Quercetin-3-Rutinoside alleviates radiation-induced lung inflammation and fibrosis via regulation of NF-κB/TGF-β1 signaling.

BACKGROUND

Radiation exposure to lungs during nuclear catastrophes or radiotherapy poses long-term side effects and can induce pulmonary injury sufficient for causing death. The strategies for preventing or reversing radiation-induced lung injuries have not been yet developed. Quercetin-3-Rutinoside (Q-3-R), a polyphenolic bioflavonoid, has shown multifaceted pharmacological applications due to its high antioxidant and anti-inflammatory properties.

PURPOSE: In the current study, the potential of Q-3-R against radiation-induced lung pneumonitis/fibrosis and the possible underlying mechanism was investigated.

STUDY

DESIGN

To evaluate the effect of Q-3-R against lung damage, C57Bl/6 mice were administered with Q-3-R (10 mg/kg b.wt.) and irradiated with a single dose of gamma radiation (12 Gy) at thoracic region.

METHODS

16 weeks after irradiation lung damage was seen by histopathological studies and staining for collagen deposition. Expression of Nuclear factor kappa-B (NF-κB), transforming growth factor-β1 (TGF-β1), Smad3, intercellular adhesion molecule 1 (ICAM-1), α-smooth muscle actin protein (α-SMA), Aquaporin 5 (AQP 5), Interleukins (IL-6, IL-18, IL-1β), tumor necrosis factor-α (TNF-α) and caspase-3 was evaluated by immunohistochemistry/western blot/Elisa. Reactive oxygen species (ROS)/ Nitric oxide (NO) scavenging potential of Q-3-R and inhibition of cell death in irradiated lungs were also assessed.

RESULTS

Mice showed signs of pneumonitis and fibrotic changes in lungs following radiation treatment. A dramatic increase in inflammatory cells and cytokines contributing to lung disease pathogenesis was observed. Furthermore, expression of NF-κB, TGF-β1, Smad3, ICAM-1, AQP5and α-SMA was found markedly up-regulated. However, pretreatment of Q-3-R significantly attenuated radiation-induced pneumonitis and fibrosis. Histological examination revealed less structural and fibrotic changes with down-regulation of AQP 5, ICAM-1, α-SMA and caspase-3 in Q-3-R pretreated irradiated groups. The formulation significantly relieved lung injury by suppressing inflammatory and pro-fibrotic cytokines such as IL-6, IL-18, IL-1β, TNF-α and TGF-β1 via inhibition of NF-κB. Q-3-R also curtailed radiation-induced ROS/NO generation and minimized DNA damage in the irradiated lungs.

CONCLUSION

The findings from the current study clearly demonstrate that Q-3-R provides radioprotection to the lungs by regulating NF-κB/TGF-β1 signaling, scavenging free radicals, preventing perivascular infiltration and prolonged inflammatory cascade which could otherwise lead to chronic radiation fibrosis. Q-3-R can be proved as a potential therapeutic agent for alleviating radiation-induced lung injury in case of planned or unplanned radiation exposure scenario.