Abstract
Radiation-induced lung injury (RILI) is one of the most common and fatal complications of thoracic radiotherapy. Inflammatory cell infiltration, imbalance of inflammatory cytokines, and oxidative damage were reported to be involved during RILI pathogenesis, especially in the early phase of RILI. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a key transcriptional regulator of antioxidative cascades, and regulates life span of mice after administration of thoracic irradiation. We investigated the effects of Nrf2 on RILI and inflammation using Nrf2-knockout, Nrf2-overexpression and wild-type mice with or without 15 Gy ionizing radiation to thorax. Our results showed that Nrf2 deficiency aggravated radiation-induced histopathological changes, macrophage and neutrophil infiltration, serum levels of pro-inflammatory cytokines (IL-6, MCP-1, IFN-γ, TNF, and IL-12p70), and the levels of peroxidation products in the mouse lung. Moreover, loss of Nrf2 reduced radiation-induced serum levels of anti-inflammatory cytokine, IL-10, and antioxidative proteins. Nrf2 overexpression significantly alleviated radiation-induced histopathological changes, macrophages and neutrophils infiltration, serum levels of pro-inflammatory cytokines, and the levels of peroxidation products in lung tissues. Nrf2 overexpression also increased the serum levels of IL-10 and antioxidative proteins. These results indicated that Nrf2 had a protective role against radiation-induced acute lung injury and inflammation, and that antioxidative therapy might be a promising treatment for RILI.
Highlights
Radiation-induced lung injury (RILI) is one of the most common and fatal complications in radiotherapy for thoracic cancers, and limits the effective radiation dosage applied to eradicate tumors
Our data indicated that infiltration of macrophages (Figures 2A,B) and neutrophils (Figures 2C,D) were significantly increased after ionizing radiation (IR) in a time-dependent manner in both wild-type mice and Nuclear factor-erythroid 2-related factor 2 (Nrf2)-knockout mice
Both F4/80 (Figures 2A,B) and MPO (Figures 2C,D) positive cell rates in lung tissues of Nrf2-knockout mice were significantly higher than those in wild-type controls. These results suggested that Nrf2 deficiency exacerbated radiation-induced infiltration of macrophages and neutrophils in the lung of mice
Summary
Radiation-induced lung injury (RILI) is one of the most common and fatal complications in radiotherapy for thoracic cancers, and limits the effective radiation dosage applied to eradicate tumors. Radiation-induced acute lung injury and inflammation involve a cascade of inflammatory events following ionizing radiation (IR) [1, 2]. Infiltration of macrophages and neutrophils in lung tissues and high serum levels of inflammatory cytokines are recognized markers for RILI and inflammation [2,3,4,5]. There is no effective prevention and treatment methods for RILI. Steroids had been used to treat RILI, severe side effects remain a huge challenge
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