Captopril reduces lung inflammation and accelerated senescence in response to thoracic radiation in mice

• Published in: Journal of radiation research 2021-03, Vol.62 (2), p.236-248
• Main Authors: Mungunsukh, Ognoon, George, Jeffy, McCart, Elizabeth A, Snow, Andrew L, Mattapallil, Joseph J, Mog, Steven R, Panganiban, Ronald Allan M, Bolduc, David L, Rittase, W Bradley, Bouten, Roxane M, Day, Regina M
• Format: Article
• Language: English
• Subjects: Aging - pathology; Analysis; Angiotensin converting enzyme; Animals; Apoptosis - drug effects; Apoptosis - radiation effects; Bacterial pneumonia; Biomarkers - metabolism; Captopril; Captopril - pharmacology; Captopril - therapeutic use; Cytokines - metabolism; Enzyme inhibitors; Female; Fundamental Radiation Science; Inflammation; Inflammation Mediators - metabolism; Interleukins; Lung - drug effects; Lung - radiation effects; Macrophages, Alveolar - drug effects; Macrophages, Alveolar - pathology; Macrophages, Alveolar - radiation effects; Mice; Mice, Inbred CBA; Pneumonia; Pneumonia - drug therapy; Pulmonary Fibrosis - pathology; Radiation; Spleen - drug effects; Spleen - radiation effects; Survival Analysis; Thorax - radiation effects; Whole-Body Irradiation; X-Rays
• ISSN: 0449-3060; 1349-9157
• DOI: 10.1093/jrr/rraa142

The lung is sensitive to radiation and exhibits several phases of injury, with an initial phase of radiation-induced pneumonitis followed by delayed and irreversible fibrosis. The angiotensin-converting enzyme inhibitor captopril has been demonstrated to mitigate radiation lung injury and to improve survival in animal models of thoracic irradiation, but the mechanism remains poorly understood. Here we investigated the effect of captopril on early inflammatory events in the lung in female CBA/J mice exposed to thoracic X-ray irradiation of 17-17.9 Gy (0.5-0.745 Gy min-1). For whole-body + thoracic irradiation, mice were exposed to 7.5 Gy (0.6 Gy min-1) total-body 60Co irradiation and 9.5 Gy thoracic irradiation. Captopril was administered orally (110 mg kg-1 day-1) in the drinking water, initiated 4 h through to150 days post-irradiation. Captopril treatment increased survival from thoracic irradiation to 75% at 150 days compared with 0% survival in vehicle-treated animals. Survival was characterized by a significant decrease in radiation-induced pneumonitis and fibrosis. Investigation of early inflammatory events showed that captopril significantly attenuated macrophage accumulation and decreased the synthesis of radiation-induced interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) pro-inflammatory cytokines in the lungs of irradiated mice. Suppression of IL-1β and TNF-α correlated with an increase of the anti-inflammatory cytokine IL-10 in the spleen with captopril treatment. We also found that captopril decreased markers for radiation-induced accelerated senescence in the lung tissue. Our data suggest that suppression of inflammation and senescence markers, combined with an increase of anti-inflammatory factors, are a part of the mechanism for captopril-induced survival in thoracic irradiated mice.