Protection of Andrographolide against Paraquat-Induced Acute Lung Injury via the AMPK/Nrf2 and PI3K/Akt Pathways

Paraquat (PQ)-induced acute lung injury (ALI) remains a public concern due to its high mortality. Andrographolide (Andro) has anti-oxidative and anti-apoptosis properties. However, the role of Andro in ALI is still unknown. Herein, the purpose was to explore the function of Andro and potential mechanisms in ALI caused by PQ. An animal model of ALI was established with an intraperitoneal injection of PQ at 20mg/kg. Andro was administered intragastrically for three consecutive days. A specific AMPK inhibitor named Compd C, Nrf2 gene knockout, and a specific PI3K inhibitor named LY294002 were used to clarify the possible mechanism. Results revealed that Andro alleviated PQ-induced histopathological changes, including congestion, hemorrhage, destroyed alveoli, and extracellular matrix deposition, and inhibited apoptosis. Andro up-regulated the p-AMPK/AMPK ratio and Nrf2 and HO-1 levels while decreasing p-PI3K and p-Akt levels. In vitro, Andro appeared to reverse the PQ-induced reductions in SOD and CAT. However, Andro weakened the capacity to promote Nrf2 with Compd C and the capacity to reduce MDA and ROS while increasing SOD and CAT after the Nrf2 gene was knocked out. Additionally, Andro mitigated apoptosis by elevating the Bcl-2/Bax ratio. Results also showed that Andro promoted the Bcl-2/Bax ratio to reduce apoptosis with LY294002. In conclusion, Andro reduces the PQ-induced ALI through the AMPK/Nrf2 and PI3K/Akt pathways. The possible mechanism involves an antioxidant capacity to activate the AMPK/Nrf2 pathway and cause anti-apoptosis suppression of the PI3K/Akt pathway.