Hepatic Radiation Injury in the Rat

Geraci, Joseph; Mariano, Mário; Jackson, K. L.

doi:10.2307/3577983

Cited by 39 publications

(8 citation statements)

References 21 publications

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“…But the dose could produce detectable hepatic and renal injury has been reported. Whole-liver irradiation of 15-Gy in a single-exposure dose would produce detectable hepatic injury in rats [29] and 25 Gy showed significant histological abnormalities and liver injury, as measured by increased rose bengal retention and liver enzymes [30]. Sharma et al [31] demonstrated that non lethal doses (10 Gy) cause subtle but immediate changes in renal function and structure in rats.…”

Section: Discussionmentioning

confidence: 99%

Abdominal irradiation modulates 5-Fluorouracil pharmacokinetics

Hsieh

Hsieh²,

Liu

et al. 2010

J Transl Med

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BackgroundConcurrent chemoradiation with 5-fluorouracil (5-FU) is widely accepted for treatment of abdominal malignancy. Nonetheless, the interactions between radiation and 5-FU remain unclear. We evaluated the influence of abdominal irradiation on the pharmacokinetics of 5-FU in rats.MethodsThe radiation dose distributions of cholangiocarcinoma patients were determined for the low dose areas, which are generously deposited around the intrahepatic target volume. Then, corresponding single-fraction radiation was delivered to the whole abdomen of Sprague-Dawley rats from a linear accelerator after computerized tomography-based planning. 5-FU at 100 mg/kg was intravenously infused 24 hours after radiation. A high-performance liquid chromatography system equipped with a UV detector was used to measure 5-FU in the blood. Ultrafiltration was used to measure protein-unbound 5-FU.ResultsRadiation at 2 Gy, simulating the daily human treatment dose, reduced the area under the plasma concentration vs. time curve (AUC) of 5-FU by 31.7% compared to non-irradiated controls. This was accompanied by a reduction in mean residence time and incremental total plasma clearance values, and volume of distribution at steady state. Intriguingly, low dose radiation at 0.5 Gy, representing a dose deposited in the generous, off-target area in clinical practice, resulted in a similar pharmacokinetic profile, with a 21.4% reduction in the AUC. This effect was independent of protein binding capacity.ConclusionsAbdominal irradiation appears to significantly modulate the systemic pharmacokinetics of 5-FU at both the dose level for target treatment and off-target areas. This unexpected and unwanted influence is worthy of further investigation and might need to be considered in clinical practice.

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Section: Discussionmentioning

confidence: 99%

Abdominal irradiation modulates 5-Fluorouracil pharmacokinetics

Hsieh

Hsieh²,

Liu

et al. 2010

J Transl Med

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“…Besides, the degree of liver fibrosis induced by regional radiotherapy was closely related to the level of radiation dose and the field used in the study. Geraci et al [20] reported that approximately 50% of the rats exposed to 25 Gy or greater died, and most of these deaths occurred in one to two months after irradiation and showed evidence of damage to the stomach. In order to maintain a relatively high survival rate during research, we chose 20 Gy as the experimental radiation dose in this study.…”

Section: Discussionmentioning

confidence: 99%

Using IVIM-MRI and R2⁎ Mapping to Differentiate Early Stage Liver Fibrosis in a Rat Model of Radiation-Induced Liver Fibrosis

Liang

Song

Xiao

et al. 2018

BioMed Research International

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Rationale and Objectives To investigate the utility of intravoxel incoherent motion MRI (IVIM-MRI) and R2⁎ mapping in diagnosing early stage liver fibrosis in a radiation-induced rat model. Materials and Methods Thirty rats were randomly divided into three groups with 10 rats in each group. Liver fibrosis was induced by exposure of right lobe of liver in each animal to 20 Gy of radiation. MRI examination was conducted at baseline, one month, two months, and three months after radiation using T1WI, T2WI, IVIM-DWI, and R2⁎ sequences. The pathological examination included hematoxylin eosin, masson trichrome, and prussian blue staining. D, D⁎, f, and R2⁎ values were measured in both left and right lobes for quantitative analysis. Results Regarding the surviving 23 rats, eight rats were diagnosed with stage F0, ten with stage F1, and five with stage F2 liver fibrosis using METAVIR Scores. The D values of right lobes decreased (P<0.05), and R2⁎ values increased (P<0.01) significantly as fibrosis levels increased. But there was no statistical difference in D⁎ (P=0.970) and f values (P=0.079). R2⁎ value showed a strong positive correlation (r=0.819, P<0.001), while D value showed a negative correlation with fibrosis stages (r=-0.424, P<0.001). D⁎ (r=0.029, P=0.744) and f values (r=-0.055, P=0.536) were poorly correlated with fibrosis levels. Conclusion IVIM-MRI and R2⁎ mapping are useful techniques for evaluating the severity of liver fibrosis in a radiation-induced rat model, and R2⁎ value is the most sensitive parameter in detecting early stage fibrosis.

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“…Instead, the histopathological appearance of RILD in humans is one of venocclusive disease (VOD), predominantly of the central and sublobular hepatic veins, with sparing of the arteries and periportal vessels [7,26,28]. Although various forms of RILD occur in animals, whole-liver irradiation failed to produce VOD in rats [11,13], dogs [8] and rhesus monkeys [29]. …”

Section: Introductionmentioning

confidence: 99%

A Nonhuman Primate Model of Human Radiation-Induced Venocclusive Liver Disease and Hepatocyte Injury

Yannam¹,

Han²,

Setoyama³

et al. 2014

International Journal of Radiation Oncology*Biology*Physics

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Background Human liver has an unusual sensitivity to radiation that limits its use in cancer therapy or in preconditioning for hepatocyte transplantation. Since the characteristic venocclusive lesions of radiation-induced liver disease do not occur in rodents, there has been no experimental model to investigate the limits of safe radiation therapy or explore the pathogenesis of hepatic venocclusive disease. Methods We performed a dose escalation study in a primate, the cynomolgus monkey, using hypofractionated stereotactic body radiotherapy in 13 animals. Results At doses ≥40Gy, animals developed a systemic syndrome resembling human radiation-induced liver disease, consisting of decreased albumin, elevated alkaline phosphatase, loss of appetite, ascites, and normal bilirubin. Higher radiation doses were lethal, causing severe disease that required euthanasia approximately 10 weeks after radiation. Even at lower doses where radiation-induced liver disease was mild or non-existent, latent and significant injury to hepatocytes was demonstrated by asialoglycoprotein-mediated functional imaging. These monkeys developed hepatic failure with encephalopathy when they received parenteral nutrition containing high concentrations of glucose. Histologically, livers showed central obstruction via an unusual intimal swelling that progressed to central fibrosis. Conclusions The cynomolgus monkey, as the first animal model of human venocclusive radiation-induced liver disease, provides a resource for characterizing the early changes and pathogenesis of venocclusion, for establishing nonlethal therapeutic dosages, and for examining experimental therapies to minimize radiation injury.

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Hepatic Radiation Injury in the Rat

Cited by 39 publications

References 21 publications

Abdominal irradiation modulates 5-Fluorouracil pharmacokinetics

Abdominal irradiation modulates 5-Fluorouracil pharmacokinetics

Using IVIM-MRI and R2⁎ Mapping to Differentiate Early Stage Liver Fibrosis in a Rat Model of Radiation-Induced Liver Fibrosis

A Nonhuman Primate Model of Human Radiation-Induced Venocclusive Liver Disease and Hepatocyte Injury

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