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

Soysouvanh, Frédéric; Benadjaoud, Mohamed Amine; Santos, M. Dos; Mondini, Michele; Lavigne, Jérémy; Bertho, Annaïg; Buard, Valérie; Tarlet, Georges; Adnot, Serge; Deutsch, Éric; Guipaud, Olivier; Paget, Vincent; François, Agnès; Milliat, Fabien

doi:10.1016/j.ijrobp.2019.12.039

Cited by 21 publications

(14 citation statements)

References 36 publications

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“…40 Using arc delivery and 3-mm beam collimation in mice, we previously showed that 5 Â 20 Gy was necessary to obtain diffuse lung fibrosis within 15 months. 41 This single-dose range of 60 Gy is in accordance with reported data of focal lung exposure. Cho et al showed that using 3-mm collimator and dorsoventral delivery, mice exposed to 40 Gy developed insignificant fibrosis; those exposed to 100 Gy demonstrated lung fibrosis, suggesting, as said by the authors, a threshold dose between 40 and 100 Gy for lung fibrosis under these conditions.…”

Section: Discussionsupporting

confidence: 91%

Preclinical Model of Stereotactic Ablative Lung Irradiation Using Arc Delivery in the Mouse: Effect of Beam Size Changes and Dose Effect at Constant Collimation

Bertho

Santos

Buard

et al. 2020

International Journal of Radiation Oncology*Biology*Physics

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Purpose: Stereotactic body radiation therapy is a therapeutic option offered to high surgical risk patients with lung cancer. Focal lung irradiation in mice is a new preclinical model to help understand the development of lung damage in this context. Here we developed a mouse model of lung stereotactic therapy using arc delivery and monitored the development of lung damage while varying the beam size and dose delivered. Methods and Materials: C57BL/6JRj mice were exposed to 90 Gy focal irradiation on the left lung using 1-mm diameter, 3 Â 3 mm 2 , 7 Â 7 mm 2 , or 10 Â 10 mm 2 beam collimation for beam size effect and using 3 Â 3 mm 2 beam collimation delivering 20 to 120 Gy for dose effect. Long-term lung damage was monitored with microecomputed tomography imaging with anatomopathologic and gene expression measurements in the injured patch and the ipsilateral and contralateral lungs. Results: Both 1-mm diameter and 3 Â 3 mm 2 beam collimation allow long-term studies, but only 3-mm beam collimation generates lung fibrosis when delivering 90 Gy. Dose-effect studies with constant 3-mm beam collimation revealed a dose of 60 Gy as the minimum to obtain lung fibrosis 6 months postexposure. Lung fibrosis development was associated with club cell depletion and increased type II pneumocyte numbers. Lung injury developed with ipsilateral and contralateral consequences such as parenchymal thickening and gene expression modifications. Conclusions: Arc therapy allows long-term studies and dose escalation without lethality. In our dose-delivery conditions, dose-effect studies revealed that 3 Â 3 mm 2 beam collimation to a minimum single dose of 60 Gy enables preclinical models

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Section: Discussionsupporting

confidence: 91%

Preclinical Model of Stereotactic Ablative Lung Irradiation Using Arc Delivery in the Mouse: Effect of Beam Size Changes and Dose Effect at Constant Collimation

Bertho

Santos

Buard

et al. 2020

International Journal of Radiation Oncology*Biology*Physics

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“…However, stress-induced and replicative senescence differed at protein level; therefore, differentially expressed proteins observed in stress-induced premature senescent fibroblasts were classified as (i) changes common with replicative senescence, (ii) changes specific to each kind of stressor, and (iii) changes related to SIPS independently of the nature of the stress applied [53]. Gene expression analyses of human diploid fibroblasts later on identified candidate genes being characteristic for premature senescent fibroblasts (induced by the chemical stressors tert-butylhydroperoxide or ethanol) as compared to replicative senescence: these included genes involved in growth arrest (PTEN, insulin-like growth factor binding protein-3, low density lipoprotein receptor-related protein 1 and caveolin-1), senescent morphogens (TGFβ-1 and lysyl oxidase-like 2) and iron metabolism (transferrin and ferritin light chain) [55].…”

Section: Replicative Senescence Versus Stress-induced Senescencementioning

confidence: 99%

Cellular Senescence in the Lung: The Central Role of Senescent Epithelial Cells

Hansel

Jendrossek

Klein

2020

IJMS

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Cellular senescence is a key process in physiological dysfunction developing upon aging or following diverse stressors including ionizing radiation. It describes the state of a permanent cell cycle arrest, in which proliferating cells become resistant to growth-stimulating factors. Senescent cells differ from quiescent cells, which can re-enter the cell cycle and from finally differentiated cells: morphological and metabolic changes, restructuring of chromatin, changes in gene expressions and the appropriation of an inflammation-promoting phenotype, called the senescence-associated secretory phenotype (SASP), characterize cellular senescence. The biological role of senescence is complex, since both protective and harmful effects have been described for senescent cells. While initially described as a mechanism to avoid malignant transformation of damaged cells, senescence can even contribute to many age-related diseases, including cancer, tissue degeneration, and inflammatory diseases, particularly when senescent cells persist in damaged tissues. Due to overwhelming evidence about the important contribution of cellular senescence to the pathogenesis of different lung diseases, specific targeting of senescent cells or of pathology-promoting SASP factors has been suggested as a potential therapeutic approach. In this review, we summarize recent advances regarding the role of cellular (fibroblastic, endothelial, and epithelial) senescence in lung pathologies, with a focus on radiation-induced senescence. Among the different cells here, a central role of epithelial senescence is suggested.

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“…To begin with, schedules with three fractions were chosen to limit uncertainties of animal repositioning during multiple fractions. Delivering five fractions generates diffuse injured areas and difficulties in damage contouring on CBCT images (21). A single study time-point at 6 months post-exposure was kept as a representative and relatively long period for lung fibrosis to develop, while remaining reasonable given mouse lifespan, and thus avoiding mouse aging and spontaneous lung tumor development.…”

Section: Discussionmentioning

confidence: 99%

“…Delivering 3 × 6.67 Gy to the mouse lung using 5 × 5 mm beam collimation induced changes in lung tissue density but no change in the Ashcroft score within 26 weeks post-exposure (20). Finally, the study by Soysouvanh et al showed that no lung fibrosis occurred following 5 fractions of 20 Gy using 3 × 3 mm collimated beam even 15 months post-exposure (21).…”

Section: Introductionmentioning

confidence: 98%

Preclinical Model of Stereotactic Ablative Lung Irradiation Using Arc Delivery in the Mouse: Is Fractionation Worthwhile?

et al. 2021

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Lung stereotactic body radiation therapy is characterized by a reduction in target volumes and the use of severely hypofractionated schedules. Preclinical modeling became possible thanks to rodent-dedicated irradiation devices allowing accurate beam collimation and focal lung exposure. Given that a great majority of publications use single dose exposures, the question we asked in this study was as follows: in incremented preclinical models, is it worth using fractionated protocols or should we continue focusing solely on volume limitation? The left lungs of C57BL/6JRj mice were exposed to ionizing radiation using arc therapy and 3 × 3 mm beam collimation. Three-fraction schedules delivered over a period of 1 week were used with 20, 28, 40, and 50 Gy doses per fraction. Lung tissue opacification, global histological damage and the numbers of type II pneumocytes and club cells were assessed 6 months post-exposure, together with the gene expression of several lung cells and inflammation markers. Only the administration of 3 × 40 Gy or 3 × 50 Gy generated focal lung fibrosis after 6 months, with tissue opacification visible by cone beam computed tomography, tissue scarring and consolidation, decreased club cell numbers and a reactive increase in the number of type II pneumocytes. A fractionation schedule using an arc-therapy-delivered three fractions/1 week regimen with 3 × 3 mm beam requires 40 Gy per fraction for lung fibrosis to develop within 6 months, a reasonable time lapse given the mouse lifespan. A comparison with previously published laboratory data suggests that, in this focal lung irradiation configuration, administering a Biological Effective Dose ≥ 1000 Gy should be recommended to obtain lung fibrosis within 6 months. The need for such a high dose per fraction challenges the appropriateness of using preclinical highly focused fractionation schedules in mice.

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

Cited by 21 publications

References 36 publications

Preclinical Model of Stereotactic Ablative Lung Irradiation Using Arc Delivery in the Mouse: Effect of Beam Size Changes and Dose Effect at Constant Collimation

Preclinical Model of Stereotactic Ablative Lung Irradiation Using Arc Delivery in the Mouse: Effect of Beam Size Changes and Dose Effect at Constant Collimation

Cellular Senescence in the Lung: The Central Role of Senescent Epithelial Cells

Preclinical Model of Stereotactic Ablative Lung Irradiation Using Arc Delivery in the Mouse: Is Fractionation Worthwhile?

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