Radioprotective Effect And Mechanism Studies Of Ilomastat

With the rapid development of nuclear technology in industry,agriculture,medicine and life sciences,radiation has an increasing impact on human beings,and the risk of radiation exposure is increasing.Radiation can cause serious damage to the body,such as the changes of metabolism,morphology and function of cells,organs and tissues,and result in the inflammation,organ damage and decrease in immunity,and eventually lead to death or carcinogenesis.Therefore,the research and development of effective radiation protection drugs are still the focus of current radiation protection research.In the current study,we,firstly,evaluated the impact of radiation on the early development of zebrafish,and the radiation susceptibility genes were screened and validated.The inhibitor of susceptibility gene were used to investigate the radiation protection effect in the irradiated C57BL/6J mouse.The aim of our study is to find an efficient drug for radiation protection.We found that:(1)After proton irradiation,zebrafish embryos or larvae showed some genetic and developmental toxicity,such as the rate of deformity and mortality of increased,the hatching rate and heartbeat rate decreased,the mitochondrial DNA content decreased,and the embryo respiration rate decreased.We collected samples 144h after radiation,and the microarray results showed that 1192 differentially expressed genes were screened out in the irradiated zebrafish,and the matrix metalloproteinase 9(mmp9)gene was significantly up-regulated.The activity of MMP9 also significantly increased.(2)The activity of MMPs increased significantly in the irradiated mice at lung site with 15Gy?-rays.The expression of mmp9 increased significantly one week after irradiation.In addition,pretreatment with 150 mg/kg of Ilomastat significantly reduced the pneumonia and fibrosis scores in the irradiated mice.At the same time,Ilomastat protected the integrity of alveolar cell structure and reduced cell apoptosis.In the end,Ilomastat improved the survival of mice.(3)Ilomastat pretreatment significantly increased the survival of mice after whole body irradiation and admistration of Ilomastat 30 min after radiation also has a better rescue effect on mice.(4)The blood indexes of mice after whole body radiation with 6 Gy?-rays decreased significantly,while Ilomastat treatment obviously promoted the recovery of hematopoietic parameters.In addition,Ilomastat significantly promoted the recovery of bone marrow HPC_S/HSCs,spleen index and splenic lymphocyte subsets ratio.Our study confirmed,for the first time,that MMPs inhibitor,Ilomastat,can improve the survival of irradiated mice before and after radiation,and promote the recovery of hematopoietic and immune system damage induced by radiation.These results suggest that Ilomastat is a potential radiation protection drug.Ilomastat can significantly alleviate radiation-induced lung injury,suggesting the guidance for clinical radiotherapy of lung cancer to reduce side effects.In the future,the best preventive or therapeutic dose,the manner of administration and protective effect on other types of radiation for Ilomastat need to be extensively studied,which can provide a more reliable theoretical basis for its clinical application of radiation protection.