LGM2605 Reduces Space Radiation-Induced NLRP3 Inflammasome Activation and Damage in In Vitro Lung Vascular Networks

Abstract

Updated measurements of charged particle fluxes during the transit from Earth to Mars as well as on site measurements by Curiosity of Martian surface radiation fluxes identified potential health hazards associated with radiation exposure for human space missions. Designing mitigation strategies of radiation risks to astronauts is critical. We investigated radiation-induced endothelial cell damage and its mitigation by LGM2605, a radioprotector with antioxidant and free radical scavenging properties. We used an in vitro model of lung vascular networks (flow-adapted endothelial cells; FAECs), exposed to gamma rays, low/higher linear energy transfer (LET) protons (3–4 or 8–10 keV/µm, respectively), and mixed field radiation sources (gamma and protons), given at mission-relevant doses (0.25 gray (Gy)–1 Gy). We evaluated endothelial inflammatory phenotype, NLRP3 inflammasome activation, and oxidative cell injury. LGM2605 (100 µM) was added 30 min post radiation exposure and gene expression changes evaluated 24 h later. Radiation induced a robust increase in mRNA levels of antioxidant enzymes post 0.25 Gy and 0.5 Gy gamma radiation, which was significantly decreased by LGM2605. Intercellular cell adhesion molecule-1 (ICAM-1) and NOD-like receptor protein 3 (NLRP3) induction by individual or mixed-field exposures were also significantly blunted by LGM2605. We conclude that LGM2605 is a likely candidate to reduce tissue damage from space-relevant radiation exposure.

Secoisolariciresinol Diglucoside Exerts Anti-Inflammatory and Antiapoptotic Effects through Inhibiting the Akt/IκB/NF-κB Pathway on Human Umbilical Vein Endothelial Cells

“…Similarly, we found that SDG also inhibited LPS-mediated HUVEC injury and apoptosis. This result is also consistent with the result that SDG reduces space radiation-induced damage in lung endothelial cell injury [24].…”

Mice Exposed to Combined Chronic Low-Dose Irradiation and Modeled Microgravity Develop Long-Term Neurological Sequelae

“…To assess the effects of prolonged spaceflight-like conditions on central nervous system (CNS) health following exposure, 6-month-old female C57BL/6J mice were either irradiated with low-dose γ-ray irradiation (0.04 Gy, LDR), hindlimb unloaded (HLU) or a combination of the two (HLU+LDR) for 21 days, followed by a 4-month readaptation period (Figure 1A). While the LDR γ-ray irradiation used does not recapitulate the entire space radiation spectrum, it constitutes a significant fraction and poses a hazard to astronauts’ health [15].…”

“…However, secondary particles produced by the interaction of SPE protons and heavy-charged GCR particles with the spacecraft structure include γ-rays and x-rays [3]. These radiation sources can also deliver a significant fraction of the total mission dose and pose a hazard to astronauts’ health [15]. For chronic irradiation exposure, we used flood sources consisting of plastic sheets embedded with the isotope 57 Co that emits medium energy (122 and 136 keV) γ-rays.…”

The Role of NLRP3 Inflammasome in Radiation-Induced Cardiovascular Injury

“…Activation of the NLPR3 inflammasome has been reported to directly induce endothelial dysfunction (Zhang et al, 2015;Erdei et al, 2018;Koka et al, 2019). A recent study showed that inhibition of radiation-induced NLRP3 inflammasome activation by LGM2605, an antioxidant and free radical scavenger, alleviated vascular damage (Chatterjee et al, 2019). Inhibitors of HMGB1 or caspase-1 significantly ameliorated endothelium-associated vasodilation in poloxamer 407 (P-407)treated Nlrp3 +/+ mice (Zhang et al, 2015).…”