Protective effects of febuxostat against paraquat- induced lung toxicity in rats: Impact on RAGE/PI3K/Akt pathway and downstream inflammatory cascades

Aims: The herbicide paraquat causes fatal lung toxicity by induction of xanthine oxidase, production of free radicals and inflammation. Febuxostat, a xanthine oxidase inhibitor and anti-gout has recently shown anti-inflammatory activity. Accordingly, this study was carried out to investigate whether febuxostat may attenuate paraquat-induced lung toxicity and to explore the possible underlying mechanisms. Main methods: Rats were administered either vehicle, a single dose of paraquat (30 mg/kg, i.p.), febuxostat (15 mg/kg, oral), or both for 14 successive days. Serum LDH and sRAGE were estimated. Lung tissue xanthine oxidase activity, SOD, TAC, MDA, and RAGE, HMGB1 gene expression, PI3K/Akt and beta-catenin protein expression, MMP-9, IL-8, VEGF and COX-2 gene expression were estimated. Key findings: Results showed that paraquat induced lung injury characterized by enhanced oxidative stress and inflammation, upregulated RAGE, HMGB1 gene expression, PI3K/Akt and beta-catenin protein expression. Administration of febuxostat inhibited the deleterious effects of paraquat on lung through inhibition of xanthine oxidase activity and related oxidative stress, downregulation of RAGE/PI3K/Akt pathway, and suppression of beta-catenin protein expression and its downstream inflammatory mediators. Significance: The present study showed that febuxostat may abrogate paraquat-induced lung toxicity and demonstrated a novel mechanism for its ameliorative effects.