Epigallocatechin gallate potentially abrogates fluoride induced lung oxidative stress, inflammation via Nrf2/Keap1 signaling pathway in rats: An in-vivo and in-silico study

• Fluoride intoxication promotes oxidative stress, inflammation and apoptosis which resulted pulmonary toxicity
• Oxidative damage to macromolecules and depleted antioxidant status has been linked with Fl – induced oxidative stress
• EGCG strongly abrogates Fl induced free radicals via Nrf2/Keap1 signaling pathway.
• EGCG pre-treatment aids in normalizing the lung physiological architecture which were altered by Fl.
• In vivo and Insilco study evidences the Nrf2/Keap-1 activation by EGCG in Fl intoxicated rats.

BackgroundSince this Nrf2-dependent cellular defense response is able to protect multi-organs, including cancer, neurodegenerative diseases, cardiovascular diseases, inflammation and chronic lung injury. The antioxidant and anti-inflammatory potential of Epigallocatechin gallate (EGCG) and Nrf2/Keap1 signaling mechanisms in pulmonary toxicity have not been clarified. In the present study, we demonstrated that protective efficacy of EGCG against fluoride (Fl) induced oxidative stress mediated lung injury in rats.MethodsThe animals were divided in to four groups. Group 1: Control rats received normal saline; Group 2 rats received EGCG (40 mg/kg/bw) alone for four weeks; Group 3 rats received Fl (25 mg/kg/bw) alone for four weeks, Group 4 rats received EGCG (90 min before administration) along with Fl for four weeks.ResultsOral administration of Fl (25 mg/kg/bw) significantly (p < 0.05) increased the ROS, inflammatory cytokines, lung edema, melonaldehyde (MDA) and myeloperoxidase (MPO) in rats. In addition, upon administration of Fl significantly (p < 0.05) decreased the antioxidant status, Nrf2, and HO-1 with increased Keap1 protein. Histological and immunohistochemical (iNOS) study also revealed the Fl induced significant (p < 0.05) changes in the lung tissue of rats. Pre-administration of EGCG significantly (p < 0.05) improved the antioxidant status, and inhibited the oxidative stress, inflammatory cytokines, and Keap1 protein via the activation of Nrf2 translocation in to the nucleus. Moreover, the molecular docking studies also support the antioxidant potential of EGCG and Nrf2 activation.ConclusionTaken together, our data indicate that EGCG potentially abrogates Fl induced oxidative lung injury by activation of the Nrf2/Keap1 pathway in rats.

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