title: Low-dose irradiation affects expression of inflammatory markers in the heart of ApoE -/- mice.
abstract: Epidemiological studies indicate long-term risks of ionizing radiation on the heart, even at moderate doses. In this study, we investigated the inflammatory, thrombotic and fibrotic late responses of the heart after low-dose irradiation (IR) with specific emphasize on the dose rate. Hypercholesterolemic ApoE-deficient mice were sacrificed 3 and 6 months after total body irradiation (TBI) with 0.025, 0.05, 0.1, 0.5 or 2 Gy at low (1 mGy/min) or high dose rate (150 mGy/min). The expression of inflammatory and thrombotic markers was quantified in frozen heart sections (CD31, E-selectin, thrombomodulin, ICAM-1, VCAM-1, collagen IV, Thy-1, and CD45) and in plasma samples (IL6, KC, MCP-1, TNFα, INFγ, IL-1β, TGFβ, INFγ, IL-10, sICAM-1, sE-selectin, sVCAM-1 and fibrinogen) by fluorescence analysis and ELISA. We found that even very low irradiation doses induced adaptive late responses, such as increases of capillary density and changes in collagen IV and Thy-1 levels indicating compensatory regulation. Slight decreases of ICAM-1 levels and reduction of Thy 1 expression at 0.025-0.5 Gy indicate anti-inflammatory effects, whereas at the highest dose (2 Gy) increased VCAM-1 levels on the endocardium may represent a switch to a pro-inflammatory response. Plasma samples partially confirmed this pattern, showing a decrease of proinflammatory markers (sVCAM, sICAM) at 0.025-2.0 Gy. In contrast, an enhancement of MCP-1, TNFα and fibrinogen at 0.05-2.0 Gy indicated a proinflammatory and prothrombotic systemic response. Multivariate analysis also revealed significant age-dependent increases (KC, MCP-1, fibrinogen) and decreases (sICAM, sVCAM, sE-selectin) of plasma markers. This paper represents local and systemic effects of low-dose irradiation, including also age- and dose rate-dependent responses in the ApoE-/- mouse model. These insights in the multiple inflammatory/thrombotic effects caused by low-dose irradiation might facilitate an individual evaluation and intervention of radiation related, long-term side effects but also give important implications for low dose anti-inflammatory radiotherapy.
authors: Department of Radiation Therapy, University of Leipzig, Leipzig, Germany.
authors: Daniel
authors: D
authors: Mathias
authors: Radiological Protection Research and Instrumentation Branch, Canadian Nuclear Laboratories, Chalk River, Ontario, Canada.
authors: Ronald E J
authors: RE
authors: Mitchel
authors: Departments of Pathology and Laboratory Medicine and Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada; Vascular Biology Group, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors: Mirela
authors: M
authors: Barclay
authors: Radiological Protection Research and Instrumentation Branch, Canadian Nuclear Laboratories, Chalk River, Ontario, Canada.
authors: Heather
authors: H
authors: Wyatt
authors: Radiological Protection Research and Instrumentation Branch, Canadian Nuclear Laboratories, Chalk River, Ontario, Canada.
authors: Michelle
authors: M
authors: Bugden
authors: Radiological Protection Research and Instrumentation Branch, Canadian Nuclear Laboratories, Chalk River, Ontario, Canada.
authors: Nicholas D
authors: ND
authors: Priest
authors: Departments of Pathology and Laboratory Medicine and Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada; Vascular Biology Group, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors: Stewart C
authors: SC
authors: Whitman
authors: Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Germany.
authors: Markus
authors: M
authors: Scholz
authors: Department of Radiotherapy and Radiation Oncology, University of Rostock, Rostock, Germany.
authors: Guido
authors: G
authors: Hildebrandt
authors: Institute of Clinical Immunology and Transfusion Medicine, University of Leipzig, Leipzig, Germany.
authors: Manja
authors: M
authors: Kamprad
authors: Department of Radiation Therapy, University of Leipzig, Leipzig, Germany.
authors: Annegret
authors: A
authors: Glasow
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D015415:Biomarkers / Q000378:metabolism*; D003037:Cobalt Radioisotopes / Q000009:adverse effects; D004195:Disease Models, Animal; D004307:Dose-Response Relationship, Radiation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005720:Gamma Rays / Q000009:adverse effects*; D006321:Heart / Q000528:radiation effects*; D006937:Hypercholesterolemia / Q000378:metabolism / Q000503:physiopathology; D007249:Inflammation / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011833:Radiation Injuries, Experimental / Q000209:etiology / Q000378:metabolism* / Q000473:pathology
chemical_list: D001057:Apolipoproteins E; D015415:Biomarkers; D003037:Cobalt Radioisotopes; D018836:Inflammation Mediators