Role of LY2109761 in radiation-induced pulmonary fibrosis in mice

Objective: To investigate the protective effects and mechanism of LY2109761 in radiation-induced pulmonary fibrosis (RIPF), and to provide a clue for the clinical treatment of RIPF. Methods: A total of 40 healthy female C57BL/6 mice were enrolled and were divided into 4 groups with 10 mice in each group randomly, including blank control group, single irradiation group, irradiation + LY50 group and irradiation + LY100 group which were given 50 and 100 mg/kg of LY2109761 respectively, twice per day. The whole lungs were irradiated by 6 MV X-rays of 12 Gy. At 2 weeks post-irradiation, pathological analyses were performed for each group to evaluate the histological changes in the irradiated lungs, including hematoxylin and eosin staining (HE) to observe morphologic changes, the Masson staining to estimate the degree of fibrosis and a combination of immunohistochemistry to analyze the expression levels of TGF-β1 and Smad2. Results: Compared with control group, the degree of fibrosis of the lung including alveolar structure changes, fibroblast proliferation and alveolar spacing was significantly enhanced at 14 d post-irradiation. Compared with irradiation group, the fibrosis degree in irradiation + LY100 group was significantly reduced(t = 4.668, P < 0.05). The degree of inflammation and fibrosis of the lung in irradiation + LY50 didn't obviously reduce compared with irradiation group (P > 0.05). The result of immunohistochemical assay showed that, the level of protein expressions of TGF-β1 and Smad2 was increased significantly after irradiation(t = 13.545, 6.418, P < 0.05), and obviously decreased in irradiation + LY100 group (t = 15.263, 6.855, P < 0.05), but just slightly reduced in irradiation + LY50 group (P > 0.05). Conclusions: LY2109761 has protective effect in radiation pulmonary fibrosis possibly by down regulating the expressions of TGF-β1/Smad2. (authors)