Amelioration of radiation-induced skin injury by adenovirus-mediated heme oxygenase-1 (HO-1) overexpression in rats

Radiation Oncology, Jan 2012

Objective Radiation-induced skin injury remains a serious concern for radiation therapy. Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme catabolism, has been reported to have potential antioxidant and anti-apoptotic properties. However, the role of HO-1 in radiation-induced skin damage remains unclear. This study aims to elucidate the effects of HO-1 on radiation-induced skin injury in rats. Methods A control adenovirus (Ad-EGFP) and a recombinant adenovirus (Ad-HO1-EGFP) were constructed. Rats were irradiated to the buttock skin with a single dose of 45 Gy followed by a subcutaneous injection of PBS, 5 × 109 genomic copies of Ad-EGFP or Ad-HO1-EGFP (n = 8). After treatment, the skin MDA concentration, SOD activity and apoptosis were measured. The expression of antioxidant and pro-apoptotic genes was determined by RT-PCR and real-time PCR. Skin reactions were measured at regular intervals using the semi-quantitative skin injury score. Results Subcutaneous injection of Ad-HO1-EGFP infected both epidermal and dermal cells and could spread to the surrounding regions. Radiation exposure upregulated the transcription of the antioxidant enzyme genes, including SOD-1, GPx2 and endogenous HO-1. HO-1 overexpression decreased lipid peroxidation and inhibited the induction of ROS scavenging proteins. Moreover, HO-1 exerted an anti-apoptotic effect by suppressing FAS and FASL expression. Subcutaneous injection of Ad-HO1-EGFP demonstrated significant improvement in radiation-induced skin injury. Conclusions The present study provides evidences for the protective role of HO-1 in alleviating radiation-induced skin damage in rats, which is helpful for the development of therapy for radiation-induced skin injury.

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Amelioration of radiation-induced skin injury by adenovirus-mediated heme oxygenase-1 (HO-1) overexpression in rats

Shuyu Zhang 1 2 3 Chuanjun Song 0 Jundong Zhou 0 2 Ling Xie 0 Xingjun Meng 0 Pengfei Liu 4 Jianping Cao 2 Xueguang Zhang 1 2 Wei-Qun Ding 3 Jinchang Wu 0 0 The Core Laboratory of Suzhou Cancer Center and Department of Radiotherapy of Suzhou Hospital Affiliated to Nanjing Medical University , Suzhou 215001 , China 1 Cultivation base of State Key Laboratory of Stem Cell and Biomaterials built together by Ministry of Science and Technology and Jiangsu Province, Soochow University , Suzhou 215006 , China 2 School of Radiation Medicine and Protection, Medical College of Soochow University , Suzhou 215123 , China 3 Department of Pathology, University of Oklahoma Health Sciences Center , Oklahoma City, 73104 , USA 4 Department of Gastroenterology, the Affiliated Jiangyin Hospital of Southeast University , Jiangyin 214400 , China - Amelioration of radiation-induced skin injury by adenovirus-mediated heme oxygenase-1 (HO-1) overexpression in rats Zhang et al. Open Access Amelioration of radiation-induced skin injury by adenovirus-mediated heme oxygenase-1 (HO-1) overexpression in rats Objective: Radiation-induced skin injury remains a serious concern for radiation therapy. Heme oxygenase-1 (HO1), the rate-limiting enzyme in heme catabolism, has been reported to have potential antioxidant and antiapoptotic properties. However, the role of HO-1 in radiation-induced skin damage remains unclear. This study aims to elucidate the effects of HO-1 on radiation-induced skin injury in rats. Methods: A control adenovirus (Ad-EGFP) and a recombinant adenovirus (Ad-HO1-EGFP) were constructed. Rats were irradiated to the buttock skin with a single dose of 45 Gy followed by a subcutaneous injection of PBS, 5 109 genomic copies of Ad-EGFP or Ad-HO1-EGFP (n = 8). After treatment, the skin MDA concentration, SOD activity and apoptosis were measured. The expression of antioxidant and pro-apoptotic genes was determined by RT-PCR and real-time PCR. Skin reactions were measured at regular intervals using the semi-quantitative skin injury score. Results: Subcutaneous injection of Ad-HO1-EGFP infected both epidermal and dermal cells and could spread to the surrounding regions. Radiation exposure upregulated the transcription of the antioxidant enzyme genes, including SOD-1, GPx2 and endogenous HO-1. HO-1 overexpression decreased lipid peroxidation and inhibited the induction of ROS scavenging proteins. Moreover, HO-1 exerted an anti-apoptotic effect by suppressing FAS and FASL expression. Subcutaneous injection of Ad-HO1-EGFP demonstrated significant improvement in radiationinduced skin injury. Conclusions: The present study provides evidences for the protective role of HO-1 in alleviating radiation-induced skin damage in rats, which is helpful for the development of therapy for radiation-induced skin injury. Introduction Radiotherapy offers valuable alternatives to primary surgical approaches for cancer patients. Despite being a useful modality for cancer therapy, ionizing radiation may injure surrounding normal tissues [1,2]. Although the skin is not the primary target, it may be significantly injured and its function profoundly impaired during radiation therapy [3,4]. While increased efforts have led to new treatment schedules that are designed to maximize antineoplastic effects and minimize skin toxicity, radiation-induced skin injury remains a serious concern, which may limit the duration of radiation and the dose delivered. In addition, nuclear accidents are another cause of such skin reactions [5,6]. Thus, the management of radiation-induced skin damage is critical for effective radiation therapy. During radiation exposure, skin tissue damage occurs instantaneously, mediated by a burst of free radicals. Irradiated cells produce reactive oxygen species (ROS), including oxygen ions, free radicals, and peroxides. The detrimental ROS can further result in damages to nuclear DNA and alterations of proteins, lipids, and carbohydrates [7]. In response to ionizing radiation exposure, signal transduction pathways, transcription factors, DNA repair enzymes and antioxidant enzymes are activated. Many of these signaling and gene expression pathways are involved in intracellular metabolic redox reactions to buffer the ROS [8]. Meanwhile, inflammatory cells are recruited and fibrogenesis and angiogenesis are initiated. High-dose ionizing radiation finally culminates in cutaneous cell death and profound impairment of skin function [4]. Heme oxygenases (HO) are microsomal enzymes that catalyse the heme ring into carbon monoxide (CO), free iron and biliverdin. Biliverdin is rapidly converted to bilirubin by biliverdin reductase. CO and bilirubin have been well described as having antioxidant and antiinflammatory properties [9,10]. The HO family consists of three homologous isoenzymes, an inducible HO-1, a constitutive HO-2 and an HO-3 with low enzymatic activity [11]. HO-1 is also known as heat shock protein 32 (HSP32), which is strongly (...truncated)


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Shuyu Zhang, Chuanjun Song, Jundong Zhou, Ling Xie, Xingjun Meng, Pengfei Liu, Jianping Cao, Xueguang Zhang, Wei-Qun Ding, Jinchang Wu. Amelioration of radiation-induced skin injury by adenovirus-mediated heme oxygenase-1 (HO-1) overexpression in rats, Radiation Oncology, 2012, pp. 4, 7, DOI: 10.1186/1748-717X-7-4