The Efficacy Of Dimethyl Sulfoxide In Protecting Against Gastrointestinal And Hematopoietic Tissue Damage Caused By Nuclear Radiation

Research BackgroundIn 1945,the United States dropped two atomic bombs,"Little Boy"and"Fat Man",over Japan,killing between 129,000 and 226,000 people in the cities of Hiroshima and Nagasaki,and shocked the world with their destructive power.Damage to the body caused by nuclear radiation,manifested as damage from ionizing radiation.The difficulty of treating nuclear radiation damage varies according to the radiation dose and the sensitivity of tissues and organs to nuclear radiation.Hematopoietic factor and hematopoietic stem cell transplantation can achieve clinical cure of patients with severe and below H-ARS,and there is no effective treatment for multi-tissue organ damage caused by very severe H-ARS,GI-ARS and nuclear radiation.Nuclear radiation damage prevention and treatment drugs are effective nuclear radiation injury treatment measures,and a lot of research has been carried out on nuclear radiation damage prevention and treatment drugs in countries around the world.According to the FDA Animal Rule and CDE requirements,the efficacy evaluation of nuclear radiation damage prevention drugs needs to be verified by two different species of animals,including large animals.Appropriate large animals,radiation methods,radiation doses and reasonable supportive treatment are important factors in establishing a model of nuclear radiation damage in large animals.Non-human primates represented by macaques and dogs represented by beagles are rich in data,histopathology,pathophysiology,and drug metabolism are similar to humans,and are commonly used in the research of nuclear radiation damage prevention and treatment drugs.Because macaques are lively and active,it is not easy to take intravenous drip rehydration supportive therapy for water-electrolyte balance disorders caused by intestinal acute radiation injury caused by higher irradiation doses,so beagles are more suitable for research on intestinal acute radiation injury prevention and treatment drugs than macaques.For the supportive treatment of beagles,500 m L daily subcutaneous fluid replacement has been reported,but the amount of fluid lost varies at different stages of the disease,and subcutaneous fluid replacement increases animal suffering.The FLASH effect provides a new research direction for tumor radiotherapy,and at the same time puts forward new inspiration for the research of nuclear radiation damage prevention and treatment drugs.The innovative discovery of the FLASH effect subverts the traditional understanding that the degree of nuclear radiation damage increases with the increase of the dose rate,and also poses challenges to the medical protection and rescue of nuclear attacks.The saturated light emission of CTFEL provides equipment support for the research of ultra-high dose rate nuclear radiation damage and prevention and treatment drugs under the"nuclear ban".As a sulfhydryl compound with efficient free radical scavenging ability,DMSO has a good protective effect against damage to oral mucosa,hematopoiesis,gastrointestinal,testicles and other tissues and organs caused by nuclear radiation.In addition,DMSO also has the characteristics of oral administration,wide effective time window,no obvious toxic side effects,chemical stability,easy access,etc.,so it is a potential ideal nuclear radiation damage protection agent.Research ObjectiveFirstly,the protective effect of DMSO on gastrointestinal and hematopoietic tissue damage caused by nuclear radiation was evaluated.Secondly,CTFEL was used to establish mouse models of uniformized ultra-high dose rate X-ray induced acute radiation injury of intestinal type and bone marrow acute radiation injury,and evaluated the protective effect of DMSO on mice with ultra-high dose rate X-ray induced bone marrow acute radiation injury,which provided experimental data support for DMSO as a potential ideal nuclear radiation damage protection agent,and also provided new ideas for ultra-high dose rate X-ray radiobiology and radiation injury prevention and treatment.Research MethodsIn this study,the protective effect of DMSO on intestinal acute radiation injury beagles and myeloid acute radiation injury macaques under anesthesia conditions was first evaluated by establishing models of intestinal acute radiation injury beagles under non-anesthesia conditions and myeloid acute radiation injury macaques under anesthesia conditions,and on the basis of medical symptomatic supportive treatment,improving animal survival rate as the main endpoint,and observing animal weight changes,nausea,vomiting,diarrhea,bloody stools and other symptoms after photographing,the protective effect of DMSO on intestinal acute radiation injury beagles and myeloid acute radiation injury macaques was evaluated.The protective effect of DMSO on small intestinal mucosal tissue and bone marrow hematopoietic tissue was analyzed by intestinal histopathological technology and peripheral blood count.By observing the changes of serum enzymes and blood biochemistry,the functional changes or damage of tissues and organs such as heart,liver and kidney in acute radiation injury were preliminarily analyzed.CTFEL was used to establish an ultra-high dose rate X-ray dose monitoring system and a mouse model of uniform ultra-high dose rate X-ray induced intestinal acute radiation injury and bone marrow acute radiation injury,and the FLASH effect of ultra-high dose rate X-ray was evaluated by observing and comparing animal survival,small intestine survival crypt for 3.5 days,regenerated crypt count,crypt apoptotic cells were count 1 d after illumination and peripheral blood cells were count after irradiation.The effect of DMSO on ultra-high dose rate X-ray radiation protection against ultra-high dose rate X-ray radiation was preliminarily evaluated by the survival and peripheral blood count analysis of ultra-high dose rate X-ray total irradiation mice.Research Results1.Using the model of intestinal acute radiation injury and the symptomatic supportive regimen of intravenous fluids in beagles,it was found that DMSO prophylactic oral administration could significantly improve the survival rate of 12.5Gy total abdominal irradiation beagles.After 12.5 Gy total abdominal irradiation,animals showed typical symptoms of intestinal acute radiation injury such as nausea,vomiting,and bloody stools.DMSO prevented the death of 4 animals in the oral administration group within 6 days after irradiation,and the survival rate was 75%.After 5～6 days after irradiation,the symptoms of the surviving animals were relieved,and they could eat independently for 6～7 days.All animals in the control group died within 6 days after irradiation.The pathological results of dead animals showed that DMSO could increase the number of intestinal mucosal proliferating cells of Beagle dogs after 12.5 Gy total abdominal irradiation,and reduce radiation-induced intestinal mucosal damage.The above results showed that the prevention of oral administration of DMSO could significantly improve the repair of intestinal damage caused by 12.5Gy total abdominal irradiation and improve the survival rate of animals.2.A model of macaques with moderate to severe bone marrow acute radiation injury established by full body irradiation of macaques from ⁶⁰Coγradiation source 5Gy was found to have a good protective effect on bone marrow acute radiation injury macaques with oral administration.In the control group,3 animals were irradiated,and1 animal died of massive bleeding due to an operation accident 17 days after irradiation,and 1 animal died 33 days after irradiation.Three animals in the DMSO group did not die during the 60 days’observation period.All surviving animals recovered their bone marrow hematopoiesis after 60 days.4 animals in the"523"positive control group,1animal died 16 days after irradiation.The results of peripheral blood cell count analysis showed that DMSO and"523"could promote the recovery of macaque white blood cell lines after total body irradiation,DMSO promoted the recovery of red blood cell lines and platelet lines after total body irradiation,and the efficacy was better than"523",and DMSO had a good protective effect on macaques with acute radiation injury to the bone marrow.Through serum biochemical detection,it was found that the macaque had obvious transient sexual function changes in the heart,liver,kidney and other tissues and organs after full body irradiation.3.The fixed frame and transmission device of local irradiation and total body irradiation of mice were optimized,and an ultra-high dose rate X-ray dose monitoring system combining active dosimeter and passive dosimeter was established by CTFEL research,and an equalizing device was added to the collimator,so that the dose difference in the same illumination plane was reduced from more than 50%to less than5%,and a mouse model of uniform ultra-high dose rate X-ray induced intestinal acute radiation injury and bone marrow acute radiation injury was established.Compared with conventional dose rate X-rays,ultra-high dose rate X-rays could not improve the survival rate of total abdominal irradiation and full-body irradiation mice,and the comparison of small intestinal survival crypts and regenerated crypt counts at 3.5 days,and the analysis of apoptotic cells in small intestinal crypts and peripheral blood counts after irradiation showed that ultra-high dose rate X-rays aggravated tissue and organ damage compared with conventional dose rate X-rays and did not have FLASH effect.DMSO preventive oral administration can promote hematopoietic recovery of mice with acute radiation injury caused by bone marrow type caused by ultra-high dose rate X-rays,significantly improve the survival rate of animals,and have a protective effect on ultra-high dose rate X-rays.Research ConclusionsIn this study,the protective effect of oral prophylaxis of DMSO on large animals with gastrointestinal and hematopoietic tissue damage caused by nuclear radiation was verified by the established models of beagle dogs with intestinal acute radiation injury and macaques with myeloid acute radiation injury.CTFEL was used to establish an ultra-high dose rate X-ray dose monitoring system and an animal irradiation model of multi-tissue organ radiation injury caused by mice with ultra-high dose rate X-rays,and it was found that ultra-high dose rate X-rays did not have FLASH effect by comparing X-ray irradiation with different dose rates,and the protective effect of DMSO on mice with ultra-high dose rate X-ray myeloid acute radiation injury was verified.Our research provides data support for DMSO as a potential ideal nuclear radiation damage protection agent,and at the same time provides new research ideas for ultra-high dose rate X-ray radiobiology and radiation damage protection research.