Phenotypic changes in irradiated endothelial cells and roles in lung injury following radiation therapy

Radiation-induced endothelial dysfunction is known to participate to the development of normal tissue damage. PAI- is implicated in the phenotypic changes of irradiated endothelial cells and KOendo mice are protected from radiation damage to the gut. Contrary to the digestive tract, lung is a flexible organ and this may have important consequences on its response to radiation exposure. Our first aim was to investigate in the lung the role previously demonstrated for PAI-1 in irradiated gut. In this way, whole thorax of PAI-1 KOendo and floxed mice were exposed to 17 Gy. Histological analyzes showed that PAI-1 KOendo induces a worsening of injuries at 2 and 13 weeks. Consequently, contrary to the gut no protection from radiation-induced lung damage is observed in PAI-1 KOendo mice. As opposed to the gut, in lung a better tolerance to high doses per fraction on a small volume is possible. Our second aim was to study the effects of a single high dose stereotactic irradiation on pulmonary tissues. Histological analyzes and scanner imaging show important injuries on the targeted volume. An ipsilateral edema can also be observed 2 weeks after irradiation but not at later times. Ipsilateral lung is moreover importantly damaged. A thickening of alveolar septa is notably observable. A transcriptomic analysis show important similarities between tissues from the ipsilateral lung and the focal lesion. As really highly damages have been observed in both scanner and histological analyzes, we decided to perform forced physical activity test on treadmill. A drastic decrease of maximal distance traveled has been observed from two weeks. These experiments highlighted a deficiency in respiratory function and all of these results show the importance of non-targeted irradiated pulmonary volume in the development of radiation-induced fibrosis. Effect of an endothelium-specific deletion of HIF-1a has been investigated in this model of stereotactic irradiation. Only few differences have been observed between KOendo and control mice. Experiments are ongoing to elucidate the protective effect shown in others studies. (author)