Acetovanillone prevents cyclophosphamide-induced acute lung injury by modulating PI3K/Akt/mTOR and Nrf2 signaling in rats

Cyclophosphamide (CP) is a medication used as an anticancer drug and to suppress the immune system. However, its clinical applications are restricted because of the toxic and adverse side effects. The present study investigated the protective effect of acetovanillone (AV), a natural NADPH oxidase inhibitor, against acute lung injury (ALI) induced by CP. Rats were administered AV (100 mg/kg) for 10 days and a single injection of CP (200 mg/kg) at day 7. At the end of the experiment, the animals were sacrificed, and lung samples were collected for analyses. CP caused ALI manifested by the histopathological alterations. Lipid peroxidation and NADPH oxidase activity were increased, whereas GSH and antioxidant enzymes were decreased in the lung of CP-intoxicated rats. Oral administration of AV prevented CP-induced lung injury and oxidative stress and enhanced antioxidant defenses. AV downregulated Keap1 and upregulated Nrf2, GCLC, HO-1, and SOD3 mRNA. In addition, AV boosted the expression of PI3K, Akt, mTOR, and cytoglobin. In vitro, AV showed a synergistic anticancer effect when combined with CP. In conclusion, AV protected against CP-induced ALI by attenuating oxidative stress and boosting Nrf2/HO-1 and PI3K/Akt/mTOR signaling. Therefore, AV might represent a promising adjuvant to prevent lung injury in patients receiving CP.