Using Integrin αvß6-Targeted Positron Emission Tomography Imaging to Longitudinally Monitor Radiation-Induced Pulmonary Fibrosis In Vivo.

PURPOSE: Radiation-induced pulmonary fibrosis (RIPF) is a potentially serious and disabling late complication of radiation therapy. Monitoring RIPF progression is challenging due to the absence of early detection tools and the difficulty in distinguishing RIPF from other lung diseases using standard imaging methods. In the lungs, integrin αvß6 is crucial in the development of RIPF, acting as a significant activator of transforming growth factor ß after radiation injury. This study aimed to investigate integrin αvß6-targeted positron emission tomography (PET) imaging ([64Cu]Cu-αvß6-BP) to study RIPF development in vivo. METHODS AND MATERIALS: We used a focal RIPF model (70 Gy delivered focally to a 3 mm spot in the lung) and a whole lung RIPF model (14 Gy delivered to the whole lung) in adult C57BL/6J mice. Small animal PET/computed tomography images were acquired 1 hour postinjection of 11.1 MBq of [64Cu]Cu-αvß6-BP. Animals were imaged for 8 weeks in the focal RIPF model and 6 months in the whole lung RIPF model. Immunohistochemistry for integrin αvß6 and trichrome staining were performed. RESULTS: In the focal RIPF model, there was focal uptake of [64Cu]Cu-αvß6-BP in the irradiated region at week 4 that progressively increased at weeks 6 and 8. In the whole lung RIPF model, minimal uptake of the probe was observed at 4 months post-radiation therapy, which significantly increased at months 5 and 6. Expression of integrin αvß6 was validated histologically by immunohistochemistry in both models. CONCLUSIONS: Integrin αvß6-targeted PET imaging using [64Cu]Cu-αvß6-BP can serve as a useful tool to identify RIPF in vivo.

Cardiac radiation improves ventricular function in mice and humans with cardiomyopathy.

BACKGROUND: Rapidly dividing cells are more sensitive to radiation therapy (RT) than quiescent cells. In the failing myocardium, macrophages and fibroblasts mediate collateral tissue injury, leading to progressive myocardial remodeling, fibrosis, and pump failure. Because these cells divide more rapidly than cardiomyocytes, we hypothesized that macrophages and fibroblasts would be more susceptible to lower doses of radiation and that cardiac radiation could therefore attenuate myocardial remodeling. METHODS: In three independent murine heart failure models, including models of metabolic stress, ischemia, and pressure overload, mice underwent 5 Gy cardiac radiation or sham treatment followed by echocardiography. Immunofluorescence, flow cytometry, and non-invasive PET imaging were employed to evaluate cardiac macrophages and fibroblasts. Serial cardiac magnetic resonance imaging (cMRI) from patients with cardiomyopathy treated with 25 Gy cardiac RT for ventricular tachycardia (VT) was evaluated to determine changes in cardiac function. FINDINGS: In murine heart failure models, cardiac radiation significantly increased LV ejection fraction and reduced end-diastolic volume vs. sham. Radiation resulted in reduced mRNA abundance of B-type natriuretic peptide and fibrotic genes, and histological assessment of the LV showed reduced fibrosis. PET and flow cytometry demonstrated reductions in pro-inflammatory macrophages, and immunofluorescence demonstrated reduced proliferation of macrophages and fibroblasts with RT. In patients who were treated with RT for VT, cMRI demonstrated decreases in LV end-diastolic volume and improvements in LV ejection fraction early after treatment. CONCLUSIONS: These results suggest that 5 Gy cardiac radiation attenuates cardiac remodeling in mice and humans with heart failure. FUNDING: NIH, ASTRO, AHA, Longer Life Foundation.