo@mail.med.upenn.edu.
authors.forename: Melpo
authors.initials: M
authors.lastname: Christofidou-Solomidou
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001194:Asbestos / Q000009:adverse effects*; D002072:Butylene Glycols / Q000494:pharmacology*; D002478:Cells, Cultured; D005960:Glucosides / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D015398:Signal Transduction
chemical_list: D000975:Antioxidants; D002072:Butylene Glycols; D005960:Glucosides; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D001194:Asbestos; C090142:secoisolariciresinol diglucoside
keywords: LGM2605; antioxidant; asbestos; lignan; macrophage; mesothelioma; oxidative stress; phase II enzymes; reactive oxygen species; secoisolariciresinol diglucoside