Radiation-induced Liver Damage Research Articles

Administration of Granulocyte Colony-Stimulating Factor Ameliorates Radiation-Induced Hepatic Fibrosis in Mice

On the basis of the recent report that granulocyte colony-stimulating factor (G-CSF) treatment significantly improves survival and liver histology among chemically injured mice, we investigated whether G-CSF administration could contribute to faster recovery and promote tissue repair after local liver irradiation. Bone marrow chimeric female C57BL/6 mice were treated with G-CSF at days 7, 14, and 21 after local liver irradiation. We assessed the fibrosis index and the origin of proliferating cells reconstituting the liver at 2 or 5 weeks after radiation challenge. At day 35 after local irradiation, we observed G-CSF treatment to significantly reduce radiation-induced liver damage and collagen deposition. In addition, hepatic hydroxyproline levels and serum fibrosis markers in mice receiving G-CSF administration after radiation challenge were significantly lower compared with those of control mice. More importantly, histological examination suggested that recovery from hepatic damage was much better among the G-CSF-treated mice. Immunofluorescence and fluorescence in situ hybridization analyses revealed that donor cells engrafted into the host liver displayed epithelium-like morphology and expressed albumin, albeit at low frequency. These results suggested that G-CSF treatment initiated endogenous hepatic tissue regeneration in response to radiation injury and ameliorated its fibrogenic effects.

Human CD34+ cells mobilized by granulocyte colony-stimulating factor ameliorate radiation-induced liver damage in mice

IntroductionOn the basis of the recently recognized potential of hematopoietic stem cells (HSCs) to give rise to hepatocytes, we have assessed the potential of granulocyte colony-stimulating factor (G-CSF)-mobilized bone marrow-derived CD34+ HSCs to contribute to faster recovery and promote regeneration process after acute liver injury by radiation.MethodsG-CSF-mobilized CD34+ HSCs (1 × 105 cells per mouse) were injected via tail vein in the irradiated femal nonobese diabetic/severe combined immunodeficient mice. Irradiated control animals received only saline infusion.ResultsThe mobilized CD34+ HSCs significantly ameliorated radiation-induced liver damage. In the liver of recipient mice killed 21 days after irradiation, human albumin+ Y-chromosome+ hepatocyte-like cells, or human cytokeratin+ Y-chromosome+ hepatocyte-like cells formed cords of hepatocytes, occupied ~30% of the 4-μm section surrounding portal tracts. Furthermore, human-specific albumin mRNA expressed in the liver and human albumin was detected in the serum only in the CD34+ HSC-treated mice.ConclusionsTreatment with G-CSF-mobilized CD34+ HSCs from bone marrow into peripheral blood could significantly promote tissue reparation after acute liver injury by radiation in mice, possibly by the ability of CD34+ HSCs to generate hepatocytes. So mobilization of CD34+ HSCs might offer a novel therapeutic approach for the treatment of radiation-induced complications after radiotherapy or other acute liver diseases in humans.

Abstract LB-208: Radiation-induced liver fibrosis is mitigated by gene therapy against transforming growth factor-ß signaling in the rat

Abstract Purpose: We investigated whether blockage the Transforming growth factor (TGF)-ß signaling ameliorated established liver radiation-induced liver fibrosis (RILF). Materials and Methods: A replication-defective adenoviral vector expressing the extracellular portion of mouse TßRII and the Fc portion of human immunoglobulin IgG fusion protein(AdT RIIFc) was produced. The entire liver was exposed to 30 Gy irradiation to generate a RILF model (RILFM). Then, RILFM animals were treated with AdT RIIFc (1× 1011 PFU, TßRII), Control virus (1×1011 PFU, AdGFP), or saline (SALIN). Delayed radiation liver injury was assessed using histology, morphometry, and immunohistochemistry. Chronic oxidative stress damage, hepatic stellate cell (HSC) activation, and hepatocyte regeneration were also analyzed. Results: Blocking TGF-ß signaling with AdT RIIFc successfully mitigated established radiation induced liver fibrosis (RILF). Compared with RILFM or AdGFP rats, AdT RIIFc-treated mice exhibited less oxidative stress damage, less HSC activation, preserved liver function. Conclusions: Modulation of TGF-ß with AdT RIIFc is feasible and ameliorates established radiation-induced liver fibrosis. These data confirm the putative role of TGF-ß in delayed radiation-induced liver damage. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-208.

CyberKnife for hepatocellular carcinoma: the first case report in Thailand

Background: CyberKnife is a frameless image-guided robotic system for stereotactic body radiotherapy. It can deliver an accurate and concentrated radiation beam to intracranial and extracranial targets for benign, malignant and some non-neoplastic conditions. Objective: To report the first hepatocellular carcinoma (HCC) treated with CyberKnife at Ramathibodi Hospital. Patient and methods: A 73- year-old man with a large right lobe hepatocellular carcinoma was treated with CyberKnife with the total dose of 4500 cGy in three fractions. Results: Two weeks after CyberKnife, he developed radiation induced liver damage (RILD). The patient was admitted for observation and supportive treatment. He was discharged with much improvement of symptoms. Abdominal MRI taken 1 and 3 months after the CyberKnife revealed a significant reduction in size of HCC. His serum alpha fetoprotein was also decreased from 833 ng/mLto 12 ng/mL. Conclusion: The present Robotic Radiosurgery was an effective alternative treatment for HCC. Early detection and proper supportive care was very important to decrease the morbidity from this serious radiation.

Protective Effects of Extracts of Vernonia amygdalina, Hibiscus sabdariffa and Vitamin C against Radiation-induced Liver Damage in Rats

The radioprotective efficacy of methanolic extracts of leaves of Vernonia amygdalina (VA) and Hibiscus sabdariffa (HS), and vitamin C (VIT C) against gamma radiation (4 Gy) induced liver damage was studied in male Wistar albino rats. VIT C was administered at a dose of 250 mg/kg body weight, while VA and HS were administered at doses; 200, 400 and 800-mg/kg body weight, orally for 4 weeks prior to radiation and 5 weeks after irradiation. The rats were sacrificed at 24 hours and 5 weeks after irradiation. Treatment with VIT C and VA (800 mg/kg) significantly (p < 0.05) decreased the gamma radiation-induced increases in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities at 24 hours after irradiation, whereas, HS (400 mg/kg) significantly (p < 0.05) decreased the serum ALT activity only. Similarly, treatment with VIT C and VA (800 mg/kg) significantly (p < 0.05) decreased the serum conjugated bilirubin levels by 56% and 29%, respectively at 24 hours. Furthermore, VIT C, VA and HS significantly (p < 0.05) decreased the levels of serum lipid peroxidation (LPO) and increased the hepatic superoxide dismutase (SOD) activities at 24 hours. Treatment for 5 weeks after irradiation with VITC, VA and HS significantly (p < 0.05) decreased the levels of unconjugated bilirubin, while VIT C and VA alone decreased the levels of conjugated bilirubin. Furthermore, treatment with VA (400 and 800 mg/kg) decreased the serum ALT activities by 25% and 34%, respectively, at 5 weeks after irradiation. Similarly, alkaline phosphatase and LPO levels were significantly (p < 0.05) attenuated following treatment with VIT C and VA (400 and 800 mg/kg) at 5 weeks after irradiation. In addition, treatment with VIT C, VA (800 mg/kg) and HS (400 and 800 mg/kg) significantly (p < 0.05) elevated the levels of reduced glutathione (GSH) by 61%, 56%, 41% and 44%, respectively, at 5 weeks. Similar elevation of antioxidant enzymes; SOD, glutathione-s-transferase and catalase were obtained in animals treated with VIT C and extracts at 5 weeks. Taken together, the results suggest that the extracts of VA and HS, and VIT C could increase the antioxidant defense systems and may probably protect animals from radiation-induced liver damage.

Antisense Oligonucleotide Inhibition of Tumor Necrosis Factor Receptor 1 Protects the Liver from Radiation-Induced Apoptosis

Liver damage by radiation limits its efficacy in cancer treatment. As radiation can generate apoptotic signals, we wished to examine the potential to protect the liver by inhibiting apoptosis through two key mediators, FAS and tumor necrosis factor receptor 1 (TNFR1). Radiation-induced liver damage was assessed by serum aspartate aminotransferase and alanine aminotransferase, hepatocyte micronucleus formation, and apoptosis assays (terminal nucleotidyl transferase-mediated nick end labeling and caspase-3 cleavage) in mice. Protection was evaluated by pretreating mice with antisense oligonucleotides (ASO) for FAS or TNFR1 prior to radiation. TNF-alpha production in liver and in Kupffer cells were determined by ELISA. Radiation increased liver FAS and TNFR1 transcription in a dose- and time-dependent manner (maximized at 25 Gy and 8 hours postirradiation). Pretreatment with ASOs for FAS and TNFR1 resulted in the inhibition of liver FAS and TNFR1 by 78% and 59%, respectively. Inductions of serum aspartate aminotransferase and alanine aminotransferase were observed at 2 hours after radiation and could be reduced by pretreating mice with ASO for TNFR1 but not FAS or control oligonucleotide. Radiation-induced liver apoptosis (terminal nucleotidyl transferase-mediated nick end labeling staining and caspase-3 activation on Western blot) and hepatocyte micronucleus formation were reduced by pretreatment with ASO for TNFR1. In addition, radiation stimulated TNF-alpha production both in irradiated liver and in cultured Kupffer cells by >50% and 100%, respectively. This study suggests that ionizing radiation activates apoptotic signaling through TNFR1 in the liver, and thus provides a rationale for anti-TNFR1 apoptotic treatment to prevent radiation-induced liver injury.

Non-Invasive Monitoring of Radiation Induced Liver Damage Using 31P Magnetic Resonance Spectroscopic Imaging

Non-Invasive Monitoring of Radiation Induced Liver Damage Using 31P Magnetic Resonance Spectroscopic Imaging

Hepatocyte growth factor gene therapy prevents radiation-induced liver damage

To transfer human HGF gene into the liver of rats by direct electroporation as a means to prevent radiation-induced liver damage. Rat whole liver irradiation model was accomplished by intra-operative approach. HGF plasmid was injected into liver and transferred by electroporation using a pulse generator. Control rats (n = 8) received electrogene therapy (EGT) vehicle plasmid and another 8 rats received HGF-EGT 100 mug 48 h before WLIR. Expression of HGF in liver was examined by RT-PCR and ELISA methods. Apoptosis was determined by TUNEL assay. Histopathology was evaluated 10 wk after whole liver irradiation. Marked decrease of apoptotic cells and down-regulation of transforming growth factor-beta 1 (TGF-beta1) mRNA were observed in the HGF-EGT group 2 d after liver irradiation compared to control animals. Less evidence of radiation-induced liver damage was observed morphologically in liver specimen 10 wk after liver irradiation and longer median survival time was observed from HGF-EGT group (14 wk) compared to control rats (5 wk). (P = 0.031). For the first time it has been demonstrated that HGF-EGT would prevent liver from radiation-induced liver damage by preventing apoptosis and down-regulation of TGF-beta1.

Radiation induced liver damage (RILD) in a cirrhotic rat model

Radiation induced liver damage (RILD) in a cirrhotic rat model

Reproducibility of organ position with respiratory gating for liver tumors: use in dose-escalation

Reproducibility of organ position with respiratory gating for liver tumors: use in dose-escalation

Amplification of engrafted hepatocytes by preparative manipulation of the host liver.

Scarcity of donor livers is a major obstacle to the general application of hepatocytes for the development of bioartificial liver assist devices as well as intracorporeal engraftment of hepatocytes for the treatment of inherited metabolic diseases. The number of hepatocytes that can be transplanted into the liver safely in a single sitting also limits the utility of this procedure. These limitations could be addressed by providing preferential proliferative advantage to the transplanted cells. Studies using transgenic mouse recipients or donors have indicated that massive repopulation of the host liver by engrafted hepatocytes requires that the transplanted cells are subjected to a proliferative stimulus to which the host hepatocytes cannot respond. Prevention of host hepatocyte proliferation has been achieved by treatment with a plant alkaloid, retrorsine. Because retrorsine is carcinogenic, we have evaluated preparative irradiation for this purpose. The proliferative stimulus may consist of the loss of hepatic mass (e.g., partial hepatectomy, reperfusion injury or induction of Fas-mediated apoptosis by gene transfer) or administration of stimulants of hepatocellular mitosis (e.g., growth factors or thyroid hormone). Potential applications of these preparative manipulations of the host liver include the treatment of inherited metabolic disorders by transplantation of allogeneic hepatocytes, hepatocyte-mediated ex vivo gene therapy, rescuing liver cancer patients from radiation-induced liver damage, and expansion of human hepatocytes in animal livers.

The Distribution and Pathological Effects of Pu in Juvenile Beagles

Twelve juvenile beagles 90 days old were injected intravenously with 2.8 ..mu..Ci /sup 239/Pu/kg. All attained normal skeletal size and normal weight. However, all died from osteosarcoma with an average survival time of 1306 +- 163 days after injection. At death the liver contained 12.7 +- 2% of the injected /sup 239/Pu, and less than 1% was in the total of kidneys, lung, and spleen. In a liver homogenate, free of nuclei and debris, most of the Pu was bound to ferritin in the cytosol or found with microsomes. No overt evidence of radiation-induced liver damage was discernible. At death, the juvenile skeletons contained 56.0 +- 3.1% compared to 44% in beagles injected as young adults. Highly active bone growth and turnover produced a skeletal redistribution pattern of Pu which differed from that observed in young adults. The cumulative average dose to the anatomical skeleton was 2850 +- 443 rad. Seventeen bone tumors were produced, located predominantly in areas with high concentrations of Pu and rapid bone turnover rates. Skeletal radiographs taken at death revealed 33 fractures, all of which had healed.