Acute Radiation-induced Injury Research Articles

Lack of association between XRCC1 SNPs and acute radiation‑induced injury or prognosis in patients with nasopharyngeal carcinoma.

The response to radiation therapy (RT) is closely associated with DNA damage repair. X-ray repair cross-complementing group-1 (XRCC1) is a key gene in the DNA damage repair pathway, and SNPs in this gene alter the expression and activity of its effector protein, which may in turn affect sensitivity to RT. Therefore, the course of tumor treatment and local control rate can be influenced. In the present study, a group of 158 patients with nasopharyngeal carcinoma (NPC) who received intensity-modulated RT at Fujian Cancer Hospital (Fuzhou, China) between July 2012 and October 2013 were included in retrospective chart review and followed up. Plasma was collected before treatment for genotype analysis of the three SNPs of XRCC1, namely Arg194Trp, Arg280His and Arg399Gln. Acute radiation-induced injuries sustained during treatment was graded according to the Radiation Therapy Oncology Group scoring criteria. Post-treatment follow-up was performed until August 2020. In the 158 cases of NPC, no statistically significant association was observed between the three SNPs of the XRCC1 gene and the severity of acute radiation-induced injury or prognosis. However, the AA genotype of XRCC1-Arg399Gln tended to be associated with worse progression-free survival (PFS) compared with the GA + GG genotype, although this was not significant (P=0.069). In addition, multivariate logistic analysis showed that nodal stage was significantly associated with the occurrence of acute severe radiation-induced oral mucositis (P=0.018), and there was also a trend towards an association between nodal stage and the incidence of acute severe radiation-induced pharyngitis; however, this was not statistically significant (P=0.061). Furthermore, multivariate Cox regression analysis showed that older age, distant metastasis and higher clinical stage were independent risk factors for PFS in patients with NPC. In conclusion, relying solely on the aforementioned SNPs of the XRCC1 gene may not provide a robust enough basis to predict the response to RT or prognosis in patients with NPC.

Abstract 811: Development of a NOX-ROS nanoinhibitor for enhancing response to radiotherapy in lung cancer cells while mitigation radiation-induced inflammation and injury in the normal lung tissue

Abstract Objective: One of the unmet clinical challenges is that many tumors remain insensitive to radiotherapy owing to intrinsic resistance or acquired resistance that leads to tumor progression or recurrence. Moreover, radiation-induced acute injury and chronic inflammation in normal tissues limit the radiation dose that can be applied to the tumor, and tolerable doses are often linked to suboptimal tumor control—even accepting side effects that lead to decreased quality of life. Our goal of the study is to develop a nanoformulated radiosensitizer that inhibits NOX-ROS signal pathway to enhance therapeutic response in tumor cells while reducing radiotoxicity in normal tissues. Methods: We developed a biomaterial-based nanoparticle radiosensitizer that acts upon abnormal redox status and altered metabolism in tumor cells to trigger a cascade of changes in signal pathways to enhance response to radiotherapy. This CD44-targeted radiosensitizer consists of a biodegradable and bioactive hyaluronic acid nanoparticle (HANP) encapsulated with a dual NOX1/4 inhibitor, GKT831 (HANP/GKT831). Orthotopic and subcutaneous NSCLC tumor mouse models using a WRJ388 cell line that was isolated from a metastatic lung adenocarcinoma in a lymph node of a KrasG12D/Lkb1null GEMM mouse were established for evaluation of the effect on the inhibition of tumor growth and protection of normal tissue after the treatment with intravenous administrations of HANP/GKT831 at 5 mg/kg (twice per week for five times) combined with radiation (2 Gy/each dose, twice per week for five times). The anti-tumor effect, immune response, and inflammation in the normal lung tissues were investigated using histological and immunofluorescence analyses. Results: Our results showed that HANP/GKT831 had stronger inhibitory effects on ROS generation and cell proliferation than that of GKT831 in mouse NSCLC tumor cells in vitro. Systemic injection of HANP/GKT831 combined with radiation had the strongest inhibition on tumor growth (~79%) compared with the combination of non-nanoformulated GKT831 with radiation treated mouse group (<50%). HANP/GKT831 combined with radiation led to an increased tumor specific CD8+ T cells in tumors and markedly reduced the level of myeloid derived suppressive cells (CD11b+/GR1+) in tumors. Furthermore, the combination of radiation and HANP/GKT831 reduced inflammatory cytokines, such as IFN-γ and TNF-α, and cells (CD11b+ cells) in the irradiated normal lung tissues. Conclusion: HANP/GKT831 is a biomaterial-based nanoparticle radiosensitizer that acts upon abnormal redox status and altered metabolism in tumor cells to trigger a cascade of changes in signal pathways to enhance the response of tumor cells to radiotherapy. It also has the potential to reduce the radiation-induced inflammatory response in normal lung tissues. Citation Format: Lei Zhu, Lumeng Zhang, Tongrui Liu, Wei Ping Qian, Wei Zhou, Lily Yang. Development of a NOX-ROS nanoinhibitor for enhancing response to radiotherapy in lung cancer cells while mitigation radiation-induced inflammation and injury in the normal lung tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 811.

Parthenolide promotes expansion of Nestin+ progenitor cells via Shh modulation and contributes to post-injury cerebellar replenishment.

Background: Regeneration of injuries occurring in the central nervous system is extremely difficult. Studies have shown that the developing cerebellum can be repopulated by a group of Nestin-expressing progenitors (NEPs) after irradiation injury, suggesting that modulating the mobilization of NEPs is beneficial to promoting nerve regeneration. To date, however, effect of exogenous pharmaceutical agonist on NEPs mobilization remains unknown. Parthenolide (PTL), a sesquiterpene lactone isolated from shoots of feverfew. Although it has been shown to possess several pharmacological activities and is considered to have potential therapeutic effects on the regeneration of peripheral nerve injury, its efficacy in promoting central nervous system (CNS) regeneration is unclear. In this study, we aimed to elucidate the role and possible mechanism of PTL on regeneration in injured CNS after irradiation using a developing cerebellum model. Methods: We investigated the radioprotective effects of PTL on the developing cerebellum by immunoblotting as well as immunofluorescence staining and ROS detection in vivo and in vitro experiments, and then determined the effects of PTL on NEPs in Nestin CFP and Nestin GFP fluorescent mice. Inducible lineage tracing analysis was used in Nestin-CreERT2×ROSA26-LSL YFP mice to label and track the fate of NEPs in the cerebellum after irradiation. Combined with cell biology and molecular biology techniques to determine changes in various cellular components in the cerebellum and possible mechanisms of PTL on NEPs mobilization in the injured developing cerebellum. Results: We found that PTL could attenuate radiation-induced acute injury of granule neuron progenitors (GNPs) in irradiated cerebellar external granule layer (EGL) by alleviating apoptosis through regulation of the cells' redox state. Moreover, PTL increased cerebellar Shh production and secretion by inhibiting the PI3K/AKT pathway, thus promoting expansion of NEPs, which is the compensatory replenishment of granule neurons after radiation damage. Conclusion: Collectively, our results indicate that activation and expansion of NEPs are critical for regeneration of the injured cerebellum, and that PTL is a promising drug candidate to influence this process.

An Investigation of the Mechanisms of Radiation-Induced Muscle Injury in a Tree Shrew (Tupaia belangeri) Model

BackgroundAnimal models suitable for investigating mechanisms behind radiation-induced muscle injury are lacking. We developed a tree shrew model of such injury and investigated pathological changes and mechanisms.MethodsAnimals were divided into control (n = 5), radiation-induced acute injury (n = 5), and radiation-induced chronic injury (n = 5) groups. Tensor veli palatini (TVP) muscles of acute injury and chronic injury groups were dissected under a microscope at 1 and 24 weeks after radiation therapy, respectively. TVP muscles were stained with HE and Masson to visualize pathological changes. ELISA was performed to measure oxidative injury. RT-qPCR and immunohistochemical staining was performed to measure expression levels of miR-206 and histone deacetylase 4 (HDAC4).ResultsCompared to the control group, acute injury group showed a significant decrease in miR-206 expression (.061 ± .38, P < .05) and a significant increase in HDAC4 expression (37.05 ± 20.68, P < .05). Chronic injury group showed a significant decrease in miR-206 expression (.23 ± .19, P < .05) and a significant increase in HDAC4 expression (9.66 ± 6.12, P < .05).DiscussionA tree shrew model of radiation-induced muscle injury was established by exposing TVP muscle region to radiation of 20-Gy. Experimental results indicated that injury caused by radiation persisted despite gradual healing of the TVP muscle and miR-206 regulatory pathway plays a key role in regulating radiation-induced muscle injury.

Study on urine biomarkers of radiation-induced injury guided by Caenorhabditis elegans as a model organism

ObjectiveUnder the guidance of model organism Caenorhabditis elegans with fine olfactory system, small molecular metabolites sensitive to high dose radiation were screened as biomarkers of acute radiation-induced injury, and their metabolic pathways were elucidated by enrichment. MethodsRats were irradiated with 12 ​Gy γ-rays to establish an acute radiation injury model, and their urine was fingerprinted using UPLC-Q/TOF-MS. Further, under the guidance of Caenorhabditis elegans as olfactory-sensitive model organism, the key differential metabolites in urine were found as biomarkers of radiation-induced injury. ResultsAfter rats were irradiated, the radiation injury urine showed a difference from control (sham-irradiated) urine, which could be distinguished by Caenorhabditis elegans. Based on metabolomics analysis, a total of 21 key differential metabolites with P value ​< ​0.05 and fold change either >2 or <0.5 were identified, which can be used as sensitive and reliable biomarkers of radiation-induced injury. The pathways were further enriched, and it was found that disorders of five metabolic pathways, including citric acid cycle and amino acid metabolism, play an important role in radiation-induced injury. ConclusionsDue to radiation injury, the metabolites in urine will change significantly. The study on biomarkers guided by model organism Caenorhabditis elegans provides a new perspective to explain the details of metabolic disorders, and also provides experimental basis for the development of new biological dosimeters.

Inflammatory response of thymus bystander effects on acute radiation-induced skin injury in rats

Inflammatory response of thymus bystander effects on acute radiation-induced skin injury in rats

Radiation-induced acute injury of intensity-modulated radiotherapy versus three-dimensional conformal radiotherapy in induction chemotherapy followed by concurrent chemoradiotherapy for locoregionally advanced nasopharyngeal carcinoma: a prospective cohort study

To address whether the addition of intensity-modulated radiotherapy (IMRT) compared to three-dimensional conformal radiotherapy (3D-CRT) aggravate radiation-induced acute injury of locoregionally advanced nasopharyngeal carcinoma (LANPC) patients with induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT). We conducted a prospective study of 182 patients in the stage III to IVb with biopsy-proven nonmetastatic LANPC who newly underwent radiotherapy and sequentially received IC, followed by CCRT at our institution. Occurring time of radiation-induced toxicities were estimated and compared using the Kaplan–Meier method and Log-rank test. The most severe acute toxicities included oral mucositis in 97.25% and dermatitis in 90.11%. Subset analysis revealed that Grade 3–4 acute dermatitis were significantly higher in the IMRT than 3D-CRT. Oral mucositis and dermatitis were the earliest occurrence of acute injuries (2 years: 60.44% and 17.58%). Patients in IMRT group achieved significantly lower risk of bone marrow toxicity, but higher risk of leukopenia and gastrointestinal injury. Multivariate analyses also demonstrated that IMRT, female gender and hepatitis were the independent prognostic factors for bone marrow toxicity. In a combined regimen of IC followed by CCRT for the treatment of LANPC, IMRT seems to be an aggressive technique with a trend towards increased gastrointestinal and hematological toxicities, but decreased bone marrow toxicity than those treated with 3D-CRT. This study provides a comprehensive summary of prospective evidence reporting the side effects in the management of LANPC patients. We quantify the occurrence risks of chemoradiotherapy-induced acute injuries through analysis of time-to-event.

Research progress on the prevention and treatment of radiation-induced intestinal injury by the genus Lactobacillus

Acute radiation-induced intestinal injury is the common complication in patients following abdominal and pelvic radiotherapy. However, no effective clinical prevention and treatment interventions are available. As the probiotics and symbiotic bacteria, many species of the genus Lactobacillus are normally present in the gastrointestinal tract and beneficial for the intestinal health. Preclinical studies have reported that the genus Lactobacillus can prevent and treat acute radiation-induced intestinal injury by protecting crypt stem cells, maintaining intestinal barrier and exerting the antioxidant effect, etc. Clinical trials have prompted that oral administration of adequate complex probiotics containing Lactobacillus spp.at one week before radiotherapy contributes to preventing radiation-induced diarrhea. In addition, oral intake of the genus Lactobacillus has the tendency to treat radiation-induced diarrhea and mitigate acute radiation proctitis. At present, no relevant adverse events have been reported. Key words: Genus Lactobacillus; Aacute radiation-induced intestinal injury; Research progress

The Involvement of SDF-1α/CXCR4 Axis in Radiation-Induced Acute Injury and Fibrosis of Skin.

Radiation-induced acute skin injury and consequent fibrosis are common complications of cancer radiotherapy and radiation accidents. Stromal cell-derived factor-1α (SDF-1α) and its receptor, CXC chemokine receptor 4 (CXCR4) have been shown to be involved in multiple cellular events. However, the role of SDF-1α/CXCR4 axis in radiation-induced acute injury and fibrosis of skin has not been reported. In this study, we found that the expression of SDF-1α and CXCR4 was significantly increased in irradiated skin tissues of humans, monkeys and rats, compared to their nonirradiated counterparts. Mice with keratinocyte-specific ablation of CXCR4 showed less severe skin damage than wild-type mice after receiving a 35 Gy dose of radiation. Consistently, subcutaneous injection of AMD3100, an FDA approved SDF-1α/CXCR4 inhibitor, attenuated skin injury and fibrosis induced by exposure to radiation in a rat model. Mechanically, the SDF-1α/CXCR4 axis promotes pro-fibrotic TGF-b/Smad signaling through the PI3K-MAPK signaling cascade in human keratinocyte HaCaT cells and skin fibroblast WS1 cells. AMD3100 inhibited Smad2 nuclear translocation and transcriptional activity of Smad2/3 induced by radiation, which suppressed the pro-fibrotic TGF-b/Smad signaling pathway activated by exposure. Taken together, these findings demonstrate the involvement of SDF-1α/CXCR4 axis in radiation-induced acute injury and fibrosis of skin, and indicate that AMD3100 would be an effective countermeasure against these diseases.

Observation of short-term clinical efficacy and adverse reactions with stereotactic radiotherapy in locally recurrent non-small cell lung cancer

Objective To investigate the short-term clinical efficacy and adverse reactions of stereotactic radiotherapy (SRT) in the treatment of locally recurrent non-small cell lung cancer (NSCLC). Methods Clinical data of 120 cases of recurrent NSCLC after radiotherapy admitted to our hospital from October 2009 to October 2015 were retrospectively analyzed. SRT was adopted for further radiotherapy. The prescription dose was 50% dose curve surrounding the target area. The total dose was 40-50 Gy, with a single dose of 4-5 Gy for 8-12 times. The chest CT was re-examined every 2 months after radiotherapy. The short-term clinical efficacy and adverse reactions were evaluated. The changes of Karnofsky performance score (KPS) and quality of life (QOL) were recorded before and after radiotherapy. Results One patient terminated the radiotherapy due to grade 3 acute radiation-induced pneumonia, 25 patients (21.0%) obtained complete remission (CR), 61 cases (51.3%) of partial remission (PR), 19 cases (16.0%) of stable disease (SD), 14 cases (11.8%) of progress disease (PD), 86 cases (72.3%) of objective remission rate (CR+ PR), and 105 cases (88.2%) of disease control (CR+ PR+ SD), respectively. Thirty-one patients experienced radiation-induced pneumonia, 23 cases of radiation-induced myelosuppression and 1 case of acute radiation-induced heart injury. All these adverse reactions were mitigated after symptomatic treatment. The KPS was significantly increased from 68.16±15.22 before SRT to 78.39±11.50 after SRT (P<0.05). The QOL was considerably elevated from 27.58±5.37 prior to SRT to 38.16±8.39 following SRT (P<0.01). Conclusion SRT is an efficacious and safe treatment of locally recurrent NSCLC, which yields controllable and tolerable adverse reactions and enhances the QOL of patients. Key words: Lung neoplasm, local recurrence/stereotactic radiotherapy; Short-term efficacy; Adverse reaction

An RNA-seq-Based Expression Profiling of Radiation-Induced Esophageal Injury in a Rat Model

Radiation-induced acute injury is the main reason for the suspension of radiotherapy and unsuccessful treatment of cancer. It is of great importance to understand the molecular mechanism of radiation-induced esophageal injury. We used RNA-seq data from normal esophageal tissue and irradiated esophageal tissues and applied computational approaches to identify and characterize differentially expressed genes and detected 40 059 messenger RNAs (mRNAs) previously annotated and 717 novel long noncoding RNAs (lncRNAs). There were 14 upregulated and 32 downregulated lncRNAs among the differentially expressed lncRNA group. Their target genes were involved in the mRNA surveillance pathway, pathological immune responses, and cellular homeostasis. Additionally, we found 853 differentially expressed mRNAs, and there were 384 upregulated and 469 downregulated mRNAs. Notably, we found that the differentially expressed mRNAs were enriched for steroid biosynthesis, the tumor necrosis factor signaling pathway, focal adhesion, pathways in cancer, extracellular matrix–receptor interaction, and so on. The response of normal esophageal tissues to ionizing radiation is multifarious. The radiation-induced cell damage response by multiple pathways followed by pathological immune responses activated. Studies on the dynamic network of molecules involved in radiation-induced esophageal injury are under way to clarify the regulatory mechanisms and identify the candidate targets.

Clinical effect of medical radiation protective ointment compared with trolamine cream to prevent acute radiation-induced skin injury in breast cancer patients undergoing radiotherapy after modified radical mastectomy

Objective To access the clinical effect of medical radiation protective ointment compared with trolamine cream to prevent acute radiation-induced skin injury in breast cancer patients undergoing radiotherapy after modified radical mastectomy. Methods Between February 2017 and February 2018, a total of 120 stage T1-4N1-3M0 eligible patients received intensity modulated radiation therapy were enrolled and matches into two groups: study group (60 cases) was administered medical radiation protective ointment from the first irradiation fraction, and control group (60 cases) received trolamine cream. When 3 grade reaction was observed, patients in control group start to administer medical radiation protective ointment until a month after radiation. Results The occurrence rate of acute breast dermal radiation reaction was 100%.Most patients in study group only underwent 1 grade radiation reaction (82%), while 2 and 3 grade radiation reaction (47% and 13%) in control group were common (P=0.000). Both pruritic degree and pain degree were higher in control group compared with study group (both P=0.000). In study group, the occurrence of 2 grade acute radiation-induced skin injury was obviously later than in control group with significant difference (P=0.000). Patients observed with 3 grade reaction relieved to certain reaction after administering medical radiation protective ointment. Conclusions Medical radiation protective ointment can effectively both alleviate and delay acute radiation-induced skin injury compared with trolamine cream. It also has therapeutic effect on 3 grade radiation reaction. Key words: Breast neoplasms/intensity modulated radiation therapy; Medical radiation protective ointment; Acute radiation-induced skin injury

Captopril attenuates lung inflammation through inhibiting the expression of CCL-2 in rats with acute radiation-induced lung injury

Objective To explore the inhibitory effect of captopril on acute radiation-induced lung injury in rats and the possible mechanism. Methods Sixty-four female Wistar rats were randomly divided into control group, irradiation group, irradiation+ low-dose captopril group, and irradiation+ high-dose captopril group. A single dose of 20 Gy was given to the right lung of all rats except those in the control group to establish a rat model of acute radiation-induced lung injury. These rats were sacrificed at 1, 2, 4, and 8 weeks. HE staining was used to observe the pathological changes in lung tissue; RT-PCR and Western blot were used to measure the mRNA and protein expression of CCL-2 in lung tissue; immunohistochemical assay was used to determine the number of monocytes (CD68) in lung tissue. A one-way analysis of variance was performed. Results Captopril significantly reduced lung inflammation in rats with acute radiation-induced lung injury (P<0.05), inhibited the accumulation of monocytes (CD68) in lung tissue (P<0.05), and decreased the content of CCL-2 in lung tissue (P<0.05). Conclusions For rats with acute radiation-induced lung injury, captopril can reduce the expression of CCL-2 to inhibit the accumulation of monocytes in lung tissue and thus attenuate lung inflammation. Key words: Captopril; Rat; Acute radiation-induced lung injury; Chemoattractant cytokine ligand 2; Macrophage

Effect of single high-dose irradiation on rat hepatic stellate cells, transforming growth factor β, and PI3K/Akt signaling pathway molecule p-Akt (S473)

Objective To investigate the effect of single high-dose irradiation on rat hepatic stellate cells (HSCs), transforming growth factor β(TGF-β), and PI3K/Akt signaling pathway. Methods A total of 40 healthy male Sprague-Dawley rats were randomly divided into model group (30 rats) and control group (10 rats). The rats in the model group were given single 6 MV X-ray irradiation of the right liver at a dose of 30 Gy, and those in the control group were given sham irradiation with the same method. At 3, 5, and 10 days after irradiation, 10 rats in the model group and 3-4 rats in the control group were randomly selected to measure the changes in the serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALP), alkaline phosphatase (ALP), total bilirubin (TB), and direct bilirubin (DB). Hematoxylin-eosin (HE) staining and Masson staining were applied for liver tissues to observe the pathomorphological changes, and immunohistochemistry was used to measure the expression of transforming growth factor-beta 1(TGF-β1), alpha-smooth muscle actin (α-SMA), and p-Akt (S473) in liver tissues. Results At 3, 5, and 10 days after irradiation, the model group showed increases in the serum levels of AST, ALT, ALP, TB, and DB, and had significantly higher serum levels of these indices than the control group. The HE staining and Masson staining showed that compared with the control group, the rats with acute liver injury induced by radiation in the model group had a significant formation of collagen fibers around the hepatic sinusoids. Immunohistochemistry showed that with the prolonged time after irradiation, the expression of TGF-β1, α-SMA, and p-Akt (S473) was gradually enhanced after irradiation, and IPP analysis showed significant differences between the two groups (P<0.000). Conclusions During the process of acute radiation-induced liver injury induced by single high-dose irradiation, with the activation of HSCs, the secretion of TGF-β1 is increased and the PI3K/Akt signaling pathway is activated. Key words: Radiation induced liv er injury; Transforming growth factor beta; Hepatic stellate cells; Signal pathway

Factors related to severe acute radiation-induced lung injury caused by IMRT for nonsmall cell lung cancer

Factors related to severe acute radiation-induced lung injury caused by IMRT for nonsmall cell lung cancer

Study of quantitative analysis of contrast-enhanced ultrasonic technique in acute radiation-induced liver injury

Objective To evaluate early diagnostic value of quantitative analysis of contrast-enhanced ultrasound (CEUS) in acute radiation-induced liver injury. Methods Sixty female rats were divided into two groups: 50 rats in an experimental group (model group) and 10 rats in a negative control group. The rats in model group were radiated with stereotactic single dose of 20Gy on their liver to establish acute radiation-induced liver injury models. Each 10 rats from model groups and 2 rats from control group were randomly selected and underwent CEUS and histopathological examination on the 3, 7, 14, 21, 28 days after radiation. The degree of injury was classified into four groups according to pathological grading: non-injured group, mild injured group, moderated injured group and severe injured group. The dynamic images of CEUS were off-line analysis and the parameters of arrival time of contrast agent to hepatic artery (HAAT), the arrival time of contrast agent to hepatic vein (HVAT), and the transit time of hepatic artery-hepatic vein (HA-HVTT) were recorded. Time intensity curve (TIC) of liver parenchyma drawn by the software of quantitative analysis was used to obtain quantitative parameters including time to peak (TTP) and peak intensity (PI). Results Along with the severity degree of radiation-induced liver injury, the quantitative parameters, PI decreased while TTP extended. PI of mild injured group, moderated injured group and severe injured group were lower than that of non-injured group (P<0.05). TTP of the three liver injuried groups was higher than non-injured group ( P<0.05). The quantitative parameters HA-HVTT of moderated injured group and severe injured group were decreased than the non-injured group (P<0.05), whereas the difference between mild injured group and non-injured group was not significant. Conclusions Quantitative analysis of CEUS can provide a certain value for early diagnosis in acute radiation-induced liver injury. Key words: Ultrasonography; Microbubbles; Radiation-induced liver injury

Protective effect of paeoniflorin in rats with acute liver injury

Objective Investigate the Protective effect of paeoniflorin in rats with acute liver injury. Methods Male SD rats were randomly divided into normal group, model group, paeoniflorin in small, middle and high dose group （20 mg/kg, 40 mg/kg, 80 mg/kg）, paeony glycoside group （50 mg/kg）. Except normal group, the rest of groups were irradiated fractionally by VARIN 21-EX linear accelerator at right liver, The paeoniflorin group and paeony glycoside group were lavaged everyday after irradiation for corresponding drugs and doses. Normal group and model group give equal volume normal saline everyday. All rats were killed on 2nd and 4th weekend. Measure rats serum AST, ALT, hepatic tissue GSH, SOD, and HE staining score. Results The rats in model group liver tissue HE staining scores increased to（2.25±0.53）on 2nd weekend, The serum levels of AST, ALT increased to（112.83±19.20）U/L, （80±21.97）U/L, it significantly increased Compared with the normal group（63.06±7.15）U/L, （42.30±4.45）U/L, P〈0.01. The liver GSH contents of paeoniflorin in each dosage groups rats were（60.89±8.43）U/mg, （67.84±9.05）U/mg, （71.92±8.11）U/mg on 2 nd weekend, Compared with the model group（37.32±11.25）U/mg, （90.54±12.12）U/mg, P〈0.05或〈0.01. Conclusions The irradiated rats go into acute liver injury on 2nd weekend, paeoniflorin has protective effect on acute liver injury in rats. Key words: Acute radiation-induced liver injury; Paeoniflorin; Rat; Protective effect

Adenovirus-Mediated Bcl-Xl Gene Therapy Combined with Pronase Treatment Protects the Small Intestine from Radiation-Induced Enteritis in Mouse Model

Intestinal injury is a major side effect of radiation treatment for many malignancies. The present study investigated whether transducing Bcl-xL, a potent anti-apoptotic gene, into intestinal epithelial cells would exert protective effects against radiation-induced acute injuries. Methods: Adenoviral vectors containing the human Bcl-xL gene (AxCABclxL) or β-galactosidase gene (AxCAlacZ) driven by the CAG promoter were generated. To increase transduction efficiency into the mucosal epithelium, the intraluminal space of the small intestine of mice was washed with buffered-saline and mucus components were digested with Pronase MS®. Gene transduction was performed by injecting 2×108 pfu adenoviral vector into the pre-treated small intestine. Transduction efficiency was examined by X-gal staining 24 hours after AxCAlacZ infection. Radiation-induced acute injury of the small intestine was induced by whole body irradiation (15 Gy) performed 24 hours after adenoviral vector infection. Apoptotic epithelial cells were visualized by TUNEL assay. Morphological analysis was assessed by histological examination. Results: Successful transduction after Pronase MS® treatment was achieved in the basal crypt epithelial cells in the ileum, thought to be the location of stem cells, as determined by X-gal staining. The AxCABclxL group demonstrated significantly fewer radiation-induced apoptotic mucosal epithelial cells when compared with the other two groups at 6 hours after irradiation (p<0.05). At 72 hours after irradiation, the morphological appearance of the small intestine in the AxCABclxL group showed significantly less radiation damage in terms of mucosal thickness (p<0.001). Conclusions: The present study indicates that Bcl-xL gene expression using adenoviral vector-mediated transduction is a valuable approach to prevent intestinal injury caused by radiation exposure.

Basic Fibroblast Growth Factor Suppresses Radiation-Induced Apoptosis and TP53 Pathway in Rat Small Intestine

The effect of basic fibroblast growth factor (bFGF) was studied in radiation-induced apoptosis in rat jejunal crypt cells. Six-week-old male Wistar rats were administered 4 mg/kg bFGF intraperitoneally 25 h before receiving 8 Gy whole-body X rays. The jejunum was removed for analysis from time 0 to 120 h after irradiation. Villus length in control rats declined steadily until 72 h, while in bFGF-treated rats the villi were longer than in the controls until 48 h. Crypt lengths were similar to villi. bFGF treatment increased Ki-67-positive cells in the jejunal crypt at 0, 24 and 48 h. The treatment with bFGF reduced the number of apoptotic cells per jejunal crypt to 23% and 10% of the control values at 3 and 6 h, respectively, and increased numbers of mitotic cells significantly at 48 and 72 h. bFGF decreased the levels of TP53, CDKN1A, Puma and Cleaved caspase 3 at 3 h as detected by Western blot analyses. Our results suggest that bFGF protected against acute radiation-induced injury by suppressing the crypt apoptotic cells including the stem cells and promoted crypt cell proliferation. The inhibition of apoptosis thus might be related to suppression of the TP53 pathway.

834. Protective Effect of Bcl-XL Gene Expression on the Radiation-Induced Acute Intestinal Injuries

Top of pageAbstract [Background] Intestinal injuries represent a major dose-limiting side effect of radiation treatment for many malignancies. Recent studies have demonstrated that mitochondrial damages occurred in the mucosal epithelial cells and subsequent release of cytochrome c from the damaged mitochondria resulting in apoptotic changes, are mainly involved in this type of injuries. The present study was designed to determine if transducing a Bcl-XL gene, a potent anti- apoptotic gene, to the epithelial cells could provide protective effects on the radiation-induced acute injuries of the small intestine. [Methods] C57Bl/6 mice were used in this study. Adenoviral vectors containing the human Bcl-XL gene (Ad-Bcl-XL) or ?-galactosidase gene (Ad-LacZ) driven by CAG promoter were generated. In order to increase the transduction efficiency to the mucosal epithelium, especially to the intestinal crypts, we first washed the intraluminal space of the small intestine with PBS and digested mucus components with pronase. Adenoviral vector infections were performed by injecting 2x10(8) pfu adenoviral vectors into 2cm portion of the pronase-treated small intestine that had been transiently clamped on both side. These clamps were removed 30 min after the vector infusion. Transduction efficiencies of the mucosal epithelial cells were examined by X-gal staining 24 hours after Ad-LacZ infection. Radiation-induced acute injuries of the small intestine were introduced by whole body irradiation (15 Gy) performed 24 hours after the adenoviral vector infection. Six hours after the radiation, apoptotic epithelial cells were visualized by TUNEL assay. Seventy-two hours after the radiation, morphological appearance of the small intestines was assessed by histological examination. [Results] With the method for adenoviral vector infection developed herein, successful transfection could be achieved to the intestinal mucosa determined by X-gal staining. When we irradiated to the mice after the vector infection, Ad-Bcl-XL group demonstrated significantly lower number of radiation-induced apoptotic mucosal epithelial cells compared with the other two control groups examined 6 hours after the irradiation (P<0.05). At 72 hours after the irradiation, morphological appearance of the small intestine of the Ad-Bcl-XL group showed significant prevention from the irradiation damages in terms of the mucosal thickness (P<0.001) compared with control groups. [Conclusion] The present study demonstrates in principle that Bcl-XL gene expression using adenoviral vector-mediated transfection could be a valuable approach in protecting intestinal injuries from ionizing radiation.