Lung Stereotactic Arc Therapy in Mice Development of Radiation Pneumopathy and Influence of HIF-1α Endothelial Deletion

J. Lavigne (1) , A. Suissa (1) , N. Verger (1) , M. dos Santos (1) , M. Benadjaoud (1) , L. Mille-Hamard (2) , I. Momken (2) , F. Soysouvanh (1) , V. Buard (1) , O. Guipaud (1) , V. Paget (1) , G. Tarlet (1) , F. Milliat (1) , A. François (1)

1 IRSN - Institut de Radioprotection et de Sûreté Nucléaire
2 UBIAE - Unité de biologie intégrative des adaptations à l'exercice

Purpose Stereotactic body radiation therapy offers good lung local tumor control by the administration of a high dose per fraction in small volumes. Stereotactic body radiation therapy preclinical modeling is now possible, and our aim was to develop a model of focal irradiation of the mouse lung and to investigate the impact of conditional hypoxia-inducible factor 1α (HIF-1α) deletion in the endothelium on radiation-induced tissue damage. Methods and Materials The Small Animal Radiation Research Platform was used to create a mouse model of focal irradiation of the lung using arc therapy. HIF-1α conditional deletion was obtained by crossing mice expressing Cre recombinase under the endothelial promoter VE-cadherin (VECad-Cre +/+ mice) with HIF-1α floxed mice. Results Lung stereotactic arc therapy allows thoracic wall sparing and long-term studies. However, isodose curves showed that neighboring organs received significant doses of radiation, as revealed by ipsilateral lung acute red hepatization and major gene expression level modifications. Conditional HIF-1α deletion reduced acute lung edema and tended to diminish neutrophil infiltrate, but it had no impact on long-term global tissue damage. Conclusions Arc therapy for focal high-dose irradiation of mouse lung is an efficient model for long-term studies. However, irradiation may have a strong impact on the structure and function of neighboring organs, which must be considered. HIF-1α conditional deletion has no beneficial impact on lung damage in this irradiation schedule. © 2019

Keywords: Biological organs; Irradiation; Mammals; Radiotherapy; Tissue; Gene expression levels; Hypoxia inducible factor 1-alpha; Ipsilateral lungs; Local tumor control; Methods and materials; Radiation-induced; Research platforms; Radiation; chlordane; cre recombinase; hypoxia inducible factor 1alpha; vascular endothelial cadherin; integrase; animal tissue; Article; cell infiltration; comparative study; cone beam computed tomography; controlled study; endothelium; follow up; gene expression; genotype; lung disease; lung edema; major gene; mouse; neutrophil; nonhuman; priority journal; quantitative analysis; radiation dose; radiation exposure; radiation induced tissue damage; radiation injury; real time polymerase chain reaction; stereotactic body radiation therapy; tissue injury; treatment planning; adverse event; diagnostic imaging; disease model; epithelial mesenchymal transition; genetics; intensity modulated radiation therapy; lung alveolus; lung fibrosis; lung tumor; metabolism; pathology; physiology; procedures; radiation pneumonia; radiation response; Animals; Cone-Beam Computed Tomography; Disease Models; Animal; Epithelial-Mesenchymal Transition; Gene Deletion; Hybridization; Genetic; Hypoxia-Inducible Factor 1; alpha Subunit; Integrases; Lung; Lung Neoplasms; Mice; Organs at Risk; Phenotype; Pulmonary Alveoli; Pulmonary Edema; Pulmonary Fibrosis; Radiation Dosage; Radiation Pneumonitis; Radiosurgery; Intensity-Modulated; Running; Selective Breeding

Domains: Life Sciences [q-bio]

J. Lavigne, A. Suissa, N. Verger, M. dos Santos, M. Benadjaoud, et al.. Lung Stereotactic Arc Therapy in Mice Development of Radiation Pneumopathy and Influence of HIF-1α Endothelial Deletion. International Journal of Radiation Oncology, Biology, Physics, 2019, 104 (2), pp.279-290. ⟨10.1016/j.ijrobp.2019.01.081⟩. ⟨hal-02489958⟩