Identification of Proteins Indicating Radiation-induced Hepatic Toxicity in Cirrhotic Rats

Radiation therapy (RT) has become particularly important recently for treatment of liver tumors, but there are few experimental investigations pertaining to radiation-induced liver injuries over long-term follow-up periods. Thus, the present study examined pathological liver features over a 10-month period using an intraoperative whole-liver irradiation model. Liver function tests were performed in blood samples, whereas cell death, cell proliferation, and fibrotic changes were evaluated pathologically in liver tissues, which were collected from irradiated rats 24 h, 1, 2, 4 and 40 weeks following administration of single irradiation doses of 0 (control), 15 or 30 Gy. The impaired liver function, increased hepatocyte number, and decreased apoptotic cell proportion observed in the 15 Gy group, but not the 30 Gy group, returned to control group levels after 40 weeks; however, the Ki-67 indexes in the 15 Gy group were still higher than those in the control group after 40 weeks. Azan staining showed a fibrotic pattern in the irradiated liver in the 30 Gy group only, but the expression levels of alpha smooth muscle actin (α-SMA) and transforming growth factor-beta 1 (TGF-β1) in both the 15 and 30 Gy groups were significantly higher than those in the control group (P < 0.05). There were differences in the pathological features of the irradiated livers between the 15 Gy and 30 Gy groups, but TGF-β1 and α-SMA expression patterns supported the gradual progression of radiation-induced liver fibrosis in both groups. These findings will be useful in the future development of protective drugs for radiation-induced liver injury.

Section: Discussionmentioning

confidence: 99%

Long-term pathological and immunohistochemical features in the liver after intraoperative whole-liver irradiation in rats

Imaeda

Ishikawa

Yoshida

et al. 2014

“…It has been reported that the process of angiogenesis in liver disease is associated with the development of fibrosis [25]. Given that ionizing radiation causes liver fibrosis [26], there is a possibility that ionizing radiation-induced angiogenesis by HHSECs may be involved in the radiation-induced liver damage. Additionally, ionizing radiation is known to induce the expression of diverse genes that play key roles in cell growth and immune responses, including interleukin-6 (IL-6), basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF), in various types of normal endothelial cell lines [27, 28].…”

Section: Discussionmentioning

confidence: 99%

Radio-sensitivities and angiogenic signaling pathways of irradiated normal endothelial cells derived from diverse human organs

Park

Song

et al. 2012

The purpose of the present investigation was to study the effects of ionizing radiation on endothelial cells derived from diverse normal tissues. We first compared the effects of radiation on clonogenic survival and tube formation of endothelial cells, and then investigated the molecular signaling pathways involved in endothelial cell survival and angiogenesis. Among the different endothelial cells studied, human hepatic sinusoidal endothelial cells (HHSECs) were the most radio-resistant and human dermal microvascular endothelial cells were the most radio-sensitive. The radio-resistance of HHSECs was related to adenosine monophosphate-activated protein kinase and p38 mitogen-activated protein kinase-mediated expression of MMP-2 and VEGFR-2, whereas the increased radio-sensitivity of HDMECs was related to extracellular signal-regulated kinase-mediated generation of angiostatin. These observations demonstrate that there are distinct differences in the radiation responses of normal endothelial cells obtained from diverse organs, which may provide important clues for protection of normal tissue from radiation exposure.

“…They found that the tumor response improved with increased radiation dose, but complications arising from increased RT doses were also observed. Radiation dose to the normal liver was a limiting factor in dose escalation; hepatic toxicity is a major obstacle in radiotherapy for HCC [30]. …”

Section: Discussionmentioning

confidence: 99%

Dosimetric differences among volumetric modulated arc radiotherapy (RapidArc) plans based on different target volumes in radiotherapy of hepatocellular carcinoma

Gong

Yin

Guo

et al. 2012

We investigated the dosimetric differences among volumetric-modulated arc radiotherapy (RapidArc, RA) plans designed for various target volumes in hepatocellular carcinoma (HCC). Ten HCC patients underwent 3D-CT scanning at free breathing (FB), 3D-CT at end inspiration hold (EIH) assisted by an Active Breathing Coordinator (ABC), and 4D-CT scanning. Gross tumor volumes (GTVs) were manually contoured on CT images. The individualized internal gross target volume (IGTV1) was obtained from 10 GTVs from 4D-CT images. Tumor individual margins were measured from GTVFB to IGTV1. The IGTV2 was obtained from GTVFB by applying individual margins. Four planning target volumes (PTV1-4) were obtained from IGTV1, IGTV2, GTVFB, and GTVEIH, respectively. An RA plan was designed for each of the PTVs (RA1–4). One 358° arc was used for PTVs1–3, while three 135° arcs were used for PTV4. It was found that PTV2 and PTV3 were larger than PTV1 and PTV4. The mean values of PTV3/PTV1 and PTV3/PTV4 were 2.5 and 1.9, respectively. The individual margins in the X, Y and Z axial directions varied greatly among these patients. There were no significant differences in the conformal index or homogeneity index among the four RA plans. RA1 and RA4 significantly reduced the radiation dose of normal liver tissue compared with RA2 and RA3 (P < 0.01). There were no significant differences between the radiation doses of the stomach and duodenum. RapidArc combined with 4D-CT or ABC technology is a promising method in radiotherapy of HCC, and accurately targeted the tumor volume while sparing more normal liver tissue.