Abstract:Thoracic radiotherapy is an effective treatment for many types of cancer; however it is also associated with an increased risk of developing cardiovascular disease (CVD), appearing mainly ≥10 years after radiation exposure. The present study investigated acute and early term physiological and molecular changes in the cardiovascular system after ionizing radiation exposure. Female and male ApoE -/mice received a single exposure of low or high dose X-ray thoracic irradiation (0.1 and 10 Gy). The level of cholest… Show more
“…Interestingly we found that very low IR doses, from 0.005 Gy onwards, enhance sICAM levels in ApoE−/− mice and, at HDR only, also in wild type mice. These findings are in line with reports of low-dose IR induced acute upregulation of sICAM in ApoE−/− mice after thorax IR at 0.1 Gy [54]. Based on our previous investigations we assume that upregulation of ICAM after low-dose IR is only transient as it was even slightly counter-regulated after 3 months [28].…”
Section: Systemic In Vivo Responses After Whole Body Irradiation (Wbi)supporting
Anti-inflammatory low-dose therapy is well established, whereas the immunomodulatory impact of doses below 0.1 Gy is much less clear. In this study, we investigated dose, dose rate and time-dependent effects in a dose range of 0.005 to 2 Gy on immune parameters after whole body irradiation (IR) using a pro-inflammatory (ApoE−/−) and a wild type mouse model. Long-term effects on spleen function (proliferation, monocyte expression) were analyzed 3 months, and short-term effects on immune plasma parameters (IL6, IL10, IL12p70, KC, MCP1, INFγ, TGFβ, fibrinogen, sICAM, sVCAM, sE-selectin/CD62) were analyzed 1, 7 and 28 days after Co60 γ-irradiation (IR) at low dose rate (LDR, 0.001 Gy/day) and at high dose rate (HDR). In vitro measurements of murine monocyte (WEHI-274.1) adhesion and cytokine release (KC, MCP1, IL6, TGFβ) after low-dose IR (150 kV X-ray unit) of murine endothelial cell (EC) lines (H5V, mlEND1, bEND3) supplement the data. RT-PCR revealed significant reduction of Ki67 and CD68 expression in the spleen of ApoE−/− mice after 0.025 to 2 Gy exposure at HDR, but only after 2 Gy at LDR. Plasma levels in wild type mice, showed non-linear time-dependent induction of proinflammatory cytokines and reduction of TGFβ at doses as low as 0.005 Gy at both dose rates, whereas sICAM and fibrinogen levels changed in a dose rate-specific manner. In ApoE−/− mice, levels of sICAM increased and fibrinogen decreased at both dose rates, whereas TGFβ increased mainly at HDR. Non-irradiated plasma samples revealed significant age-related enhancement of cytokines and adhesion molecules except for sICAM. In vitro data indicate that endothelial cells may contribute to systemic IR effects and confirm changes of adhesion properties suggested by altered sICAM plasma levels. The differential immunomodulatory effects shown here provide insights in inflammatory changes occurring at doses far below standard anti-inflammatory therapy and are of particular importance after diagnostic and chronic environmental exposures.
“…Interestingly we found that very low IR doses, from 0.005 Gy onwards, enhance sICAM levels in ApoE−/− mice and, at HDR only, also in wild type mice. These findings are in line with reports of low-dose IR induced acute upregulation of sICAM in ApoE−/− mice after thorax IR at 0.1 Gy [54]. Based on our previous investigations we assume that upregulation of ICAM after low-dose IR is only transient as it was even slightly counter-regulated after 3 months [28].…”
Section: Systemic In Vivo Responses After Whole Body Irradiation (Wbi)supporting
Anti-inflammatory low-dose therapy is well established, whereas the immunomodulatory impact of doses below 0.1 Gy is much less clear. In this study, we investigated dose, dose rate and time-dependent effects in a dose range of 0.005 to 2 Gy on immune parameters after whole body irradiation (IR) using a pro-inflammatory (ApoE−/−) and a wild type mouse model. Long-term effects on spleen function (proliferation, monocyte expression) were analyzed 3 months, and short-term effects on immune plasma parameters (IL6, IL10, IL12p70, KC, MCP1, INFγ, TGFβ, fibrinogen, sICAM, sVCAM, sE-selectin/CD62) were analyzed 1, 7 and 28 days after Co60 γ-irradiation (IR) at low dose rate (LDR, 0.001 Gy/day) and at high dose rate (HDR). In vitro measurements of murine monocyte (WEHI-274.1) adhesion and cytokine release (KC, MCP1, IL6, TGFβ) after low-dose IR (150 kV X-ray unit) of murine endothelial cell (EC) lines (H5V, mlEND1, bEND3) supplement the data. RT-PCR revealed significant reduction of Ki67 and CD68 expression in the spleen of ApoE−/− mice after 0.025 to 2 Gy exposure at HDR, but only after 2 Gy at LDR. Plasma levels in wild type mice, showed non-linear time-dependent induction of proinflammatory cytokines and reduction of TGFβ at doses as low as 0.005 Gy at both dose rates, whereas sICAM and fibrinogen levels changed in a dose rate-specific manner. In ApoE−/− mice, levels of sICAM increased and fibrinogen decreased at both dose rates, whereas TGFβ increased mainly at HDR. Non-irradiated plasma samples revealed significant age-related enhancement of cytokines and adhesion molecules except for sICAM. In vitro data indicate that endothelial cells may contribute to systemic IR effects and confirm changes of adhesion properties suggested by altered sICAM plasma levels. The differential immunomodulatory effects shown here provide insights in inflammatory changes occurring at doses far below standard anti-inflammatory therapy and are of particular importance after diagnostic and chronic environmental exposures.
“…Wild type mice models are resistant to atherosclerosis development due to the low level of low-density lipoprotein (LDL), therefore, apolipoprotein E-deficient (ApoE−/−) mice and LDL receptor knock-out mice which display poor lipoprotein clearance with subsequent accumulation of cholesterol, that promote the development of atherosclerotic plaques, are the most common mice models to study the pathophysiology of atherosclerosis. We observed increased serum GDF-15 and CXCL10 in both female and male ApoE−/− mice at 24 h after low and high dose local thoracic irradiation, which was validated to be secreted from the coronary artery and microvascular endothelial cells in vitro (Ramadan et al 2021a , b ). GDF-15 and CXCL10 are proatherogenic inflammatory markers, and they are promising biomarkers in cardiovascular diseases in humans, including atherosclerosis (Xu et al 2011 ; Tavakolian Ferdousie et al 2017 ).…”
Section: Out-of-field Effects: Model Systems and Mechanismsmentioning
confidence: 75%
“…This macrovascular and microvascular damage could be triggered during thoracic radiotherapy by the scattered radiation doses received in the heart region, which may damage the endothelium directly, by inducing DNA damage, oxidative stress, cell death, inflammation, and premature cell senescence to initiate the atherosclerosis process, that may expand via bystander signaling to non-irradiated endothelial cells as shown in Fig. 1 (Ramadan et al 2021a , b ). Fig.…”
Section: Out-of-field Effects: Model Systems and Mechanismsmentioning
confidence: 99%
“…Not all the cells are affected by bystander signaling (yellow cell). Figure adapted from (Ramadan et al 2021a , b ) …”
Section: Out-of-field Effects: Model Systems and Mechanismsmentioning
Partial body exposure and inhomogeneous dose delivery are features of the majority of medical and occupational exposure situations. However, mounting evidence indicates that the effects of partial body exposure are not limited to the irradiated area but also have systemic effects that are propagated outside the irradiated field. It was the aim of the “Partial body exposure” session within the MELODI workshop 2020 to discuss recent developments and insights into this field by covering clinical, epidemiological, dosimetric as well as mechanistic aspects. Especially the impact of out-of-field effects on dysfunctions of immune cells, cardiovascular diseases and effects on the brain were debated. The presentations at the workshop acknowledged the relevance of out-of-field effects as components of the cellular and organismal radiation response. Furthermore, their importance for the understanding of radiation-induced pathologies, for the discovery of early disease biomarkers and for the identification of high-risk organs after inhomogeneous exposure was emphasized. With the rapid advancement of clinical treatment modalities, including new dose rates and distributions a better understanding of individual health risk is urgently needed. To achieve this, a deeper mechanistic understanding of out-of-field effects in close connection to improved modelling was suggested as priorities for future research. This will support the amelioration of risk models and the personalization of risk assessments for cancer and non-cancer effects after partial body irradiation.
“…Preclinical studies in mice are expected to provide additional insights since the same mechanisms of arterial inflammation and oxidative stress have been implicated in IR-related vascular disease. However, in preclinical models, altered vascular reactivity, inflammation and oxidative stress have been reported within a few weeks after treatment 22-25 . Our experiments, conducted one year after IR, aimed to bridge the knowledge gap regarding long-term effects in preclinical models.…”
Background: The incidental use of statins during radiation therapy has been associated with a reduced long-term risk of developing atherosclerotic cardiovascular disease. Objectives: Determine if irradiation causes chronic vascular injury and whether short-term administration of statins during and after irradiation is sufficient to prevent chronic injury compared to long-term administration. Methods: C57Bl/6 mice were pretreated with pravastatin for 72 hours and then exposed to 12 Gy x-ray head-and-neck irradiation. Subsequently, they received pravastatin either for one additional day or for one year. Carotid arteries were tested for vascular reactivity and altered gene expression one year after irradiation. Results: Treatment with pravastatin for 24 hours reduced the loss of endothelium-dependent vasorelaxation and protected against enhanced vasoconstriction after IR. It lowered the expression of some markers associated with inflammation and oxidative stress and modulated that of subunits of the voltage and Ca2+ activated K+ (BK) channel in the carotid artery one year after irradiation. Treatment with pravastatin for one year completely reversed the changes caused by irradiation. Conclusions: In mice, short-term administration of pravastatin is sufficient to reduce chronic vascular injury after irradiation. Long-term administration eliminates the effects of irradiation. These findings suggest that a prospective treatment strategy involving statins could be effective in patients undergoing radiation therapy. The optimal duration of treatment in humans has yet to be determined.
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