Kaempferol Mitigates Pseudomonas aeruginosa-Induced Acute Lung Inflammation Through Suppressing GSK3β/JNK/c-Jun Signaling Pathway and NF-κB Activation

Background: Pseudomonas aeruginosa, one of the common bacterial pathogens causing nosocomial pneumonia, is characterized as highly pathogenic and multidrug-resistant. Kaempferol (KP), a natural flavonoid, has been shown to exhibit effectiveness in treating infection-induced lung injury. Methods: We applied network pharmacology to explore the underlying mechanisms of KP in treating P. aeruginosa pneumonia and further validated them through a mouse model of acute bacterial lung infection and an in vitro macrophage infection model. Results: The in vivo studies demonstrated that treatment with KP suppressed the production of proinflammatory cytokines, including TNF, IL-1β, IL-6, and MIP-2, and attenuated the neutrophil infiltration and lesions in lungs, leading to an increased survival rate of mice. Further studies revealed that KP treatment enhanced the phosphorylation of GSK3β at Ser9 and diminished the phosphorylation of JNK, c-Jun, and NF-κB p65 in lungs in comparison to the mice without drug treatment. Consistently, the in vitro studies showed that pretreatment with KP reduced the activation of GSK3β, JNK, c-Jun, and NF-κB p65 and decreased the levels of the proinflammatory cytokines in macrophages during P. aeruginosa infection. Conclusions: KP reduced the production of proinflammatory cytokines by inhibiting GSK3β/JNK/c-Jun signaling pathways and NF-κB activation, which effectively mitigated the P. aeruginosa-induced acute lung inflammation and injury, and elevated the survival rates of mice.