Genistein Alleviates Radiation-Induced Pneumonitis by Depressing Ape1/Ref-1 Expression to Down-regulate Inflammatory Cytokines

The aim of the study was to investigate the role of genistein in alleviating radiation-induced pneumonitis (RIP) through down-regulating levels of the inflammatory cytokines by inhibiting the expression of apurinic/apyrimidinic endonuclease 1/redox factor-1 (Ape1/Ref-1). Fifty female C57BL/6J mice (8 weeks old) were randomly divided into a control group, a pure irradiation (IR) group and a genistein + IR group. At the four time points after IR, hematoxylin, and Masson's trichrome stainings were used to examine the pathological changes and collagen fiber deposition. Flow cytometry was used to detect reactive oxygen system (ROS) changes, EMSA was used to estimate the nuclear factor kappa B (NF-kappa B) transcriptional activities and an ELISA assay was used to measure the levels of TGF-beta 1, IL-1 beta, TNF-alpha, and IL-6 in the serum and bronchoalveolar lavage fluid (BALF) 2 weeks after IR. The pathological detection results showed acute inflammatory/fibrinoid exudation of the thoracic tissue after IR, which was significantly alleviated with genistein. The IR-induced an APE1 protein expression increase and NF-kappa B was effectively suppressed by genistein (P < 0.05). The induction of the inflammatory cytokines TGF-beta 1, IL-1 beta, TNF-alpha, and IL-6 by IR were in turn inhibited in the serum and BALF of the genistein-pretreated mice (P < 0.05). In addition, the ROS production was significantly boosted in the A549 cells after IR, which could be down-regulated by the pretreatment of genistein. The results demonstrate that genistein alleviates RIP by attenuating the inflammatory response in the initiation of RIP. A possible target of genistein is the Ape1/ref-1, which regulates key inflammatory cytokines by activating the NF-kappa B.