Abstract
Background The interaction of asbestos with macrophages drives two key processes that are linked to malignancy: (1) the generation of reactive oxygen species (ROS)/reactive nitrogen species (RNS) and (2) the activation of an inflammation cascade that drives acute and chronic inflammation, with the NLRP3 inflammasome playing a key role. Synthetic secoisolariciresinol diglucoside (SDG), LGM2605, is a nontoxic lignan with anti-inflammatory and antioxidant properties and was evaluated for protection from asbestos in murine peritoneal macrophages (MF). Methods MFs were exposed to crocidolite asbestos ± LGM2605 given 4 hours prior to exposure and evaluated at various times for NLRP3 expression, secretion of inflammasome-activated cytokines (IL-1β and IL-18), proinflammatory cytokines (IL-6, TNFα, and HMGB1), NF-κB activation, and levels of total nitrates/nitrites. Results Asbestos induces a significant (p < 0.0001) increase in the NLRP3 subunit, release of proinflammatory cytokines, NLRP3-activated cytokines, NF-κB, and levels of nitrates/nitrites. LGM2605 significantly reduced NLRP3 ranging from 40 to 81%, IL-1β by 89–96%, and TNFα by 67–78%, as well as activated NF-κB by 48-49% while decreasing levels of nitrates/nitrites by 85–93%. Conclusions LGM2605 reduced asbestos-induced NLRP3 expression, proinflammatory cytokine release, NF-κB activation, and nitrosative stress in MFs supporting its possible use in preventing the asbestos-induced inflammatory cascade leading to malignancy.
Highlights
Recent studies have indicated that the pathogenesis of asbestos-induced cancers involves chronic inflammation which is facilitated by the cytokines interleukin-1 beta (IL1β), the chemokine tumor necrosis factor alpha (TNFα), and high mobility group box-1 (HMGB1) and eventual oxidative tissue damage caused by persistent asbestos fibers [1, 2]
We further investigated the observation of decreased nitrosative stress with LGM2605 treatment by determining protein and mRNA levels of inducible nitric oxide synthase in asbestos-exposed macrophages
Asbestos fiber internalization generates a significant increase in intracellular reactive oxygen species (ROS), and there is considerable evidence that asbestos-initiated chronic oxidative stress contributes to carcinogenesis and fibrosis by promoting oxidative DNA damage and regulating redox signaling pathways in exposed cells [25]
Summary
Recent studies have indicated that the pathogenesis of asbestos-induced cancers involves chronic inflammation which is facilitated by the cytokines interleukin-1 beta (IL1β), the chemokine tumor necrosis factor alpha (TNFα), and high mobility group box-1 (HMGB1) and eventual oxidative tissue damage caused by persistent asbestos fibers [1, 2]. Frustrated phagocytosis of asbestos fibers by macrophages and mesothelial cells generates intracellular reactive oxygen species (ROS) and reactive nitrogen species (RNS) which, besides being deleterious due to direct oxidative damage, activate proinflammatory transcription factors such as NF-κB, leading to the generation of numerous proinflammatory cytokines. The interaction of asbestos with macrophages drives two key processes that are linked to malignancy: (1) the generation of reactive oxygen species (ROS)/reactive nitrogen species (RNS) and (2) the activation of an inflammation cascade that drives acute and chronic inflammation, with the NLRP3 inflammasome playing a key role. LGM2605 reduced asbestos-induced NLRP3 expression, proinflammatory cytokine release, NF-κB activation, and nitrosative stress in MFs supporting its possible use in preventing the asbestos-induced inflammatory cascade leading to malignancy
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