Unilateral Fractionated Thoracic Irradiation Induces Abscopal Injury in Contralateral Lung through NF-κB Pathway

Radiotherapy may cause acute and late damage to off-target abscopal tissues, and the underlying signaling factors need further exploration. This study aimed to investigate whether local irradiation could induce damage in non-irradiated abscopal lung tissues using a murine model subjected to fractionated irradiation (8 Gy per fraction over three days) targeted to the right lung. It was found that unilateral fractionated thoracic irradiation could induce progressive tissue injury in the contralateral lung. The exclusion of scattered radiation as a contributor to the observed structural injury and acute DNA damage was confirmed. Notably, unilateral fractionated thoracic irradiation increased macrophages with NF-κB activation. Therapeutic inhibition of NF-κB, as well as administration of cimetidine, markedly mitigated radiation-induced pneumonitis and fibrosis in the contralateral lung. These results demonstrate that abscopal lung injury following unilateral irradiation may be driven by increased macrophages, offering novel mechanistic insight and a potential treatment for lung injury associated with thoracic radiotherapy.