dosimetry-for-cell-irradiation-using-orthovoltage-40-300-kv-x-ray

Dosimetry for Cell Irradiation using Orthovoltage (40-300 kV) X-Ray Facilities

The importance of dosimetry protocols and standards for radiobiological studies is self-evident. Several protocols have been proposed for dose ...

Institute for Radiological Protection and Nuclear Safety (IRSN)

Damage to vessels is one of the most common effects of therapeutic irradiation on normal tissues. We undertook a study in patients treated with preoperative radiotherapy and demonstrated in vivo the importance of proliferation, migration, and fibrogenic phenotype of vascular smooth muscle cells (VSMCs) in radiation-induced vascular damage. These lesions may result from imbalance in the cross talk between endothelial cells (ECs) and VSMCs. Using co-culture models, we examined whether ECs influence proliferation, migration, and fibrogenic phenotype of VSMCs. In the presence of irradiated ECs, proliferation and migration of VSMCs were increased. Moreover, expressions of alpha-smooth muscle actin, connective tissue growth factor, plasminogen activator inhibitor type 1, heat shock protein 27, and collagen type III, alpha 1 were up-regulated in VSMCs exposed to irradiated ECs. Secretion of transforming growth factor (TGF)-beta1 was increased after irradiation of ECs, and irradiated ECs activated the Smad pathway in VSMCs by inducing Smad3/4 nuclear translocation and Smad-dependent promoter activation. Using small interferring RNA targeting Smad3 and a TGFbeta-RII neutralizing antibody, we demonstrate that a TGF-beta1/TGF-beta-RII/Smad3 pathway is involved in the fibrogenic phenotype of VSMCs induced by irradiated ECs. In conclusion, we show the importance of proliferation, migration, and fibrogenic phenotype of VSMCs in patients. Moreover, we demonstrate in vitro that ECs influence these fundamental mechanisms involved in radiation-induced vascular damages.

Influence of endothelial cells on vascular smooth muscle cells phenotype after irradiation: implication in radiation-induced vascular damages.

Intestinal radiation injury is a dose-limiting factor in radiation therapy for abdominal and pelvic cancers. Because transforming growth factor-beta1 is a key mediator involved in radiation-induced damage, we hypothesized that its target gene, plasminogen activator inhibitor type 1 (PAI-1), is an essential mediator of intestinal radiation toxicity. In a model of radiation enteropathy, survival was monitored and intestinal radiation injury was assessed in both wild-type (Wt) and PAI-1 knockout mice. Immunohistochemical labeling of PAI-1 was also assessed in patients treated with preoperative radiotherapy for rectal adenocarcinoma. Finally, the molecular mechanisms involved in radiation-induced PAI-1 expression were investigated. We found that PAI-1 -/- mice exhibited increased survival and better intestinal function compared with Wt mice. Intestinal radiation injury was attenuated in irradiated PAI-1 -/- mice compared with irradiated Wt mice, and irradiation increased blood cell-endothelial cell interactions in Wt but not PAI-1 -/- mice. In vivo, radiation-induced intestinal damage in mice, as well as in patients treated with radiotherapy, was associated with the up-regulation of PAI-1 in the endothelium. In vitro, irradiation increased PAI-1 expression in endothelial cells by a p53/Smad3-dependent mechanism. Together, these data demonstrate that PAI-1 plays a critical role in radiation-induced intestinal damage, suggesting that PAI-1 is an attractive target for preventing or reducing the side effects of radiation therapy.

Essential role of plasminogen activator inhibitor type-1 in radiation enteropathy.

More than half of cancers are treated with radiation therapy alone or in combination with surgery and/or chemotherapy. The goal of radiation therapy is to deliver enough ionising radiation to destroy cancer cells, without exceeding the level that the surrounding healthy cells can tolerate. Unfortunately, radiation-induced normal tissue injury is still a dose limiting factor in the treatment of cancer with radiotherapy. Early and late side-effects not only limit radiation dose escalation, but might also affect the patient's quality of life. Vascular injury is one of the most common effects of radiotherapy on normal tissues. Radiation-induced fibrogenesis is characterized by an orchestrated pathological wound-healing response in which the radiation-induced endothelium dysfunction plays a critical role. Irradiated endothelial cells acquire a proinflammatory, procoagulant and prothrombotic phenotype. The knowledge of molecular mechanisms involved in endothelium dysfunction following radiation is needed to identify therapeutic targets and develop strategies to prevent and /or reduce side-effects of radiation therapy.

[Role of endothelium in radiation-induced normal tissue damages].

Radiotherapy is one of the most important treatments of primary and metastatic brain tumors. Unfortunately, it can involve moderate to severe complications among which leukoencephalopathy is very frequent and implies cognitive deficits such as memory, attention and executive dysfunctions. However, the incidence of this complication is not well established and the risk factors and process are poorly understood. The main objective of the study is to improve knowledge on radio-induced leukoencephalopathy based on pluridisciplinar approaches combining cognitive, biologic, imagery and dosimetric investigations.

EpiBrainRad: an epidemiologic study of the neurotoxicity induced by radiotherapy in high grade glioma patients.

Lung cancer will be treated more frequently using stereotactic body radiation therapy, and preclinical research to model long-term toxicity of ablative doses of radiation is crucial. Stereotactic lung irradiation of a small volume can induce radiation pneumonitis and fibrosis in normal tissues.

Stereotactic Lung Irradiation in Mice Promotes Long-Term Senescence and Lung Injury.

Every year, millions of people around the world benefit from radiation therapy to treat cancers localized in the pelvic area. Damage to healthy tissue in the radiation field can cause undesirable toxic effects leading to gastrointestinal complications called pelvic radiation disease. A change in the composition and/or function of the microbiota could contribute to radiation-induced gastrointestinal toxicity. In this study, we tested the prophylactic effect of a new generation of probiotic like  () on acute radiation-induced colonic lesions. Experiments were carried out in a preclinical model of pelvic radiation disease. Rats were locally irradiated at 29 Gray in the colon resulting in colonic epithelial barrier rupture. Three days before the irradiation and up to 3 d after the irradiation, the  A2-165 strain was administered daily (intragastrically) to test its putative protective effects. Results showed that prophylactic  treatment limits radiation-induced para-cellular hyperpermeability, as well as the infiltration of neutrophils (MPO+ cells) in the colonic mucosa. Moreover,  treatment reduced the severity of the morphological change of crypts, but also preserved the pool of Sox-9+ stem/progenitor cells, the proliferating epithelial PCNA+ crypt cells and the Dclk1+/IL-25+ differentiated epithelial tuft cells. The benefit of  was associated with increased production of IL-18 by colonic crypt epithelial cells. Thus,  treatment protected the epithelial colonic barrier from colorectal irradiation. New-generation probiotics may be promising prophylactic treatments to reduce acute side effects in patients treated with radiation therapy and may improve their quality of life.

Article	Year
Influence of endothelial cells on vascular smooth muscle cells phenotype after irradiation: implication in radiation-induced vascular damages. The American journal of pathology\| PubMed ID: 17003501	2006
Essential role of plasminogen activator inhibitor type-1 in radiation enteropathy. The American journal of pathology\| PubMed ID: 18276785	2008
[Role of endothelium in radiation-induced normal tissue damages]. Annales de cardiologie et d'angeiologie\| PubMed ID: 18579118	2008
EpiBrainRad: an epidemiologic study of the neurotoxicity induced by radiotherapy in high grade glioma patients. BMC neurology\| PubMed ID: 26684198	2015
Stereotactic Lung Irradiation in Mice Promotes Long-Term Senescence and Lung Injury. International journal of radiation oncology, biology, physics\| PubMed ID: 31987976	2020
Prophylactic treatment prevents the acute breakdown of colonic epithelial barrier in a preclinical model of pelvic radiation disease. Gut microbes\| PubMed ID: 32985332	2020

Fabien Milliat

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