Radiation mitigating properties of the lignan component in flaxseed

Wholegrain flaxseed (FS), and its lignan component (FLC) consisting mainly of secoisolariciresinol diglucoside (SDG), have potent lung radioprotective properties while not abrogating the efficacy of radiotherapy. However, while the whole grain was recently shown to also have potent mitigating properties in a thoracic radiation pneumonopathy model, the bioactive component in the grain responsible for the mitigation of lung damage was never identified. Lungs may be exposed to radiation therapeutically for thoracic malignancies or incidentally following detonation of a radiological dispersion device. This could potentially lead to pulmonary inflammation, oxidative tissue injury, and fibrosis. This study aimed to evaluate the radiation mitigating effects of FLC in a mouse model of radiation pneumonopathy. We evaluated FLC supplemented diets containing SDG lignan levels comparable to those in 10percent and 20percent whole grain diets. 10percent or 20percent FLC diets as compared to an isocaloric control diet (0percent FLC) were given to mice (C57/BL6) (n of15 to 30 mice/group) at 24, 48, or 72 hours after single-dose (13.5 Gy) thoracic x-ray treatment (XRT). Mice were evaluated 4 months post XRT for blood oxygenation, lung inflammation, fibrosis, cytokine and oxidative damage levels, and survival. FLC significantly mitigated radiation-related animal death. Specifically, mice fed 0percent FLC demonstrated 36.7percent survival 4 months post XRT compared to 60 to 73.3percent survival in mice fed 10percent-20percent FLC initiated 24 to72 hours post XRT. FLC also mitigated radiation-induced lung fibrosis whereby 10percent FLC initiated 24 hours post XRT significantly decreased fibrosis as compared to mice fed control diet while the corresponding TG beta1 levels detected immunohistochemically were also decreased. Additionally, 10 to 20percent FLC initiated at any time point post radiation exposure, mitigated radiation-induced lung injury evidenced by decreased bronchoalveolar lavage (BAL) protein and inflammatory cytokine/chemokine release at 16 weeks post XRT. Importantly, neutrophilic and overall inflammatory cell infiltrate in airways and levels of nitrotyrosine and malondialdehyde (protein and lipid oxidation, respectively) were also mitigated by the lignan diet. Dietary FLC given early post XRT mitigated radiation effects by decreasing inflammation, lung injury and eventual fibrosis while improving survival. FLC may be a useful agent, mitigating adverse effects of radiation in individuals exposed to incidental radiation, inhaled radioisotopes or even after the initiation of radiation therapy to treat malignancy. (Authors abstract)
Ionizing radiation can cause deleterious effects.  Humans are exposed to ionizing radiation above background levels during air and space travel, from nuclear accidents, and through the use of electronic devices.  Radiation pneumonopathy is defined as a significant clinical toxicity from thoracic radiation. Patients receiving large doses of radiation to the lung demonstrate two adverse clinical scenarios. It has become highly desirable to find an agent that is non toxic, cost effective, and safe for multiple administrations with beneficial effects spanning a long radiation exposure and post radiation exposure recovery phase. Flaxseed (FS) and its bioactive lignan component (FLC) have been shown as potent protectors against radiation-induced lung injury when given prior to radiation exposure. Specifically, dietary FS decreased radiation-induced oxidative lung tissue damage, decreased lung inflammation and prevented lung fibrosis. The current study was performed to ascertain whether FLC, in addition to its radioprotective properties, could also be an effective mitigator of radiation toxicity when administered at different time points soon after radiation exposure to the lung. Evidence provided in this study provides novel, strong support that the bioactive ingredient in whole grain FS responsible for its radiation mitigating properties is the lignan component and more specifically SDG. The lignan component of flaxseed, enriched in the lignan SDG, administered within just 24 to 72 hours postthoracic radiation enhanced survival and mitigated the chronic lung injury induced by XRT. by: 1) improving blood oxygenation levels, 2) decreasing lung injury by lowering BAL protein levels, 3) reducing pulmonary fibrosis by decreasing collagen content and TGF beta1 levels of lung tissues, 4) reducing lung inflammation by decreasing WBC influx into the airways and most importantly, 5) reducing oxidative tissue damage as shown by decreased protein nitration in lung tissue and lipid peroxidation in BAL fluid 6) improving overall animal survival.

XRT induced lung inflammation and impaired blood oxygenation (decreased SaO2) were improved with 10 and 20percent FLC diet when initiated after XRT. Improved blood oxygenation of all FLC fed mouse groups may lead to decreased levels of tissue hypoxia and may therefore explain the mitigation of adverse radiation effects even when diets are initiated post challenge.
This is the first report that FLC mitigated pulmonary inflammation when given hours post initial XRT challenge. The results show significant mitigation of lung injury in all the experimental FLC diet fed groups. This may be attributed to decreased inflammatory cell influx and membrane oxidation in FLC supplemented mice. Decreased oxidative tissue damage was noted in FLC fed mice, as evidenced by the tissue levels of nitrotyrosine and MDA levels in the BAL fluid. This  study showed for the first time that via FLC, fibrotic processes associated with high TGF-beta1 levels in lung tissues can be blunted even when the protective agent is given postradiation damage, i.e., as a radiation mitigator. FLC mediated decline in both lung hydroxyproline levels and fibrotic index were more prominent when diet was started preventively, i.e., 3 weeks prior to XRT. This suggests that further development or modification of the bioactive component(s) of FLC has the potential to further improve the properties of this novel dietary radiation mitigator.
Prolonged FLC administration in these animal models has not led to any significant toxicity. This is a critically important feature, since administering a radiation mitigator that possessed even mild toxicity in healthy individuals to a large population following radiation exposure could lead to severe toxicity in individuals with additional medical co-morbidities. Furthermore, FLC has a long, stable shelf life and is easy to administer orally at an affordable price.

FLC diet given within 24 to 72 hours after thoracic radiation exposure has benefits in terms of morbidity and mortality. In summary, this study demonstrates that FLC surpassed whole grain FS in its antioxidant, anti-inflammatory and anti-fibrotic mitigation properties when administered after thoracic XRT. FLC altered immediate XRT-induced markers of lung damage, creating a radioprotective milieu post-XRT, and provided high levels of circulating antioxidants from the continued metabolism of its bioactive lignans.  There is an unmet need to identify a radiation-mitigating agent that is effective in blunting adverse radiation effects to the lung, while being at the same time inexpensive, nontoxic, and easy-to-deliver to the wider population that may include people with diverse underlying medical conditions. These findings that the lignan component in flaxseed is a potent mitigator of radiation induced lung injury in a preclinical model of radiation pneumonopathy signifies the potential for the use of FLC in clinical settings. (Editors comments)