LAUSR

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 &bgr;‐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 &bgr;‐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 &bgr;‐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.