Inactivation of Thrombomodulin by Ionizing Radiation in a Cell-Free System: Possible Implications for Radiation Responses in Vascular Endothelium

Ross, Christopher C.; MacLeod, Stewart L.; Plaxco, Jason; Froude, Jeffrey W.; Fink, Louis M.; Wang, Junru; Stites, Wesley E.; Hauer‐Jensen, Martin

doi:10.1667/rr1148.1

Cited by 15 publications

(11 citation statements)

References 44 publications

(40 reference statements)

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“…Thrombomodulin has been included in this study, for its function as a crucial player in the maintenance of the haemostatic balance. It is involved in vascular thromboresistance and anticoagulant homeostasis [ 26 – 28 ] but may also affect the expression of adhesion molecules [ 29 ]. During radiotherapy, dose-dependent increases of plasma TM in cancer patients were observed and it has been suggested as a marker of radiation-induced endothelial cell injury [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

Low-Dose Irradiation Affects Expression of Inflammatory Markers in the Heart of ApoE -/- Mice

Mathias¹,

Mitchel

Barclay

et al. 2015

PLoS ONE

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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.

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Section: Introductionmentioning

confidence: 99%

Low-Dose Irradiation Affects Expression of Inflammatory Markers in the Heart of ApoE -/- Mice

Mathias¹,

Mitchel

Barclay

et al. 2015

PLoS ONE

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“…Deficiencies in endothelial TM are associated with a variety of disease states, including vascular diseases [ 16 ], graft- versus -host disease [ 17 ] and infectious diseases [ 18 ], and therapeutic use of recombinant TM or APC reduces mortality in patient with disseminated intravascular coagulation and/or severe sepsis [ 19 – 21 ]. Moreover, ionizing radiation reduces TM expression and function, both indirectly and directly [ 22 , 23 ], and radiation-induced loss of TM appears to be involved in both early and delayed radiation toxicity [ 3 , 24 ]. Conversely, systemic administration of recombinant TM or APC protects mice from lethality partly by accelerating recovery of hematopoietic cells [ 4 ].…”

Section: Discussionmentioning

confidence: 99%

Thrombomodulin Contributes to Gamma Tocotrienol-Mediated Lethality Protection and Hematopoietic Cell Recovery in Irradiated Mice

et al. 2015

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Systemic administration of recombinant thrombomodulin (TM) confers radiation protection partly by accelerating hematopoietic recovery. The uniquely potent radioprotector gamma tocotrienol (GT3), in addition to being a strong antioxidant, inhibits the enzyme hydroxy-methyl-glutaryl-coenzyme A reductase (HMGCR) and thereby likely modulates the expression of TM. We hypothesized that the mechanism underlying the exceptional radioprotective properties of GT3 partly depends on the presence of endothelial TM. In vitro studies confirmed that ionizing radiation suppresses endothelial TM (about 40% at 4 hr after 5 Gy γ-irradiation) and that GT3 induces TM expression (about 2 fold at the mRNA level after 5 μM GT3 treatment for 4 hr). In vivo survival studies showed that GT3 was significantly more effective as a radioprotector in TM wild type (TM+/+) mice than in mice with low TM function (TMPro/-). After exposure to 9 Gy TBI, GT3 pre-treatment conferred 85% survival in TM+/+ mice compared to only 50% in TMPro/-. Thus, GT3-mediated radiation lethality protection is partly dependent on endothelial TM. Significant post-TBI recovery of hematopoietic cells, particularly leukocytes, was observed in TM+/+ mice (p = 0.003), but not in TMPro/- mice, despite the fact that GT3 induced higher levels of granulocyte colony stimulating factor (G-CSF) in TMPro/- mice (p = 0.0001). These data demonstrate a critical, G-CSF-independent, role for endothelial TM in GT3-mediated lethality protection and hematopoietic recovery after exposure to TBI and may point to new strategies to enhance the efficacy of current medical countermeasures in radiological/nuclear emergencies.

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“…Exposure to 1.8–80 Gy 137 Cs γ-radiation caused oxidation of Met388 at the thrombin-binding site of TM, leading to radiation dose-dependent impairment of the TM-thrombin complex formation, and insufficient activation of protein C (Ross et al 2008). Irradiation leads to changes in levels of coagulation factors (TM, factors II, V, VII, VIII, IX, X, XI and XII) and soluble fibrin, increasing blood clotting times, haemorrhage, and microvascular fibrin clots in lung, liver and kidneys of irradiated animals (Krigsfeld and Kennedy 2013; Krigsfeld et al 2012, 2013).…”

Section: Radiation-induced Immune Mediatorsmentioning

confidence: 99%

Radiation, inflammation and the immune response in cancer

et al. 2018

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Radiation is an important component of cancer treatment with more than half of all patients receive radiotherapy during their cancer experience. While the impact of radiation on tumour morphology is routinely examined in the pre-clinical and clinical setting, the impact of radiation on the tumour microenvironment and more specifically the inflammatory/immune response is less well characterised. Inflammation is a key contributor to short- and long-term cancer eradication, with significant tumour and normal tissue consequences. Therefore, the role of radiation in modulating the inflammatory response is highly topical given the current wave of targeted and immuno-therapeutic treatments for cancer. This review provides a general overview of how radiation modulates the inflammatory and immune response-(i) how radiation induces the inflammatory/immune system, (ii) the cellular changes that take place, (iii) how radiation dose delivery affects the immune response, and (iv) a discussion on research directions to improve patient survival, reduce side effects, improve quality of life, and reduce financial costs in the immediate future. Harnessing the benefits of radiation on the immune response will enhance its maximal therapeutic benefit and reduce radiation-induced toxicity.

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Inactivation of Thrombomodulin by Ionizing Radiation in a Cell-Free System: Possible Implications for Radiation Responses in Vascular Endothelium

Cited by 15 publications

References 44 publications

Low-Dose Irradiation Affects Expression of Inflammatory Markers in the Heart of ApoE -/- Mice

Low-Dose Irradiation Affects Expression of Inflammatory Markers in the Heart of ApoE -/- Mice

Thrombomodulin Contributes to Gamma Tocotrienol-Mediated Lethality Protection and Hematopoietic Cell Recovery in Irradiated Mice

Radiation, inflammation and the immune response in cancer

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