Resveratrol reduces radiation-induced liver damage and fibrosis,and may be related to inhibiting cellular aging and reducing inflammation

Abstract

Objective

To research whether radiation-induced liver damage and fibrosis could be mitigated by resveratrol (RSV) and to elucidate its underlying mechanism.

Methods

A radiation-induced liver damage (RILD) model of murine was constructed. RSV was used as an intervention agent. The effects of RSV on inflammatory reaction, apoptosis, senescence, fibrosis, survival, and liver functions were detected by β-Gal, Sirius red, Masson's trichrome, and Tunnel staining using an automated biochemistry analyzer. The protein expression levels of P16 and P21 were detected by Western blot.

Results

RSV alleviated inflammatory injury of RILD mice. RSV decreased the serum pro-inflammatory cytokines of RILD mice. RSV alleviated radiation-induced hepatocellular senescence. The protein expression levels of P16 and P21 in RILD mice were decreased with RSV administration. RSV decreased the number of apoptotic cells in the early stage of RILD. RSV alleviated liver fibrosis and liver function in RILD mice.

Conclusions

RSV reduces RILD and fibrosis, and may be related to inhibiting cellular aging and reducing inflammation.

Keywords

Radiotherapy radiation-induced liver damage resveratrol hepatocellular senescence and inflammation

Introduction

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide, with an increasing incidence in China.¹ Two main types of fatty liver disease, alcoholic fatty liver disease (AFLD) and nonalcoholic fatty liver disease (NAFLD), contribute to the progression toward liver fibrosis, even HCC.² The pathological mechanisms of AFLD and NAFLD were found to overlap in aspects such as lipid metabolism disorders, insulin resistance, oxidative stress, inflammatory responses, mitochondrial dysfunction, gut microbiota imbalance, and genetic factors. Moreover, Sarcopenia is also a common cause for patients with cirrhosis and HCC.³ With the development of radiotherapy techniques, stereotactic ablative body radiotherapy (SABRT), for example, has been increasingly used in the treatment of hepatocellular carcinoma (HCC). Therefore, RT has become an indispensable part of the comprehensive treatment of HCC. However, as radiation therapy increases, radiation-induced liver injury (RILD) inevitably emerges, leading to many radiation-induced liver diseases. Because of the low tolerance of the liver to radiation, RT is limited in the treatment of HCC, and the incidence of RILD is 5%-10% in patients who receive a dosage exceeding 30 Gy.⁴

RILD is categorized into “classic” and “non-classic” types. The patients with classic RILD are typically within 4 months after the hepatic RT and the representative symptoms include hepatomegaly and anicteric ascites, with weight gain, fatigue, increased abdominal girth, and a highly increased level of alkaline phosphatase. In contrast, patients sufferred from non-classic RILD present liver function abnormalities, with dramatically elevated serum transaminases within 3 months after the RT. Therefore, RILD can lead to liver failure, which can severely impair patients’ health and lives. Veno-occlusive disease (VOD) is the pathological hallmark of RILD, which is characterized by endothelial cell damage, hepatic stellate cell activation, and hepatocellular loss and dysfunction, accompanied by hepatic sinusoidal endothelial death. The activated hepatic stellate cells (HSCs) participate in cytokines regeneration in hepatocytes and regulate inflammation and fibrosis.^5–9

Radiation-induced production of reactive oxygen species (ROS), which causes oxidative stress, leads to cellular senescence and the secretion of pro-inflammatory cytokines. For instance, IL-6, TGF-β, and IL-1α stimulate fibroblast proliferation and collagen generation in radiation-induced pulmonary fibrosis (RIPF).¹⁰ Recently, it has been reported that rapamycin reduced cell senescence and ameliorated radiation-induced pulmonary fibrosis in a murine model via inhibition of the mTOR pathway.^1°Consistently, our previous data also indicated that radiation could induce hepatocellular senescence in the RILD mice.¹¹

TGF-β1 is an important regulator of liver fibrosis, which can promote liver fibrosis by activating downstream of Smad2 and Smad3.¹² Smad2/3 expression is significantly increased in liver fibrosis mice induced by carbon tetrachloride (CCl₄).¹³ Smad7, a negative regulator of the TGF-β1/Smad signaling pathway, mainly inhibits TGF-β1 signal transduction by competing with Smad3 to inhibit the progression of liver fibrosis. Smad7 knockout promotes liver fibrogenesis in mice,¹⁴ which indicates that the TGF-β1/Smad signaling pathway and the related cytokines play critical roles in liver fibrosis.¹⁵

RILD is well characterized by the loss of parenchymal hepatocytes, congestion, distortion of the lobular architecture, venous obstruction, and other clinical symptoms such as increased liver enzymes, ascites, and fatigue.^16,17 Nevertheless, until now, no effective and specific pharmacologic treatments for mitigating RILD have been reported.¹⁸ Therefore, it is essential to develop approaches to minimize toxicity. Natural product intake has been considered to have radioprotective properties in preventing ionizing radiation injury.¹⁹ Resveratrol (trans-3’,4’,5’-trihydroxystilbene, RSV), a natural compound extracted from plants, which has extensive properties of antioxidation, anti-inflammation, antitumor, and many other characteristics, such as cardiovascular protection, protection against neurodegenerative diseases, promotion of autophagy, restoration of endothelial function, free radical scavenger, and lifespan extension.^20,21 A recent study suggested that RSV ameliorated sarcopenic obesity through metabolic disease-related pathways, including those associated with nonalcoholic fatty liver disease, and inflammatory factors.²² Therefore, we aimed to explore the effect of resveratrol on radiation-induced liver damage and to elucidate its underlying mechanism.

Materials and methods

Establishment of RILD model

Male C57BL/6 mice (aged 6–8 weeks, 20 ± 2 g) with specific pathogen free (Beijing Huafukang Biotechnology Co., Ltd, Beijing, China) were anesthetized by intraperitoneal injection with 3.5% chloral hydrate (10 ml/kg) and subjected to the following radiation. The liver was exposed to a radiation source and irradiated with single dose：16 Gy (dose rate: 350 cGy/min), whereas the other organs neighboring the liver were shielded by lead strips to ensure being protected from the irradiation. The first time of administrations was completed 30 min ahead of irradiation, and repeated every day during the following first month, and then repeated every three day3 from the second month to the sixth month. This is the diagrammatic drawing of irradiations (eg. RT) and radiotherapy and RSV treatment (eg. Drug admin) (Supplementary Figure 1). RT. All animal experiments were approved by the Ethics Committee of the Sichuan University. The institutional and Government Review Boards also approved all animal studies.

Administration of RSV

The mice were divided into four groups (n = 6 per group). (1) RT+RSV (irradiation + 20 mg/kg resveratrol); (2) RT + vehicle (irradiation + 10 ml/kg PBS containing 5% ethyl alcohol); (3) RT + DEX (irradiation+1 mg/kg dexamethasone); (4) Control (normal control group); (5) RSV (20 mg/kg resveratrol). A 50 mg/mL stock solution of RSV was prepared by diluting in anhydrous ethanol, and then a working solution was made by diluting with PBS buffer to a 20 mg/kg suspension for the following administration. The normal control group did not receive any gavage. All the administrations were completed 30 min ahead of irradiation, repeated every day in the first month, and then repeated every three days from the second month to the sixth month. The mice were sacrificed at the end of the first month (day 30) and the sixth month (day 180) to assess RILD. The liver tissues and serum were collected and stored for the following experiments.

Histopathology

Paraffin-embedded sections (4 μm) of the livers were prepared for the hematoxylin and eosin (H&E), Masson's trichrome, Sirius red, and terminal -deoxynucleotidyl transferase mediated nick end labeling (TUNEL) staining using the standard procedures with the commercial reagent kits (Beijing Solarbio Science & Technology Co.,Ltd, Beijing, China). Frozen sections (6 μm) of the livers were prepared for the β-gal staining using the Senescence β-Galactosidase Staining Kit (Cell Signaling Technology Inc., Danvers, MA, USA).

Measurement of biochemistry indexes

Serum amino leucine transferase (ALT) and aspartate transaminase (AST) were analyzed by an automated biochemical analyzer (TBA-2000FR, Toshiba, Tokyo, Japan) with the commercial reagent kits (Nanjing Jiancheng Bioengineering Research Institute, Nanjing, China).

Measurement of cytokines

After anesthetizing the mice, the blood was collected and centrifuged at 3000 rpm for 15 min to separate the serum. TGF-β1, IL-6, and IL-17 were determined by enzyme-linked immunosorbent assay (ELISA) according to the manufacturer's instructions of the commercial reagent kits (R&D System, Minneapolis, MN, USA). Each sample was assayed in triplicates.

Western blot analysis

Tissue lysates were prepared using RIPA buffer (Millipore Corp.) and protein concentration were analyzed using the BCA protein assay kit (Millipore Corp.). The quantified protein lysates were separated on 10% SDS-PAGE gel and then transferred onto a polyvinylidene difluoride (PVDF) membrane (Millipore Corp., Burlington, MA, USA). The membrane was sequentially incubated with anti-P21 (#64016, 1:1000) and anti-P16 (#82172, 1:8000) antibodies (Cell Signaling Technology Beverly, MA, USA) overnight at 4 °C followed by incubation with the horseradish peroxidase-conjugated secondary antibodies at room temperature for 1 h. The blots were visualized using a chemiluminescence kit (Millipore Corp.). β-actin was used as a control.

Statistical analyses

Statistical analyses were performed using the statistical package for social sciences version 26.0 (IBM Corp., Armonk, NY, USA). All data were represented as mean ± standard deviation (SD) with at least three independent experiments. The statistical significances among groups were analyzed by one-way ANOVA followed by Dunnett's test. p < 0.05 was considered significantly different.

Results

RSV alleviated inflammatory injury of RILD

Morphology and inflammation on day 30 (lower panel) and day 180 (upper panel) after irradiation were observed by H&E staining. On day 30, RILD in both RT+vehicle and RT+DEX groups were apparent compared with the other groups. In RT+vehicle group, there were incomplete cellular structure and cytolysis surrounding the hepatic lobule, and damaged structural integrity in the hepatic cord. Whereas the liver morphology in RT+RSV and the Ctrl groups was relatively complete without any apparent damage. On day 180，except for the Ctrl and RSV groups, the other groups had some degrees of inflammatory changes. As shown in Figure 1, RT+Vehicle and RT+DEX groups got serious injury one month after radiation. However, RT+RSV group only presented reduced injury, and no significant damage was found in RSV and CON groups. In the six month with radiation, the injury was more severe with deeper inflammatory cell exudation in RT+Vehicle, RT+DEX and RT+RSV groups when compared to one month of radiation. RT+RSV group achieved mild inflammatory response in contrast to RT+Vehicle or RT+DEX group, while no obvious injury was observed in both RSV and CON groups (Figure 1).

Figure 1.

Representative photomicrographs of H&E staining to detect inflammatory lesions of mice liver (Scale bar: 50 μm) (n = 6). On day 30, RILD in both RT+vehicle and RT+DEX groups were apparent compared with the other groups. In RT+vehicle group, there were incomplete cellular structure and cytolysis surrounding the hepatic lobule, and damaged structural integrity in the hepatic cord. Whereas the liver morphology in RT+RSV and the Ctrl groups was relatively complete without any apparent damage. On day 180，except for the Ctrl and RSV groups, the other groups had some degrees of inflammatory changes. As shown in Figure 1, RT+Vehicle and RT+DEX groups got serious injury one month after radiation. However, RT+RSV group only presented reduced injury, and no significant damage was found in RSV and CON groups. In the six month with radiation, the injury was more severe with deeper inflammatory cell exudation in RT+Vehicle, RT+DEX and RT+RSV groups when compared to one month of radiation. RT+RSV group achieved mild inflammatory response in contrast to RT+Vehicle or RT+DEX group, while no obvious injury was observed in both RSV and CON groups.

Il-6, IL-17, IL-1 are inflammatory cytokine, and changes in plasma inflammatory cytokine indicate changes in liver inflammation. IL-6 could stimulate fibroblastic proliferation and collagen generation in radiation-induced pulmonary fibrosis (RIPF). White liver inflammatory injury participates in the RILD and RSV could alleviate liver fibrosis and reduce the inflammatory cytokines secretion. The serum IL-6 level in RT+Vehicle group was highest among all the groups on day 30 and day 180 (P < 0.05). Compared with RT+DEX group, IL-6 in RT+RSV group was significantly decreased (P < 0.05). Similarly, RT+vehicle group also showed remarkably higher IL-17 level than the other groups (P < 0.05), while RT+RSV group had lower IL-17 than RT+DEX group (P < 0.05). The serum IL-1β level in RT+Vehicle group was highest among all the groups on day 30 and day 180 (P < 0.05, Figure 2).

Figure 2.

The contents of the serum inflammatory cytokines (n = 6, repeat 3times). The serum IL-6 level in RT+Vehicle group was highest among all the groups on day 30 and day 180 (P < 0.05). Compared with RT+DEX group, IL-6 in RT+RSV group was significantly decreased (P < 0.05). Similarly, RT+vehicle group also showed remarkably higher IL-17 level than the other groups (P < 0.05), while RT+RSV group had lower IL-17 than RT+DEX group (P < 0.05). The serum IL-1β level in RT+Vehicle group was highest among all the groups on day 30 and day 180 (P < 0.05).

RSV alleviated radiation-induced hepatocellular senescence

The cell's senescence has a vital role in RILD assessment. The hepatocytes’ senescence was detected by β-gal staining (Figure 3A-C). On day 180, the hepatocytes’ senescence was observed in each group. The ratio of senescent cells in the RT+vehicle group was the highest, whereas the ratio in the RT+RSV group was significantly reduced compared with the RT+vehicle group (p < 0.05). And the ratio in the RT+DEX group was also dramatically reduced compared with that in the RT+vehicle group (p < 0.01). On day 180, the ratio of the senescent cells in the five groups progressively increased compared with that on day 30. Among them, the ratio of the senescent cells in the RT+RSV group was significantly decreased than that in the RT+vehicle group (p < 0.001). Similar results were obtained in the RT+DEX group. Therefore, the treatment effects of RSV on RILD were approximately equal to that of dexamethasone, which was a common drug for alleviating radiation-induced liver injuries. P16 and P21, vital makers of senescence, were detected by western blots, and the results showed that the expression levels of P16 and P21 were decreased with RSV administration (Figure 3D), which revealed that the irradiation-induced cell senescence at the early stage (day 30) and late stage (day 180) occurred in RILD, and RSV treatment could protect for long term.

Figure 3.

Effects of RSV on senescence induced by irradiation. (A-C) Histological assessment of the liver senescence by β-gal staining. (A) β-gal staining for detecting the senescent cells on day 180 (upper panel) and day 30 (lower panel) after the irradiation. (B) The apparent senescence-positive cells in the RT+vehicle group on day 30 and day 180 after irradiation (arrow). (C) Quantification of the senescent cells on day 30 and day 180 after irradiation. Error bars depict SEM. * p < 0.05, ** p < 0.01 by one-way ANOVA (n = 6, repeat 3times). Representative β-gal-stained liver images from five experimental groups (nuclear staining by new fast red). Scale bar: 50 μm. (D) Western blot for P16 and P21 in mice livers on day 30 and day 180 after the irradiation. Actin was used as an endogenous control.

RSV decreased the number of apoptotic cells in the early stage of RILD

The apoptotic cells on day 30 after the irradiation were assessed by TUNEL staining. The results showed that radiation-induced apoptosis was increased significantly after irradiation and could be alleviated by RSV administration (Figure 4). The effects of RSV treatment in inhibition of apoptosis were more effective than dexamethasone, but there was no statistical significance between RT+RSV and RT+Dex groups (p > 0.05).

Figure 4.

Improvement of RILD after RSV administration on day 30 by apoptosis analysis. (A) The apoptotic cells were analyzed by TUNEL assay. (B) Quantification of the apoptotic cells on day 30 after irradiation. Error bars depict SEM. * p < 0.05, ** p < 0.01 by one-way ANOVA; n = 3 mice per group. Representative TUNEL-stained liver sections from four experimental groups (nuclear staining by methyl green). Scale bar: 50 μm.

RSV alleviated liver fibrosis induced by irradiation

Tissue fibrosis is a consequence of radiation injury, which can gradually progress into fibrosis and cirrhosis of the liver from chronic inflammation. Tissue fibrosis was detected on day 30 by Masson's trichrome staining and liver cirrhosis on day 180 by Sirius red staining, respectively (Figure 5). No obvious collagen deposition was seen in theRT group on day 30 after irradiation (Figure 5A), whereas after 6 months of irradiation, abundant collagen I deposition occurred in the RT+vehicle group, and the degree of fibrosis in the RT+vehicle group was the most severe. However, the degree of fibrosis in the RT+RSV group was significantly alleviated compared with that in the RT+vehicle group (Figure 5B, C).

Figure 5.

Analysis of collagen deposition and fibrosis of the liver after RSV treatment in RILD. Representative images of Sirius red and Masson's trichrome stained liver sections from the experimental groups. (A) Masson's trichrome staining on day 30 after irradiation. Scale bar: 50 μm. (B), Sirius red staining on day 180 after irradiation (red color represents collagen I). Scale bar: 500 μm, 50 μm. (C) semi-quantitative analysis of type 1 collagen. 3 fields of view were randomly selected for each section to observe the liver，For the change of viscera morphology, Image-Pro Plus 6.0 software was used to analyze the collagen area of fiber and calculate the volume fraction of collagen, which was equal to collagen area/total tissue area ×100%.

RSV improved liver function induced by irradiation

The levels of ALT and AST are commonly used liver function indexes. ALT reflected the liver function of the early stage, while AST reflected that of the late stage. The results showed that both ALT and AST levels in the RT+RSV group were significantly lower than that in the RT+vehicle group (p < 0.05). Therefore, RSV treatment could dramatically decrease ALT and AST in RILD (Figure 6).

Figure 6.

Detection of liver function by measurement of ALT and AST after RSV administration. Serum levels of ALT and AST on day 30 and day 180. Error bars depict SEM. * p < 0.05 by one-way ANOVA (n = 6, repeat 3times).

Discussion

Exposure to ionizing radiations induces cell senescence and apoptosis. The senescent endothelial cells are characterized by decreased production of nitric oxide (NO) and thrombomodulin and increased expression levels of adhesion molecules, ROS and inflammatory cytokines. Therefore, severe injuries were increased by the effects of amplified and repeated irradiations. The radiation-induced senescent endothelial cells exhibited diverse senescence-like phenotypes including changes in cell morphology, permanent cell-cycle arrest, and increased staining for senescence-associated β-galactosidase (SA-β-gal).²³ The senescent cells can exist for prolonged periods, accumulate with age, and develop a persistent pro-inflammatory phenotype, called the senescence-associated secretory phenotype (SASP), which affects the cellular microenvironment and impair tissue function.^24–26

The RSV can prevent the process of senescence by increasing glutathione levels, reducing cell death and accumulation of ROS, and capturing free radicals directly in cells.^27–30 The senescence and apoptosis of tissue endothelial cells were induced by ionizing radiation in a dose-dependent manner. Senescent and apoptotic endothelial cells were observed in the group exposed to high radiation dose (>10 Gy) as the majority in the acute injury stage and the group exposed to moderate dose (>0.5 and <10 Gy) as the majority in chronic damage stage, respectively.²³ Our results showed that the radiation-induced senescence of hepatocytes was reduced significantly after the RSV administration, which indicated that the radiation caused senescence and the senescence played a vital role in the progression of liver injury. The RSV could alleviate the senescence caused by the X-ray radiation in mice. Additionally, the radiation-induced apoptosis of hepatocytes that were assayed by TUNEL staining, was reduced after the RSV treatment, which indicated that the RSV could protect the hepatocytes against apoptosis induced by the X-ray radiation. However, it remained unclear whether senescence happened earlier than apoptosis or whether damaged cells avoided apoptosis in favor of senescence. Thus, to address this hypothesis that targeting cellular senescence may be an effective treatment in chronic damage of radiation-induced liver diseases, further studies to elucidate the link between radiation-induced tissue injury and senescence should be carried out.

Both inflammatory cell infiltration and exudation into the liver and inflammation play a key role in the early stage of RILD. The senescent cells can secrete pro-inflammatory cytokines. Cell apoptosis is associated with ER stress, which often induces inflammation and injury in the liver.³¹ All of these factors aggravate radiation-induced liver injury. Anti-inflammatory effects of RSV by inhibiting the expression of the pro-inflammatory factors, reducing the chemo-attraction and recruitment of the immune cells to the inflammatory site, and reducing the expression of inflammatory markers.^32–34 In the present study, the inflammatory infiltration in the liver exposed to the X-ray was reduced significantly after the RSV intervention, and thus, mitigated the extent of liver injury. The P21 expression was significantly decreased with the RSV administration compared to that without the RSV treatment. The inflammatory cytokines IL-6 and IL-17 in the serum were decreased significantly after the RSV intervention. All of these results indicated that reducing inflammatory cell infiltration and inflammatory cytokines secretion may be one of the mechanisms in alleviating radiation-induced liver injury by RSV.

Liver fibrosis, an early stage of liver cirrhosis, which is regarded as one of the incurable diseases, progresses into a complicated pathological fibrogenic process. The excessive deposition of collagen I and III in the liver leads to fibrosis, which is induced by chronic liver damage.^35,36 The HSCs play a key role in the initiation, progression, and regression of liver fibrosis, which can be activated after the liver injury or culture in vitro,³⁷ whereas the non-proliferative, quiescent phenotype is maintained in the normal liver.³⁸ The HSCs can stimulate the fibroblasts and bone marrow-derived myofibroblasts to produce collagen by secreting fibrogenic factors. In addition, the senescent pneumocytes can stimulate the fibroblasts’ proliferation and secretion of collagen and pro-fibrotic molecules. Studies revealed that RSV could reduce the collagen I production from the HSCs and had a similar effect in the other liver fibrosis models.^39–41 Our data demonstrated that significantly increased liver fibrosis was observed in the late stage of the radiation-induced liver injury detected by the Sirius red staining, and the collagen deposition was ameliorated after the RSV treatment. In contrast, no apparent collagen deposition in the early stage of the radiation-induced liver injury was found by the Masson staining. These results implied that the liver fibrosis induced by the X-ray radiation mainly occurred in the late stage of RILD and very slightly occurred in the early stage of RILD and that RSV could alleviate liver fibrosis. The ALT and AST serum levels are sensitive indices for assessing liver function and are elevated in liver damage. Our results demonstrated that both ALT and AST levels were significantly increased in the X-ray radiation-induced liver damage.

Taken together, our results indicated that the irradiation-induced apparent hepatocyte senescence phenotype and liver fibrosis. Senescence may participate in the process of radiation-induced liver injury and play a vital role in causing RILD. The underlying mechanisms and links between senescence and radiation-induced liver injury should be supported by future studies. Moreover, the radiation-induced liver injury was alleviated by the RSV administration. Our findings provided a new strategy for radiation-induced liver injury treatment.

Supplemental Material

sj-docx-1-ini-10.1177_17534259251352623 - Supplemental material for Resveratrol reduces radiation-induced liver damage and fibrosis, and may be related to inhibiting cellular aging and reducing inflammation

Supplemental material, sj-docx-1-ini-10.1177_17534259251352623 for Resveratrol reduces radiation-induced liver damage and fibrosis, and may be related to inhibiting cellular aging and reducing inflammation by Songhui Zhai, He Xu, Jianxin Xue, Lu Gan, Fang Gao and Lijuan Hu in Innate Immunity

Footnotes

ORCID iD

Lijuan Hu

Ethical considerations

This study was approved by the Ethics Committee of the Sichuan University.

Authors’ contributions

All authors have read and approved the manuscript.

guarantor of integrity of the entire study: Lijuan Hu

study concepts: Lijuan Hu, Jianxin Xue

study design: Jianxin Xue, Lu Gan

definition of intellectual content: Jianxin Xue

literature research: Songhui Zhai, He Xu

clinical studies: /

experimental studies: He Xu,Fang Gao

data acquisition: Songhui Zhai, He Xu

data analysis: Songhui Zhai, He Xu

statistical analysis: Songhui Zhai, He Xu

manuscript preparation: He Xu

manuscript editing: Songhui Zhai,

manuscript review: Lijuan Hu

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Supplemental material

Supplemental material for this article is available online.

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