Intonation of Nrf2 and Hif1-α pathway by curcumin prophylaxis: A potential strategy to augment survival signaling under hypoxia

Abstract

Background: Pulmonary surfactant oxidation leads to alveolar collapse- a condition often noticed in high altitude pulmonary edema (HAPE). The present study was aimed to determine the effect of curcumin prophylaxis in augmenting the phase II antioxidant enzymes and surfactant proteins expression in enabling the pulmonary surfactant homeostasis under hypoxia.

Methods: A549 cells were exposed to 3% hypoxia for different time durations (1 h, 3 h, 6 h, 12 h and 24 h). The Cells were pretreated (1 h) with 10 μM curcumin and exposed to hypoxia. The in-vivo results were extrapolated into in-vivo system using male Sprague Dawley rats, exposed to a stimulated altitude of 7620 m for 6 h. The rats were supplemented with curcumin (50 mg/kgBW) 1 h prior to hypoxia exposure.

Results: Results showed that, the expression of surfactant proteins (SPs) A and B decreased from 3 h of hypoxic exposure, whereas expression of SP-C and SP-D proteins were increased within 1 h of hypoxic exposure over control cells. Hypoxic exposure resulted into significant increase in protein and lipid peroxidation (p < 0.001), reduced levels of antioxidants (GSH, GPx and SOD) (p < 0.001) along with significant down regulation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and Heme oxygenase-1 (HO-1) in A549 cells over control. However, the curcumin supplementation both in-vitro and in-vivo resulted into increased expressions of HO-1 and Nrf2 significantly (p < 0.001), which enabled the cells in balanced expression of SPs with reduced levels of oxidants. Further curcumin significantly enhanced the levels of antioxidant enzymes in BALF along with stabilized expression of hypoxia inducible factor 1(HIF-1α) followed by reduced expression of vascular endothelial growth factor (VEGF) in lungs of rats. The immunohistochemistry observations provided substantial evidence of enhanced surfactant protein expressions in lungs of curcumin administered hypoxia exposed rats.

Conclusion: These results indicate that curcumin augment survival signaling by reinforcing the induction of phase II antioxidant enzymes thereby enabling the pulmonary surfactant homeostasis under hypoxia.

Keywords: Alveolar epithelium; Curcumin; Hypoxia; Nrf2; Phase II antioxidant enzymes; Surfactant proteins.