P-Glycoprotein Mitigates Paraquat-Induced Apoptosis in A549 Cells via the P38 MAPK-Regulated Mitochondrial Apoptotic Pathway

The main pathological change in paraquat (PQ)-induced poisoning is acute lung injury, which can result in respiratory failure and possibly death, and there is currently no effective treatment. P-glycoprotein (P-gp) plays a crucial role in the distribution and regulation of diverse chemical agents and toxins, as well as in the resistance of cancer cells to multiple drugs. This study assessed the involvement of P-gp in the development of acute lung injury caused by PQ and investigated the underlying molecular mechanisms. An ABCB1 overexpression lentiviral plasmid was constructed, and a stable P-gp-overexpressing cell line was obtained by infecting A549 cells with lentiviral particles produced by 293 T cells. A549 cells overexpressing P-gp were treated with or without PQ for 24 h. Apoptotic mechanisms involving mitochondrial membrane potential, caspase activity, and the P38 MAPK signaling pathway were also analyzed. The results showed that P-gp could alleviate proliferation toxicity and cell apoptosis induced by PQ, improve mitochondrial membrane potential, reduce caspase-3 activity, and mitigate oxidative stress imbalance and lipid peroxidation. PQ exposure increased P38 MAPK activity in A549 cells, which was attenuated by P-gp and the antioxidant NAC, leading to decreased ROS generation and suppressing P38 MAPK activity. Suppression of P38 MAPK activity using SB203580 mitigated cell damage and apoptosis, but had no inhibitory effect on oxidative stress. These findings suggest that P38 MAPK signaling participates in the development of PQ-caused acute lung injury. Additionally, the results suggest that P-gp alleviates PQ-induced acute lung injury by impairing the mitochondrial apoptotic pathway that is regulated by ROS/P38 MAPK.