Pharmacologic Inhibition of HIF-1 alpha Attenuates Radiation-Induced Pulmonary Fibrosis in a Preclinical Image Guided Radiation Therapy

Abstract

Purpose: Radiation-induced pulmonary fibrosis (RIPF) is a long-term side effect of thoracic radiation therapy. Hypoxia-induced vascular endothelial mesenchymal transition (EndMT) can occur during the development of RIPF. Here, we examined the direct contribution of endothelial HIF-1 alpha (EC-HIF1 alpha) on RIPF. Methods and Materials: An inducible Cre-lox-mediated endothelial Hif1a deletion mouse line was used to evaluate the potential of HIF-1 alpha inhibition to suppress RIPF. To evaluate the effects of a pharmacologic HIF-1 alpha inhibitor on RIPF after image guided radiation therapy (IGRT) for spontaneous lung adenocarcinoma, we generated conditional tdTomato; K-Ras(G12D); and p53 (flox/flox) mice to facilitate tracking of tumor cells expressing tdTomato. Results: We found that vascular endothelial-specific HIF-1 alpha deletion shortly before radiation therapy inhibited the progression of RIPF along with reduced EndMT, whereas prolonged deletion of endothelial HIF-1 alpha before irradiation did not. Moreover, we revealed that postirradiation treatment with the novel HIF-1 alpha inhibitor, 2-methoxyestradiol (2-ME) could efficiently inhibit RIPF and EndMT. In addition, IGRT using primary mouse models of non-small cell lung cancer showed that combined treatment of 2-ME with ablative high-dose radiation therapy efficiently inhibited RIPF and the growth of both multifocal and single tumors, concomitantly reducing radiation-induced EndMT of normal as well as tumor regions. Conclusion: These results suggest that a negative regulator of HIF-1 alpha-mediated EndMT, such as 2-ME, may serve as a promising inhibitor of RIPF in radiation therapy. (C) 2020 The Author(s). Published by Elsevier Inc.