Dietary flaxseed administered post thoracic radiation treatment improves survival and mitigates radiation-induced pneumonopathy in mice

Flaxseed (FS) is a dietary supplement known for its antioxidant and anti-inflammatory properties. Radiation exposure of lung tissues occurs either when given therapeutically to treat intrathoracic malignancies or incidentally, such as in the case of exposure from inhaled radioisotopes released after the detonation of a radiological dispersion devise (RDD). Such exposure is associated with pulmonary inflammation, oxidative tissue damage and irreversible lung fibrosis. We previously reported that dietary FS prevents pneumonopathy in a rodent model of thoracic X-ray radiation therapy (XRT). However, flaxseed�s therapeutic usefulness in mitigating radiation effects post-exposure has never been evaluated. We evaluated the effects of a 10%FS or isocaloric control diet given to mice (C57/BL6) in 2 separate experiments (15 to 25 mice/group) on 0, 2, 4, 6 weeks post a single dose 13.5 Gy thoracic XRT and compared it to an established radiation-protective diet given preventively, starting at 3 weeks prior to XRT. Lungs were evaluated four months post-XRT for blood oxygenation levels, inflammation and fibrosis. Irradiated mice fed a 0% FS diet had a 4 month survival rate of 40% as compared to 70 to 88% survival in irradiated FS-fed mouse groups. Additionally, all irradiated FS fed mice had decreased fibrosis compared to those fed 0% FS. Lung OH Proline content ranged from 96.5+/- 7.1 to 110.2 +/- 7.7 μg/ml in all irradiated FS fed mouse groups, as compared to 138 +/- 10.8 μg/ml for mice on 0% FS. Concomitantly, bronchoalveolar lavage (BAL) protein and weight loss associated with radiation cachexia was significantly decreased in all FS fed groups. Inflammatory cell influx to lungs also decreased significantly except when FS diet was delayed by 4 and 6 weeks post XRT. All FS fed mice (irradiated or not), maintained a higher blood oxygenation level as compared to mice on 0% FS. Similarly, multiplex cytokine analysis in the BAL fluid revealed a significant decrease of specific inflammatory cytokines in FS fed mice. Dietary FS given post-XRT mitigates radiation effects by decreasing pulmonary fibrosis, inflammation, cytokine secretion and lung damage while enhancing mouse survival. Dietary supplementation of FS may be a useful adjuvant treatment mitigating adverse effects of radiation in individuals exposed to inhaled radioisotopes or incidental radiation. (Authors abstract)
Exposure to whole-body irradiation induces acute radiation syndrome (ARS), with damage to hematopoietic, gastrointestinal and central nervous system. Radiation pneumonopathy can cause toxicity from thoracic radiation. Patients receiving large doses of radiation to the lung show an acute radiation pneumonopathy whereby a �pneumonitic� or exudative reaction occurs. In the second type of radiation-induced lung injury, occurring within several months after exposure, the lung tissue enters the �late fibrotic� phase, in which the number of inflammatory cells (particularly neutrophils) decrease and a marked thickening of alveolar walls due to collagen deposition can be noted histopathologically. This group has identified flaxseed and its bioactive lignan component as potent protectors against radiation-induced lung toxicity when given prior to radiation exposure. Previous work has shown that dietary flaxseed decreased radiation-induced oxidative lung tissue damage, decreased lung inflammation and prevented lung fibrosis. This study was performed to determine whether dietary flaxseed can also be effective as a mitigator of radiation toxicity, i.e., when administered after radiation exposure to the lung.  The data showed that FS increased survival and mitigated the acute and chronic damage induced by X-ray radiation exposure of lung tissues when administered days and weeks after radiation exposure. Results show that FS significantly ameliorates the XRT-induced damage by improving survival and body weight of mice fed with FS not only when diet was given prior to XRT but also when diet was started 2, 4 and 6 weeks after XRT. The FS diet mitigated the deleterious effects of XRT by: a) improving pulmonary hemodynamics and blood oxygenation levels, b) decreasing lung injury by lowering BAL protein levels, c) reducing pulmonary fibrosis by decreasing collagen content of lung tissues, d) reducing lung inflammation by decreasing WBC influx into the airways and by e) oxidative modification of mouse lungs as evidenced by levels of lipid peroxidation. BAL cytokine analysis suggested an alteration of the chronic inflammatory profile of irradiated lungs favoring a mitigated radiation effect as a result of the FS diet. The FS diet protected mice from XRT-induced mortality whether given therapeutically or preventively. XRT-induced lung inflammation and impaired blood oxygenation (decreased PaO2) were improved with FS diet when initiated prior to or days and weeks after XRT. This is the first report that antioxidant agents, such as the FS diets, mitigate pulmonary inflammation when given weeks post initial challenge.  FS was protective against experimental radiation fibrosis. The FS mediated decline in both lung OH-Proline levels and FI was more prominent when diet was started preventively, i.e., 3 weeks prior to XRT. The cytokine levels of the lung tissues and fluids reflect levels comparable to chronic inflammation and not acute responses. Several cytokines associated with inflammation were significantly lower in irradiated FS-fed mice for example decreased IL-6 levels, reflecting a low inflammatory state of lung tissues. Flaxseed also decreased cell mediated inflammation by decreasing IL-12 levels. VEGF is an endothelial cell specific growth factor that contributes to angiogenesis and vascular permeability. In FS-fed irradiated animals low VEGF levels were observed as compared to untreated controls. FS appears to be a potential agent in mitigating radiation damage. (Editors comments)