A unique radioprotective effect of resolvin E1 reduces irradiation-induced damage to the inner ear by inhibiting the inflammatory response

Abstract

Background: In addition to the direct effects of irradiation, the induced inflammatory response may play an important role in the damage to the inner ear caused by radiotherapy for the treatment of head and neck cancers. Resolvin E1 (RvE1) has anti-inflammatory activity, acting by reducing neutrophil infiltration and proinflammatory cytokine expression. Therefore, in this study we sought to confirm whether the inflammation induced by irradiation was involved in damage to the inner ear after radiotherapy and to investigate the protective effect and underlying mechanism of RvE1 using mouse models. Methods: A dose of RvE1 was delivered by intraperitoneal injection to mice before irradiation. Changes in the auditory brainstem response (ABR), relative balance ability, inner ear morphology and the expression levels of inflammatory factors in the inner ear were analyzed on days 7 and 14 after irradiation and compared among different experimental groups. Results: Changes of ABR and relative balance ability showed the inner functions of experimental mice presented severe damage after irradiation, but the damage was significantly alleviated after RvE1 pretreatment compared to irradiation alone. Morphological analysis of the inner ear showed severe damage to the cochlea and vestibule after irradiation. In contrast, damage to the cochlea and vestibule was significantly reduced in the RvE1-pretreated group compared to that in the irradiation alone group. Along with these functional and morphological changes, the mRNA expression level of anti-inflammatory factors interleukin-2 was significantly increased, while those of proinflammatory factors interleukin-6 and tumor necrosis factor-α were significantly decreased in the inner ear of mice after RvE1 pretreatment compared to irradiation alone. Conclusions: We believe that inflammation induced by irradiation is involved in the damage to the inner ear caused by radiotherapy, and that RvE1 reduces the damage caused by irradiation to the inner ear by regulating the induced inflammatory response.

Radiation-induced NF-κB activation is involved in cochlear damage in mice via promotion of a local inflammatory response

“…The thickness of the lead block was 10 cm, and the radiometric rate was 400 cGy/min. All of these radiation procedures were the same as used in our previous studies [ 7 ].…”

“…A dose of 20 Gy was selected to irradiate the inner ear from both sides in one fraction. This dose was determined according to the results of the previous animal experiment, and ensured robust survival of all experimental mice along with observable hearing loss and detectable morphological damage to the cochlea, which could be observed via auditory brainstem response, hematoxylin & eosin (H&E) staining and scanning electron microscopy (SEM) [ 7 ].…”

“…For a long time, the radiation dose to the inner ear was considered to be responsible for the damage to the cochlea and SNHL [ 4 ]. However some studies have reported that the inflammatory response induced by radiation can cause apoptosis of hair cells of the inner ear [ 5 ], and a large number of inflammatory cells appear in the inner ear of irradiated experimental animals [ 6 , 7 ]. Our previous experimental study of mice found the proinflammatory resolution mediator Resolvin E1 obviously ameliorated post-radiation damage to the cochlear hair cells [ 7 ].…”

“…However some studies have reported that the inflammatory response induced by radiation can cause apoptosis of hair cells of the inner ear [ 5 ], and a large number of inflammatory cells appear in the inner ear of irradiated experimental animals [ 6 , 7 ]. Our previous experimental study of mice found the proinflammatory resolution mediator Resolvin E1 obviously ameliorated post-radiation damage to the cochlear hair cells [ 7 ]. The research indicated that inflammation induced by radiation was involved in damage to the cochlea and SNHL in addition to the direct effects of the radiation.…”

“…Based on a previous report that the inflammatory response induced by radiation is involved in damage to the cochlea [ 7 ], and the central role of NF-κB in the inflammatory response and disease [ 8–11 ], we had reasons to believe that radiation-induced NF-κB activation may be involved in damage to the cochlea. Thus we designed this animal experiment to explore the regulatory effects of radiation-induced NF-κB activation in damage to the cochlea and to provide an experimental foundation for cochlear protection during radiotherapy for head and neck cancer.…”