Mitigation of tissue toxicity related to lung exposure to ionizing radiation is highlyrelevant to accidental or intentional exposure to high doses of radiation. The cytotoxiceffects of ionizing radiation in normal lung parenchyma are mediated by the generationof reactive oxygen species (ROS) and are propagated by ROS-driven oxidative stresspointing towards a central role of tissue antioxidant defense. Preliminary data obtainedfrom an exploratory R21 award showed that whole grain dietary flaxseed (FS)ameliorated the adverse effects of thoracic radiation by significantly enhancing overallmouse survival, blocking late phase lung fibrosis and modulating cell cycle, TGF-beta1and apoptosis genes. Additionally, using acute models of pulmonary inflammation suchas lung ischemia/reperfusion injury (related to transplantation injury) known to bemediated by generation of ROS, we were able to indicate that flaxseed via its lignancomponent, mitigated oxidative tissue damage and decreased lung inflammation.Mechanistic studies revealed a potent antioxidant effect of flaxseed mediated by the dualaction of it lignan component in a) direct ROS scavenging and b) boosting of endogenousantioxidant enzyme defenses via activation of the Nrf2/ARE pathway. We, therefore,hypothesize that flaxseed lignans via their direct antioxidant, anti-inflammatory and anti-fibrotic action may be a novel therapeutic strategy to alleviate acute and chronicradiation-induced lung toxicity. Although we have only studied flaxseed and its lignanmetabolites preventively in the context of radiation pneumonopathy, we believe that itsuse in mitigating post-exposure radiation injury will be equally effective. We havedeveloped and characterized a mouse model of radiation pneumonopathy and in additionto using conventional methodologies to evaluate lung injury parameters we propose novelstate of the art imaging methodologies using positron emission tomography (PET) andmicro-computed tomography (CT) to perform longitudinal studies to evaluate lignan-mediated mitigation of lung toxicity in response to ionizing radiation. Goal 1 will focuson determining whether flaxseed lignans mitigate acute and chronic lung toxicity in micerelated to external thoracic radiation while Goal 2 will focus on their role in mitigatinginternal thoracic radiation. The flaxseed lignan complex (FLC), is safe and can beadministered to patients formulated in a tablet and is currently evaluated in clinical trialsin the US and abroad so clinical translation is highly feasible.
Effective and safe delivery of an agent with anti-inflammatory, antioxidant and anti-fibrotic properties would have clear value in radiation pneumonopathy. Our preliminary data shows robust protection by whole grain flaxseed from radiation induced lung fibrosis associated with decreased levels of ROS production and oxidative tissue damage and identifies lignan component of flaxseed as the likely mediator of these effects. A lignan complex, rich in the plant lignan precursor secoisolariciresinol diglucoside (SDG) was isolated from flaxseed. SDG is metabolized by the colonic microflora to the mammalian lignans and is hypothesized to mediate the observed potent radioprotective effects. We propose in the current study to investigate the therapeutic role of Flaxseed lignan complex (FLC) in mitigating external and internal radiation-induced pneumonopathy model led in mice. While the FLC will be added in the rodent diet for the proposed study, it can be administered to patients formulated in a 1300mg tablet that is already being evaluated in several clinical trials in the US, China, Canada and Denmark, thus facilitating translation of the preclinical findings of the proposed work, to the clinic within a short period of time. The shelf life of FLC tablets is >3 years which allows safe stockpiling of this agent for immediate use in case of a dirty bomb explosion and contamination of civilians.
