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

Imaeda, Masumi; Ishikawa, Hitoshi; Yoshida, Yukari; Takahashi, Tetsuya; Ohkubo, Yu; Musha, Atsushi; Komachi, Mayumi; Nakazato, Yoichi; Nakano, Takashi

doi:10.1093/jrr/rru005

Cited by 18 publications

(17 citation statements)

References 28 publications

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“…Criteria for diagnosing fibrosis as steatohepatitis in animals have not been determined. Therefore, many previous studies that have shown fibrosis in the liver in rodents as determined by Azan staining was assessed by comparison to control animals (Arima et al, 2014;Imaeda et al, 2014;Inami et al, 2015;Kolodziejczyk et al, 2015), which is consistent with this study. Therefore, we assessed the fibrosis in Mongolian gerbils fed a highfat/high-sucrose diet with β-carotene compared to those without β-carotene, as well as those fed a normal diet.…”

Section: Discussionsupporting

confidence: 88%

High-dose β-carotene exacerbates high-fat/high-sucrose diet-inducible fibrosis in the liver of Mongolian gerbils

Kondo

Hariya

Mochizuki

2019

Fundam. Toxicol. Sci.

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β-Carotene, a natural additive that is often used for food coloring, is converted into vitamin A in the body and it removes reactive oxygen species. β-Carotene accumulates in the liver and adipose tissue, where it can induce adverse effects if present in excess. In this study, we determined whether β-carotene supplementation of a high-fat/high-sucrose diet enhances liver inflammation and fibrosis in Mongolian gerbils, which accumulate β-carotene in the liver. Ten-week-old male Mongolian gerbils were divided into four groups and fed either a normal diet, a high-fat/high-sucrose diet, a high-fat/high-sucrose diet supplemented with a low dose of β-carotene (0.001%), or a high-fat/high-sucrose diet supplemented with a high dose of β-carotene (0.004%). An oral glucose tolerance testing was performed after 12 weeks, and non-fasted serum and tissue samples were collected after 13 weeks of diet feeding. The high dose of β-carotene increased triglycerides and total cholesterol serum concentrations. Intake of a high-fat/high-sucrose diet with a high dose of β-carotene increased the β-carotene content, volume occupied by fat droplets, degree of fibrosis, and protein levels of matrix metalloprotease-9 (a marker of inflammation in steatohepatitis) in the liver. These data suggest that the intake of excessive amounts of β-carotene for 13 weeks exacerbates high-fat/high-sucrose diet-inducible inflammation and fibrosis in the liver in Mongolian gerbils. This model is suitable for studying the mechanism of β-carotene-induced liver injury, including liver fibrosis.

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Section: Discussionsupporting

confidence: 88%

High-dose β-carotene exacerbates high-fat/high-sucrose diet-inducible fibrosis in the liver of Mongolian gerbils

Kondo

Hariya

Mochizuki

2019

Fundam. Toxicol. Sci.

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“…The oxidation of liver enzymes may underlie some radiation-induced alterations in hepatic function [2] . In addition to impaired liver function, increased apoptotic cell proportion, decreased hepatocyte number and fibrosis were also observed in irradiated livers [3] . Approximately 5 to 10 percent of the patients who receive a radiation dose in excess of 30Gy develop radiation-induced liver damage (RILD) [4] , [5] , [6] ; when the dose is increased to 43Gy, the prevalence of RILD increases to 50% [7] .…”

Section: Introductionmentioning

confidence: 99%

Hepatocyte Growth Factor Gene-Modified Adipose-Derived Mesenchymal Stem Cells Ameliorate Radiation Induced Liver Damage in a Rat Model

Zhang

Zhou

et al. 2014

PLoS ONE

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Liver damage caused by radiotherapy is associated with a high mortality rate, but no established treatment exists. Adipose-derived mesenchymal stem cells (ADSCs) are capable of migration to injured tissue sites, where they aid in the repair of the damage. Hepatocyte growth factor (HGF) is critical for damage repair due to its anti-apoptotic, anti-fibrotic and cell regeneration-promoting effects. This study was performed to investigate the therapeutic effects of HGF-overexpressing ADSCs on radiation-induced liver damage (RILD). ADSCs were infected with a lentivirus encoding HGF and HGF-shRNA. Sprague-Dawley (SD) rats received 60Gy of irradiation to induce liver injury and were immediately given either saline, ADSCs, ADSCs + HGF or ADSCs + shHGF. Two days after irradiation, a significant reduction in apoptosis was observed in the HGF-overexpressing ADSC group compared with the RILD group, as assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Scanning electron microscopy showed chromatin condensation after irradiation, which was ameliorated in the group that received ADSCs and was reversed in the group that received HGF-overexpressing ADSCs. HGF-overexpressing ADSCs ameliorated radiation- induced liver fibrosis through down regulation of α-SMA and fibronectin. Hepatocyte regeneration was significantly improved in rats treated with ADSCs compared with rats from the RILD group), as assessed by Ki-67 immunohistochemistry. Rats that received HGF-overexpressing ADSCs showed an even greater level of hepatocyte regeneration. HGF-overexpressing ADSCs completely blocked the radiation-induced increase in the enzymes ALT and AST. The effect of mitigating RILD was compromised in the ADSC + shHGF group compared with the ADSC group. Altogether, these results suggest that HGF-overexpressing ADSCs can significantly improve RILD in a rat model, which may serve as a valuable therapeutic alternative.

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“…In a review of DC therapy, various reasons for the limitations of the treatment's efficacy were suggested, including inhibition of immune responses by regulatory T cells (Treg) and increase of the Treg number by transforming growth factor‐β (TGF‐β) . The elevated expression of TGF‐β1 was reported after whole or partial liver irradiation in in vivo studies . Therefore, irradiation to the normal liver using the TomoHelical mode might lead to increases in TGF‐β1 and Treg number, decreasing the efficacy of DC‐based vaccine therapy.…”

Section: Discussionmentioning

confidence: 99%

“…14 Palliative 3DCRT against the whole liver has also been used for multiple liver metastases in the past in Japan. Generally, the liver is sensitive to radiation and up to [30][31][32][33][34][35] Gy against the whole liver is considered to be the safe limit. 15 These doses are not high enough to obtain long-term control of liver metastases.…”

Section: Discussionmentioning

confidence: 99%

“…31 The elevated expression of TGF-β1 was reported after whole or partial liver irradiation in in vivo studies. 32,33 Therefore, irradiation to the normal liver using the TomoHelical mode might lead to increases in TGF-β1 and Treg number, decreasing the efficacy of DC-based vaccine therapy. It was reported that the pretreatment NLR, MLR, and PLR were associated with the prognosis of patients with malignant solid tumors.…”

Section: Discussionmentioning

confidence: 99%

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Helical tomotherapy for chemo‐refractory multiple liver metastases

et al. 2019

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Background Despite advances in chemotherapy, curing multiple liver metastases is quite rare. Even when response is obtained, regrowth of the tumors is almost inevitable. We aimed to evaluate the efficacy and adverse events of helical tomotherapy for chemo‐refractory multiple liver metastases. Methods Forty‐five patients with chemo‐refractory multiple (3‐10) liver metastases after standard systemic chemotherapy entered the single‐institutional prospective study. Liver metastases were the major disease; however, 31 also had uncontrolled primary lesions and/or other metastases. The prescribed dose was 55 Gy in 25 fractions. The median planning target volume (PTV) and normal liver volume (NLV) of first treatment were 128 cm3 and 1175 cm3, respectively. The median of V15Gy, V30Gy, and mean dose to NLV were 45%, 23%, and 19.4 Gy, respectively. Results Forty‐two patients (93%) completed the planned treatment. Median survival time (MST) for all patients was 8 months, and the 1‐year survival rate was 29%. The median local control (LC) period was 5 months and the 6‐month control rate of irradiated tumors was 33%. A ≥30% decrease in tumor markers was observed in 31%. The most common grade 3 toxicity was lymphocytopenia (40%), followed by fatigue (6%). Radiation‐induced liver disease (RILD) was not observed. Pancreatic cancer as the primary tumor, distant metastases outside the liver, low pretreatment neutrophil‐to‐lymphocyte ratio (NLR), and low pretreatment monocyte‐to‐lymphocyte ratio (MLR) were associated with poorer prognoses. Conclusions Helical tomotherapy for chemo‐refractory multiple liver metastases is a feasible and potentially effective treatment. Incorporating tomotherapy into the first‐line treatment in combination with systemic chemotherapy should be considered. Trial registration number CROG 12005.

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

Cited by 18 publications

References 28 publications

High-dose β-carotene exacerbates high-fat/high-sucrose diet-inducible fibrosis in the liver of Mongolian gerbils

High-dose β-carotene exacerbates high-fat/high-sucrose diet-inducible fibrosis in the liver of Mongolian gerbils

Hepatocyte Growth Factor Gene-Modified Adipose-Derived Mesenchymal Stem Cells Ameliorate Radiation Induced Liver Damage in a Rat Model

Helical tomotherapy for chemo‐refractory multiple liver metastases

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