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)