title: Radiation mitigating properties of the lignan component in flaxseed.
abstract: BACKGROUND
  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.
  
  
  METHODS
  We evaluated FLC-supplemented diets containing SDG lignan levels comparable to those in 10% and 20% whole grain diets. 10% or 20% FLC diets as compared to an isocaloric control diet (0% FLC) were given to mice (C57/BL6) (n=15-30 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.
  
  
  RESULTS
  FLC significantly mitigated radiation-related animal death. Specifically, mice fed 0% FLC demonstrated 36.7% survival 4 months post-XRT compared to 60-73.3% survival in mice fed 10%-20% FLC initiated 24-72 hours post-XRT. FLC also mitigated radiation-induced lung fibrosis whereby 10% FLC initiated 24-hours post-XRT significantly decreased fibrosis as compared to mice fed control diet while the corresponding TGF-beta1 levels detected immunohistochemically were also decreased. Additionally, 10-20% 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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Medicine, Pulmonary, Allergy and Critical Care Division, University of Pennsylvania, 3615 Civic Center Boulevard, Abramson Research Building, Suite 1016C, Philadelphia, PA 19104, USA.
authors.forename: Ralph
authors.initials: R
authors.lastname: Pietrofesa
authors.forename: Jason
authors.initials: J
authors.lastname: Turowski
authors.forename: Sonia
authors.initials: S
authors.lastname: Tyagi
authors.forename: Floyd
authors.initials: F
authors.lastname: Dukes
authors.forename: Evguenia
authors.initials: E
authors.lastname: Arguiri
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Busch
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Gallagher-Colombo
authors.forename: Charalambos C
authors.initials: CC
authors.lastname: Solomides
authors.forename: Keith A
authors.initials: KA
authors.lastname: Cengel
authors.forename: Melpo
authors.initials: M
authors.lastname: Christofidou-Solomidou
mesh_terms: D000821:Animal Feed; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D002072:Butylene Glycols / Q000008:administration & dosage*; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D005355:Fibrosis / Q000209:etiology / Q000517:prevention & control; D019597:Flax; D005960:Glucosides / Q000008:administration & dosage*; D053208:Kaplan-Meier Estimate; D017705:Lignans / Q000008:administration & dosage; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D055370:Lung Injury / Q000150:complications / Q000378:metabolism / Q000517:prevention & control*; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils; D010100:Oxygen / Q000097:blood; D008517:Phytotherapy; D011833:Radiation Injuries, Experimental / Q000150:complications / Q000378:metabolism / Q000517:prevention & control*; D017564:Radiation Pneumonitis / Q000209:etiology / Q000473:pathology; D011837:Radiation-Protective Agents / Q000008:administration & dosage*; D012639:Seeds; D015996:Survival Rate; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D002072:Butylene Glycols; D016207:Cytokines; D005960:Glucosides; D017705:Lignans; D011837:Radiation-Protective Agents; D053773:Transforming Growth Factor beta1; C002744:3-nitrotyrosine; D014443:Tyrosine; D008315:Malondialdehyde; D010100:Oxygen; C090142:secoisolariciresinol diglucoside
references.citation: Hematol Oncol Clin North Am. 2004 Feb;18(1):41-53
references.pmid: 15005280
references.citation: Free Radic Biol Med. 2006 Jun 1;40(11):1903-13
references.pmid: 16716892
references.citation: Radiat Res. 2012 Dec;178(6):568-80
references.pmid: 23106213
references.citation: Int J Radiat Oncol Biol Phys. 1995 Jan 15;31(2):361-9
references.pmid: 7836090
references.citation: Am J Physiol Lung Cell Mol Physiol. 2000 Apr;278(4):L719-25
references.pmid: 10749749
references.citation: Gene Ther. 1998 Feb;5(2):196-208
references.pmid: 9578839
references.citation: J Radiat Res. 2009 May;50(3):177-82
references.pmid: 19377267
references.citation: Eur J Radiol. 2007 Aug;63(2):167-77
references.pmid: 17630244
references.citation: Cancer Biol Ther. 2009 Jan;8(1):47-53
references.pmid: 18981722
references.citation: Radiat Res. 2010 May;173(5):590-601
references.pmid: 20426658
references.citation: Int J Radiat Oncol Biol Phys. 1981 Oct;7(10):1365-70
references.pmid: 7033190
references.citation: Radiat Res. 1990 Nov;124(2):147-55
references.pmid: 2247595
references.citation: Int J Radiat Oncol Biol Phys. 2006 Jul 1;65(3):876-81
references.pmid: 16751069
references.citation: Curr Drug Targets. 2010 Nov;11(11):1386-94
references.pmid: 20583979
references.citation: Risk Anal. 2006 Apr;26(2):501-14
references.pmid: 16573636
references.citation: Singapore Med J. 2007 Oct;48(10):950-7
references.pmid: 17909684
references.citation: N Engl J Med. 2007 Nov 29;357(22):2277-84
references.pmid: 18046031
references.citation: Radiother Oncol. 2006 Nov;81(2):196-205
references.pmid: 17069914
references.citation: Radiat Res. 1996 Jul;146(1):61-7
references.pmid: 8677299
references.citation: BMC Cancer. 2011 Jun 24;11:269
references.pmid: 21702963
references.citation: Radiat Res. 1989 Jul;119(1):1-14
references.pmid: 2756101
references.citation: Respirology. 2012 Jan;17(1):66-71
references.pmid: 22023053
references.citation: Int J Radiat Oncol Biol Phys. 1995 Aug 30;33(1):99-109
references.pmid: 7642437
references.citation: Int J Radiat Oncol Biol Phys. 1987 Sep;13(9):1355-9
references.pmid: 3040647
references.citation: Int J Radiat Oncol Biol Phys. 1984 Feb;10(2):243-51
references.pmid: 6323362
references.citation: Radiat Res. 2012 May;177(5):e0025-39
references.pmid: 22468702
references.citation: J Nutr. 2006 Jun;136(6):1545-51
references.pmid: 16702319
references.citation: Radiat Res. 2010 May;173(5):579-89
references.pmid: 20426657
references.citation: Transl Oncol. 2012 Aug;5(4):230-7
references.pmid: 22937174
references.citation: Free Radic Res. 2007 Nov;41(11):1273-82
references.pmid: 17957541
references.citation: Semin Radiat Oncol. 2003 Jul;13(3):333-45
references.pmid: 12903021
references.citation: Am J Physiol Lung Cell Mol Physiol. 2008 Feb;294(2):L255-65
references.pmid: 18083772
references.citation: Radiat Res. 1994 Dec;140(3):347-55
references.pmid: 7972687
references.citation: Int J Radiat Oncol Biol Phys. 2011 Jul 1;80(3):860-8
references.pmid: 21493014
references.citation: Arch Biochem Biophys. 1961 May;93:440-7
references.pmid: 13786180
references.citation: Radiat Res. 1989 Jul;119(1):15-31
references.pmid: 2756106
references.citation: Free Radic Biol Med. 2010 Apr 15;48(8):1034-43
references.pmid: 20096348
references.citation: Int J Radiat Biol. 2004 Jan;80(1):3-10
references.pmid: 14761845
references.citation: Int J Radiat Oncol Biol Phys. 1977 May-Jun;2(5-6):475-90
references.pmid: 885753
references.citation: Oncologist. 2010;15(4):360-71
references.pmid: 20413641
references.citation: Hematol Oncol Clin North Am. 2004 Feb;18(1):55-80
references.pmid: 15005281