Protective Effects of Naringenin on 5-Fluorouracil Induced Pulmonary Toxicity Via Modulation of NF-κB and Nrf2 Pathway

5-Fluouracil (FU) is an anti -cancer drug, most commonly used to treat solid malignancies across the globe, and Naringenin (NG) is a natural flavonoid with antioxidant properties. The present study was conducted on rats, which were divided into four groups to estimate the ameliorative effect of NG (100 mg/kg BW/day for 28 days- Group -3) against 5 -FU -induced pulmonary toxicity (20 mg/kg BW/dayGroup-2 for first 5 days). Group -1 rats were treated with normal saline, whereas group -4 rats were treated with the combination of both NG + 5 -FU with same above protocol. During the subsequent period, six rats were sacrificed from each group on the 14 th and 28 th day of the experiment. Lung tissues were collected for various analyses like antioxidants profile, cytokine profile, histopathology, immunohistochemical and ultrastructure pathology. 5 -FU -induced toxicity was characterized by a significant (p<0.05) increase in TBARS in group 2, along with a significant (p<0.05) reduction in GSH and SOD concentration on the 14 th and 28 th day of the experiment. Whereas, the combination group showed a significant decrease in thiobarbituric acid reactive substrate (TBARS) and increased GSH and SOD levels. Further, a significant (p<0.05) increase in pro -inflammatory cytokines (TNF-alpha, IL -6, TGF-beta and IL -1 beta) along with a considerable (p<0.05) lower level of IL -10 was observed in group 2 rats and significant improvement in all the parameters were observed in group -4 rats. In addition, on histopathological examination (HP), severe lung damage was observed along with oedema and mild fibrous tissue proliferation were noted which was further supported by scanning electron microscopy. Immunostaining of lung sections revealed strong positivity for NF -kappa B, COX -2 and TNF-alpha expressions. However, treatment with NG exhibited a moderate decrease in the intensity of tissue damage observed in group 4 rats compared to group 2 rats. Overall, the intensity of toxicity was more evident on 28 th day than 14 th day in group 2 rats and a notable improvement in NG treatment of group -4 rats. Based on results, we suggested that NG had protective effects in ameliorating 5 -FU -induced pulmonary toxicity.