Abstract
Dioscin showed various pharmacological effects in our previous studies; however, the effects and mechanisms against lung ischemia/reperfusion injury (LI/RI) have not been reported. Hypoxia/reoxygenation (H/R) models were established using A549 and primary AEC-II cells, while LI/RI models were established in rats and mice. The effects of dioscin on oxidative stress, inflammation and apoptosis in vivo and in vitro were investigated. The mechanisms were investigated focus on dioscin regulating FXR/LKB1 signaling pathway. Dioscin improved cell viability and mitochondrial membrane potential, reduced reactive oxygen species level, and inhibited H/R-mediated cell apoptosis. It also significantly decreased the lung wet/dry weight ratio, ameliorated levels of oxidative stress indicators, and enhanced the mitochondrial membrane potential and inhibited cell apoptosis in vivo. The results of mechanism research showed that dioscin activated FXR/LKB1 signals by increasing the expression of p-LKB1 and p-AMPKα, promoting the nuclear translocation of Nrf2, up-regulating the levels of HO-1, NQO1 and GCLC, expressed against oxidative stress. Furthermore, dioscin reduced Cyt C released, decreased the expression levels of Caspase-9 and Caspase-3 during apoptosis. Dioscin suppressed inflammation by inhibiting NF-κB translocation, reducing the expression levels of NF-κB, HMGB1, COX-2, IL-1β, IL-6 and TNF-α. The transfection of FXR or LKB1 siRNA further confirmed that the protective effect of dioscin against LI/RI was attributable to the regulation of FXR/LKB1 signaling pathway. Our research showed that dioscin exhibited potent activity against LI/RI, by adjusting the levels of FXR/LKB1-mediated oxidative stress, apoptosis, and inflammation, and should be considered as a new candidate for treating LI/RI.
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