Abstract
Radiation‐induced lung injury (RILI) is the major complication of thoracic radiation therapy, and no effective treatment is available. This study explored the role of high‐mobility group box 1 (HMGB1) in acute RILI and the therapeutic effect of glycyrrhizin, an inhibitor of HMGB1, on RILI. C57BL/6 mice received a 20 Gy dose of X‐ray radiation to the whole thorax with or without administration of glycyrrhizin. Severe lung inflammation was present 12 weeks after irradiation, although only a mild change was noted at 2 weeks and could be alleviated by administration of glycyrrhizin. Glycyrrhizin decreased the plasma concentrations of HMGB1 and sRAGE as well as TNF‐α, IL‐1β and IL‐6 levels in the bronchoalveolar lavage fluid (BALF). The expression of RAGE was decreased while that of TLR4 was significantly increased at 12 weeks, but not 2 weeks, after irradiation in mouse lung tissue. In vitro, the expression of TLR4 increased in RAW 264.7 cells after conditioning with the supernatant from the irradiated MLE‐12 cells containing HMGB1 but showed no change when conditioned medium without HMGB1 was used. However, conditioned culture had no effect on RAGE expression in RAW 264.7 cells. Glycyrrhizin also inhibited the related downstream transcription factors of HMGB/TLR4, such as NF‐κB, JNK and ERK1/2, in lung tissue and RAW 264.7 cells when TLR4 was activated. In conclusion, the HMGB1/TLR4 pathway mediates RILI and can be mitigated by glycyrrhizin.
Highlights
Despite the progress in modern radiotherapy techniques, radiation‐ induced lung injury (RILI) remains the main complication of radiother‐ apy for thoracic malignancies.[1]
High‐mobility group box 1 (HMGB1) is a DNA molecular chaper‐ one that is constitutively expressed in the cell nucleus and serves as a damage‐associated molecular pattern (DAMP) when it is released into the extracellular space.[7]
Many transcription factors are involved in the high‐mobility group box 1 (HMGB1)/TLR4 signalling pathway; we examined the expression of NF‐κB, JNK and ERK1/2 in vivo and in vitro when TLR4 was activated
Summary
Despite the progress in modern radiotherapy techniques, radiation‐ induced lung injury (RILI) remains the main complication of radiother‐ apy for thoracic malignancies.[1]. High‐mobility group box 1 (HMGB1) is a DNA molecular chaper‐ one that is constitutively expressed in the cell nucleus and serves as a damage‐associated molecular pattern (DAMP) when it is released into the extracellular space.[7] DAMPs, similar to pathogen‐associated mo‐ lecular patterns (PAMPs), can activate the immune system by binding to pattern recognition receptors (PRRs).[8] HMGB1 was first identified as a late mediator in a sepsis model[9] and is thought to play a vital role in many diseases.[10] An increasing number of reports have con‐ firmed the functions of HMGB1 in infectious and sterile inflammation, and many therapies targeting HMGB1 have been developed.[11,12] Some studies reported that radiation could lead to HMGB1 translocation and release, but its role in RILI has not been explicitly revealed.[13,14]. To explore the role of HMGB1 in the development of RILI and the radioprotective mechanism of GL, we performed studies and tried to find whether GL can mitigate RILI by inhibiting the HMGB1/TLR4 signalling pathway
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