Near-infrared Nrf2 activator IR-61 dye alleviates radiation-induced lung injury

Abstract

Oxidative stress injury and subsequent inflammatory response are considered to play critical roles in radiation-induced lung injury (RILI). Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor that regulates oxidative stress response and represses inflammation, but its therapeutic value in RILI remains elusive. Our previous studies have shown that the near-infrared (NIR) IR-61 dye evokes intracellular antioxidant defense by enhancing Nrf2 signaling and promoting anti-inflammatory effects. We established a model of RILI in mice exposed to whole-thoracic irradiation. The results showed that IR-61 treatment notably improved pulmonary functions by decreasing lung density and diminishing airway resistance. In addition, IR-61 significantly ameliorated radiation-induced inflammatory cell infiltration and proinflammatory cytokine (IL-1β, IL-6, and TNF-α) release, thereby mitigating inflammatory response. Furthermore, IR-61 mitigated radiation-induced lung fibrosis by decreasing the collagen deposition and the levels of fibrogenesis-related factors (collagen I, collagen III, α-SMA, and fibronectin). More importantly, IR-61 was found to accumulate in the mitochondria of macrophages in irradiated lung tissues. Therefore, the functions of IR-61 in macrophages were further studied in irradiated macrophage cell lines, MH-s and RAW 264.7 in vitro. The results indicated that IR-61 upregulated the expression of Nrf2 and heme oxygenase-1 (HO-1) and decreased the levels of reactive oxygen species (ROS) and pro-inflammatory cytokines (IL-1β and IL-6) in macrophages after radiation. In summary, our study suggests that IR-61 effectively mitigates RILI by activating Nrf2 signaling in irradiated lung tissues. In particular, Nrf2-mediated anti-inflammatory and antioxidant effects in irradiated lung tissue macrophages play critical roles in protecting against RILI.

Keywords:

• IR-61
• radiation-induced lung injury
• macrophages
• oxidative stress
• Nrf2

Author contributions

CMS designed this study and supported funding. JCZ and Yang Wang designed and performed the experiments, analyzed the data, and wrote the manuscript. WCC, ML, CZ, FW, and WY provided support in the animal studies. LC, ZYY, and Yu Wang provision of study materials. ZWW and YWW reviewed and revised the manuscript. All authors read and approved the final manuscript.

Disclosure statement

All the authors have no financial conflict of interest to disclose. The authors are responsible for the content and writing of the article.

Additional information

Funding

This work was supported by the Key Program of the National Natural Science Foundation of China (82030056) and the Intramural Research Project Grants (2021-JCJQ-ZD-077-11, AWS17J007, and 2018-JCJQ-ZQ-001).