To Investigate the Role of Inflammasome in Radiation-Induced-Liver Injuries and Bystander Effects

Radiotherapy (RT) had a limited role in treating hepatocellular carcinoma (HCC) because of the poor radiation tolerance of normal liver; the clinical symptoms caused by radiation-induced liver diseases (RILD) may occur within weeks or months after RT. The introduction of new radiotherapy techniques such as image-guided techniques, stereotactic body radiation therapy (SBRT) and even particle beam treatment makes radiation oncologists can provide new treatment protocols with hypofractionation scheme and considerably higher biological equivalent dose (BED) for treating HCC, but the effects of this type of therapy to normal liver toxicity still need more investigation . This study aims to investigate the normal liver responses to radiation at the initial phase and how to apply these responses for clinical use. We hypothesize that Kupffer cell and the activation of its inflammasome are the first signals of acute tissue inflammation following radiation therapy, which contribute to the metabolic disorder and fluctuations in sinusoidal system within the irradiated area. Specific intervention drugs will be tested to block inflammasome activation and investigate its effects on the following RILD. In addition, molecular imagines, such as FDG-PET and DCE-MRI, will also be applied to examine the physiological changes in damaged liver tissue, and find out its correlation with the activation of inflammasome at various dose levels and time points. The findings from imaging could serve as biomarkers to provide real-time information of tissue damage during the treatment, especially suitable for early range verification and treatment plan re-optimization during SBRT or particle beam treatment on HCC. In addition to study the in situ responses, another aim in this study is to investigate the correlation between inflammasome activation and radiation-induced bystander effect (RIBE), and block this pathway by intervention drugs. Radiation-induced bystander effect (RIBE) depicts the behaviors of surrounding nonirradiated normal tissue, acting as similar as radiation-damaged tissue, through signal transduction by inflammatory cells. Our hypothesis is that radiation-induced inflammatory response will be propagated into surrounding non-irradiated cells and induce effects. In addition to possible adverse effects, RIBE might induce gain of liver volume and function at later stage. Metabolomics will be applied to investigate the underlying mechanism. Specific aims: 1. To examine the correlation of radiation-induced inflammaosome activation with early radiation-induced liver diseases and delineate the range by FDG-PET imaging. 2. To study radiation-induced changes in hepatic sinusoids and delineate the range by DCE-MRI. 3. To explore the bystander effect on normal liver tissue following RT, and block it by intervention drugs and study the subsequent effects.

Project ID:PC10507-0278
External Project ID:MOST105-2314-B182-017