Low dose 100 cGy irradiation as a potential therapy for pulmonary hypertension

Abstract

Pulmonary hypertension (PH) is an incurable disease characterized by pulmonary vascular remodeling and ultimately death. Two rodent models of PH include treatment with monocrotaline or exposure to a vascular endothelial growth factor receptor inhibitor and hypoxia. Studies in these models indicated that damaged lung cells evolve extracellular vesicles which induce production of progenitors that travel back to the lung and induce PH. A study in patients with pulmonary myelofibrosis and PH indicated that 100 cGy lung irradiation could remit both diseases. Previous studies indicated that murine progenitors were radiosensitive at very low doses, suggesting that 100 cGy treatment of mice with induced PH might be an effective PH therapy. Our hypothesis is that the elimination of the PH-inducing marrow cells by low dose irradiation would remove the cellular influences creating PH. Here we show that low dose whole-body irradiation can both prevent and reverse established PH in both rodent models of PH.

Keywords: endothelial progenitor cells; low dose irradiation; pulmonary hypertension.

Figure 1

Low dose 100 cGy WBI can prevent PH development as well as reverse established PH in Su/Hx‐induced PH mouse model. (a) Schematic of experimental design using 100 cGy WBI to prevent PH development in a prophylactic model. Mice underwent 100 cGy WBI and then 3 weeks of hypoxia with weekly Sugen 5416 injections. (b) Low dose 100 cGy WBI appears to have reduced RVSP in irradiated compared to nonirradiated Su/Hx‐PH mice in the prophylactic model. (c) Low dose 100 cGy WBI prevents the development of right ventricular hypertrophy in Su/Hx‐treated mice as indicated by Fulton's Index (RV/LV + S) in the prophylactic model. (d) Schematic of experimental design using 100 cGy WBI to reverse established PH in a therapeutic model. Mice underwent 3 weeks of hypoxia treatment with weekly Sugen 5416 injections then received 100 cGy WBI. (e) Low dose 100 cGy WBI appears to normalize RVSP in irradiated compared to nonirradiated Su/Hx‐PH mice in the therapeutic model. (f) Fulton's Index indicates that 100 cGy WBI reverses established right ventricular hypertrophy in Su/Hx‐treated mice in the therapeutic model. Data in (b), (c), (e), and (f) are mean ± standard error of the mean, **p < 0.01, ***p < 0.001, and ****p < 0.0001, one‐way analysis of variance with multiple comparisons. LV + S: left ventricle plus septum; PH: pulmonary hypertension; RV: right ventricular; RVSP: right ventricular systolic pressure; Su/Hx: Sugen 5416‐ and hypoxia‐treated mice; Su/Hx + rad: Sugen 5416‐, hypoxia‐, and radiation‐treated mice; Ve/Nx: vehicle‐ and normoxia‐treated mice; Ve/Nx + rad: vehicle‐, normoxia‐, and radiation‐treated mice; WBI: whole‐body irradiation

Figure 2

Low dose 100 cGy WBI can reverse established PH in MCT‐induced PH mouse model. (a) Schematic of experimental design using 100 cGy WBI to reverse established PH in MCT‐induced PH model. Mice received weekly MCT injection for 4 weeks before receiving 100 cGy WBI. (b) Low dose 100 cGy WBI reverses RVSP in MCT‐PH mice. (c) Low dose 100 cGy WBI reverses right ventricular hypertrophy in MCT‐treated mice as indicated by Fulton's index (RV/LV + S). (d) Immunohistochemical staining of α‐SMA (brown color) in the lung from PBS control mice, MCT‐treated mice, MCT and radiation‐treated mice. Original magnification ×200. Data in (b) and (c) are mean ± standard error of the mean, *p < 0.05 and **p < 0.01, one‐way analysis of variance with multiple comparisons. LV + S: left ventricle plus septum; MCT: monocrotaline; PH: pulmonary hypertension; RV: right ventricular; RVSP: right ventricular systolic pressure; PBS: phosphate‐buffered saline‐treated mice; PBS + rad: PBS‐ and radiation‐treated mice; MCT: MCT‐treated mice; MCT + rad: MCT‐ and radiation‐treated mice; WBI: whole‐body irradiation [Color figure can be viewed at wileyonlinelibrary.com]