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-Kappa B), transforming growth factor-beta 1 (TGF-beta 1), Smad3, intercellular adhesion molecule 1 (ICAM-1), alpha-smooth muscle actin protein (alpha-SMA), Aquaporin 5 (AQP 5), In-terleukins (IL-6, IL-18, IL-1 beta), tumor necrosis factor-alpha (TNF-alpha) and caspase-3 was evaluated by immunohisto-chemistry/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 dra-matic increase in inflammatory cells and cytokines contributing to lung disease pathogenesis was observed. Furthermore, expression of NF-Kappa B, TGF-beta 1, Smad3, ICAM-1, AQP5and alpha-SMA was found markedly up-regulated. However, pretreatment of Q-3-R significantly attenuated radiation-induced pneumonitis and fibrosis. Histolog-ical examination revealed less structural and fibrotic changes with down-regulation of AQP 5, ICAM-1, alpha-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-1 beta, TNF-alpha and TGF-beta 1 via inhibition of NF-Kappa B. Q-3-R also curtailed radiation-induced ROS/NO generation and minimized DNA damage in the irra-diated lungs.Conclusion: The findings from the current study clearly demonstrate that Q-3-R provides radioprotection to the lungs by regulating NF-Kappa B/TGF-beta 1 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.