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

Abstract

BackgroundFlaxseed (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.MethodsWe evaluated the effects of a 10%FS or isocaloric control diet given to mice (C57/BL6) in 2 separate experiments (n = 15-25 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.ResultsIrradiated mice fed a 0%FS diet had a 4-month survival rate of 40% as compared to 70-88% 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 (Mean ± SEM) 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.ConclusionsDietary 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.

Dietary flaxseed modulates the miRNA profile in irradiated and non-irradiated murine lungs

“…29 Bronchoalveolar lavage (BAL) fluid revealed an increase in polymorphonuclear (PMN) cell content. In light of previous reports that FS reduced BAL fluid white blood cell count and PMN content in a mouse model of radiation pneumonitis, 17,30 our findings suggest a beneficial role of FS in reducing lung inflammation by reducing miR-142-3p. Of additional interest are associations of both of FS-downregulated miRNAs-miRs-142-3p and -150-and cancer: a positive correlation of miR-142-3p and lung carcinogenesis, 31,32 as well as a role of increased miR-150 through deregulation of cell cycle control.…”

“…10,16,17,30,57 Mice were obtained from Charles River and irradiated at 6-8 wk of age under animal protocols approved by the Institutional Animal Care and Use Committee (IACUC) of the University of Pennsylvania. Animals were housed in conventional cages under standardized conditions with controlled temperature and humidity and a 12:12-h day-night light cycle.…”

“…This set-up consists of a single, anterior 225 kV, 15 mA X-ray beam with a 0.15 mm Cu at an SSD of 35 cm that is designed to accurately reproduce the internal radiation dose distribution in mice that were used in previous studies. [16][17][18]30,57 The dosimetry and shielding of this system has been tested extensively. 28 The dose of radiation is a single fraction delivered via single AP (anterior-posterior) approach.…”

Plant Extracts and Plant-Derived Compounds: Promising Players in Countermeasure Strategy Against Radiological Exposure: A Review

“…Table 1 shows that many of them act by scavenging ROS and other free radicals, and by decreasing the radiation-induced increase in the level of TGF-β1, TNF-α, IFN-γ, WBC influx in tissue, IL-1β, IL-2, IL-4, IL-6, IL-12, IL-17, MIP-1α, VEGF, etc, all of them being key players in inflammatory response (Xie et al, 2006;Kim et al, 2007;Lee et al, 2007;Day et al, 2008;Qiu et al, 2008;Christofidou-Solomidou et al, 2011;Hei et al, 2011;Janko et al, 2012;Monceau et al, 2013;Pragya et al, 2014). Others act against radiation exposure by inducing the expression of Mn-SOD, GSH, CAT, and GPx, the important members of antioxidant defence system (Han et al, 2005;Gottfredsen et al, 2014) or modulate the immune response against radiation exposure Qiu et al, 2008;Pragya et al, 2014;Yu et al, 2014).…”

“…Using the pulse oximetry, a non-invasive way of determining arterial blood oxygenation levels, it was shown that mice fed with 10% FS diet had an significant (p≤0.05) increase percentage of arterial O 2 levels, particularly in IR+FS (0 week) and IR+FS (2 weeks) compared to mice fed 0% diet following IR exposure. Additionally, cytokine analysis of BALF in mice sacrificed 4 months post-irradiation indicated a significant (p≤0.0005 to ≤0.05) reduction in the levels of IL-1β, IL-2, IL-4, macrophage inflammatory protein-1α (MIP-1α), IL-6, IL-12, IL-17 and vascular endothelial growth factor (VEGF), in all of the irradiated FS diet fed groups as compared to irradiated mice on control diet (Christofidou-Solomidou et al, 2011). Reports indicate a similar reduction even after delaying FS diet by as long as 6 weeks post-radiation exposure.…”