The Treatment Effects And Mechanism Of Andrographolide On Radiation-induced Lung Injury

Radiotherapy is so important among the treatment of malignant tumors that 50%of patients with malignant tumors will receive it as their treatment strategy.However,because the lungs are highly sensitive to radiation,radiation·induced lung injury is a common complication of radiotherapy for chest tumors,not only seriously affecting the normal treatment of cancer patients as well as the quality of their life,but also li?miting the application of radiotherapy.Therefore,searching effective drugs for the prevention and treatment of radiation-induced lung injury has a very important clini?cal significance.In Chapter l,to start with,the application progress of radiotherapy for chest tumors was introduced in detail,consisting of the technical development,the clinical application and the challenges it faced with.And then,we reviewed the research on the progress of radiation induced lung injury from three aspects.Firstly,the pathoge?nesis of radiation-induced lung injury was investigated.Secondly,the relevant signal pathway and the influencing factors were discussed and thirdly,the clinical drugs used for prevention and treatnent were summarised.In Chapter 2,we established radiation-induced lung injury model in mice and investigated the effects of andrographolide.Firstly,bilateral lung of mice were irra-diated 18 Gy with a 6 MV-X line linear accelerator,followed by intraperitoneal injec-tion with different dose of andrographolide every two days in the next 4 weeks.We found that the infiltration of inflammatory cells and the activation of NF-?B were in-hibited by andrographolide at the time of 4th and 8th week after radiation.Also,the levels of ILs,TNF-?,TGF-? were decreased and alveolar hyperemia,edema wall thickening as well as alveolar cavity narrowing were ameliorated significantly,sug-gesting that andrographolide has an excellent treatment effects on radiation-induced pneumonia.When it comes to 20th and 30th week after radiation,a series of sympo-toms were found in mice in the IR group,such as the proliferation of myofibroblasts,the changes of a-SMA and other EMT-related molecular and the deposition of collagen,while all these changes were reversed by intraperitoneal injection with andro-grapholide.Finally,we found that andrographolide could improve the survival rate of mice.In a word,all these results demonstrated that andrographolide could effectively ameliorate radiation-induced lung injury.In Chapter 3,we studied the mechanism how andrographolide ameliorated the radiation-induced lung injury.Two key events in the process of radiation-induced lung injury,cell activation and pyroptosis in macrophages and EMT in pulmonary epithelial cells were researched.Experimental datas showed that andrographolide could inhibit radiation-induced activation of Caspase-1,GSDMD in macrophages,inhibit Caspase-1-dependent cell death,reduce the production and release of IL-1?,IL-1?,TNF-? and other cytokines production,reduce LDH release.What's more,in epithelial cells,andrographolide could inhibit the TGF-?/Smad signaling pathway,increasing the expression of the epithelium marker E-cadherin as well as decreasing the level of interstitial marker N-cadherin,Vimentin and ?-SMA,thus improve EMT.As such,it's easy for us to speculate that andrographolide ameliorated radia-tion-induced lung injury by inhibiting cell activation and pyroptosis in macrophages at the stage of radiation pneumonia,followed by inhibiting EMT of pulmonary epi?thelial cells at the stage of radiation-induced lung fibrosis.In Chapter 4,on the basis of the previous work in our laboratory,we studied how PSAP,the target of andrographolide,regulated cell activation and pyroptosis in macrophages and the process of EMT in pulmonary epithelial cells.Making use of PSAP gene knockout mice,lentivirus interference and other tools,we found that PSAP could negatively regulate cell pyroptosis in macrophages and the process of EMT in pulmonary epithelial cells.Moreover,the effects of andrographolide disappeared when PSAP was deleted,indicating that andrographolide inhibited cell pyroptosis in macrophages and the process of EMT in pulmonary epithelial cells by targeting PSAP.In summary,we found that andrographolide could ameliorate radiation-induced lung injury in a manner of inhibiting cell activation and pyroptosis in macrophages at the stage of radiation pneumonia and suppressing EMT of pulmonary epithelial cells at the stage of radiation-induced lung fibrosis by targeting PSAP.So,it is reasonable to take andrographolide as an effective drug that can be used in clinical to cure pa?tients with radiation-induced lung injury.With the intention to solve clinical problems,our study provided a new potential drug for the treatment of radiation-induced lung injury in clinical and also found the new founctions of PSAP in regulating macro?phage pyroptosis and EMT.